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Mutations on LRRK2 gene modify risks for both Crohn’s and Parkinson’s
Crohn’s and Parkinson’s diseases seem to share a common genetic risk pathway, mediated by mutations in a gene that modify disease risk in both directions.
A multidisciplinary collaboration of researchers have discovered that the Crohn’s risk variant N2081D in the leucine-rich repeat kinase 2 (LRRK2) gene lies close to variant G2019S, the major genetic risk factor for both sporadic and familial Parkinson’s. However, protective mutations also occur in the LRRK2 gene, and Ken Y. Hui, MD, of Yale University, New Haven, Conn., and his associates identified two that, when combined, significantly decrease the risk of Crohn’s.
The team first discovered the association in an exome sequencing study of 50 Crohn’s patients of Ashkenazi Jewish descent. This identified more than 4,000 potentially high-yield mutations, which they then examined in a pure Ashkenazi cohort of 1,477 Crohn’s patients and 2,614 healthy controls.
In this phase, the researchers found that N2081D in LRRK2 was associated with a 73% increased odds of Crohn’s. The LRRK2 N551K variant was associated with protection against Crohn’s, reducing odds for the disease by 35% (odds ratio, 0.65), as was R1398H, which conferred a 29% reduction in the likelihood of developing the disease (OR, 0.71). It has been known that these two mutations can combine to provide a protective genetic signature, and the team investigated this compound interaction as well.
After repeated analyses in large, unique case-control cohorts and tissue samples, they determined that the N2081D allele increased the odds of Crohn’s by 70% in the Ashkenazi subjects and by 60% in non-Ashkenazi subjects. The allele was associated with a 10% increased likelihood of Parkinson’s among the Ashkenazi cohort and a 30% increased likelihood among the non-Ashkenazi cohort.
The researchers also examined the two protective alleles, N551K and R1398H, in these further analyses. In the Ashkenazi cohort, N551K decreased the likelihood of Crohn’s by 33%, and it decreased the likelihood of Parkinson’s by 23% in non-Ashkenazi subjects (OR, 0.67 and 0.77, respectively).
In the Ashkenazi cohort, R1398H reduced the odds of Crohn’s by 29% and the odds of Parkinson’s by 16% (OR, 0.71 and 0.84, respectively). In the non-Ashkenazi cohort, the risk reduction was not significant.
Finally, they examined the effect of the mutations on macrophages isolated from four Crohn’s patients who carried the N2081D allele, as well as five patients with the two protective mutations N551K and R1398H and four patients with no mutation. When the macrophages were put in nutrient starvation, those from the N2081D carriers exhibited impaired resting acetylation of alpha-tubulin and poor response to cellular stress. Decreased alpha-tubulin acetylation is associated with poor protein transport through the cytoskeleton. “In contrast, the highest basal acetylation of alpha-tubulin was detected in macrophages of noncarriers and carriers of the protective N551K + R1398H mutations,” the investigators wrote.
“Our study strongly implicates the contribution of LRRK2 in Crohn’s disease risk,” they concluded. “The LRRK2 N2081D risk allele and the N551K/R1398H protective alleles, as well as numerous other variants within the LRRK2 locus, revealed shared genetic effects between Crohn’s and Parkinson’s risk, providing a potential biological basis for clinical co-occurrence. Our findings suggest that LRRK2 may be a useful target for developing drugs to treat Crohn’s disease.”
The research was supported by a variety of grants from the National Institutes of Health, the National Science Foundation, and various other foundations. Five of the authors reported consulting for various pharmaceutical companies or companies selling genetic information products. None of the other authors had relevant disclosures.
SOURCE: Hui K et al. Sci Transl Med. 2018. doi: 10.1126/scitranslmed.aai7795
Crohn’s and Parkinson’s diseases seem to share a common genetic risk pathway, mediated by mutations in a gene that modify disease risk in both directions.
A multidisciplinary collaboration of researchers have discovered that the Crohn’s risk variant N2081D in the leucine-rich repeat kinase 2 (LRRK2) gene lies close to variant G2019S, the major genetic risk factor for both sporadic and familial Parkinson’s. However, protective mutations also occur in the LRRK2 gene, and Ken Y. Hui, MD, of Yale University, New Haven, Conn., and his associates identified two that, when combined, significantly decrease the risk of Crohn’s.
The team first discovered the association in an exome sequencing study of 50 Crohn’s patients of Ashkenazi Jewish descent. This identified more than 4,000 potentially high-yield mutations, which they then examined in a pure Ashkenazi cohort of 1,477 Crohn’s patients and 2,614 healthy controls.
In this phase, the researchers found that N2081D in LRRK2 was associated with a 73% increased odds of Crohn’s. The LRRK2 N551K variant was associated with protection against Crohn’s, reducing odds for the disease by 35% (odds ratio, 0.65), as was R1398H, which conferred a 29% reduction in the likelihood of developing the disease (OR, 0.71). It has been known that these two mutations can combine to provide a protective genetic signature, and the team investigated this compound interaction as well.
After repeated analyses in large, unique case-control cohorts and tissue samples, they determined that the N2081D allele increased the odds of Crohn’s by 70% in the Ashkenazi subjects and by 60% in non-Ashkenazi subjects. The allele was associated with a 10% increased likelihood of Parkinson’s among the Ashkenazi cohort and a 30% increased likelihood among the non-Ashkenazi cohort.
The researchers also examined the two protective alleles, N551K and R1398H, in these further analyses. In the Ashkenazi cohort, N551K decreased the likelihood of Crohn’s by 33%, and it decreased the likelihood of Parkinson’s by 23% in non-Ashkenazi subjects (OR, 0.67 and 0.77, respectively).
In the Ashkenazi cohort, R1398H reduced the odds of Crohn’s by 29% and the odds of Parkinson’s by 16% (OR, 0.71 and 0.84, respectively). In the non-Ashkenazi cohort, the risk reduction was not significant.
Finally, they examined the effect of the mutations on macrophages isolated from four Crohn’s patients who carried the N2081D allele, as well as five patients with the two protective mutations N551K and R1398H and four patients with no mutation. When the macrophages were put in nutrient starvation, those from the N2081D carriers exhibited impaired resting acetylation of alpha-tubulin and poor response to cellular stress. Decreased alpha-tubulin acetylation is associated with poor protein transport through the cytoskeleton. “In contrast, the highest basal acetylation of alpha-tubulin was detected in macrophages of noncarriers and carriers of the protective N551K + R1398H mutations,” the investigators wrote.
“Our study strongly implicates the contribution of LRRK2 in Crohn’s disease risk,” they concluded. “The LRRK2 N2081D risk allele and the N551K/R1398H protective alleles, as well as numerous other variants within the LRRK2 locus, revealed shared genetic effects between Crohn’s and Parkinson’s risk, providing a potential biological basis for clinical co-occurrence. Our findings suggest that LRRK2 may be a useful target for developing drugs to treat Crohn’s disease.”
The research was supported by a variety of grants from the National Institutes of Health, the National Science Foundation, and various other foundations. Five of the authors reported consulting for various pharmaceutical companies or companies selling genetic information products. None of the other authors had relevant disclosures.
SOURCE: Hui K et al. Sci Transl Med. 2018. doi: 10.1126/scitranslmed.aai7795
Crohn’s and Parkinson’s diseases seem to share a common genetic risk pathway, mediated by mutations in a gene that modify disease risk in both directions.
A multidisciplinary collaboration of researchers have discovered that the Crohn’s risk variant N2081D in the leucine-rich repeat kinase 2 (LRRK2) gene lies close to variant G2019S, the major genetic risk factor for both sporadic and familial Parkinson’s. However, protective mutations also occur in the LRRK2 gene, and Ken Y. Hui, MD, of Yale University, New Haven, Conn., and his associates identified two that, when combined, significantly decrease the risk of Crohn’s.
The team first discovered the association in an exome sequencing study of 50 Crohn’s patients of Ashkenazi Jewish descent. This identified more than 4,000 potentially high-yield mutations, which they then examined in a pure Ashkenazi cohort of 1,477 Crohn’s patients and 2,614 healthy controls.
In this phase, the researchers found that N2081D in LRRK2 was associated with a 73% increased odds of Crohn’s. The LRRK2 N551K variant was associated with protection against Crohn’s, reducing odds for the disease by 35% (odds ratio, 0.65), as was R1398H, which conferred a 29% reduction in the likelihood of developing the disease (OR, 0.71). It has been known that these two mutations can combine to provide a protective genetic signature, and the team investigated this compound interaction as well.
After repeated analyses in large, unique case-control cohorts and tissue samples, they determined that the N2081D allele increased the odds of Crohn’s by 70% in the Ashkenazi subjects and by 60% in non-Ashkenazi subjects. The allele was associated with a 10% increased likelihood of Parkinson’s among the Ashkenazi cohort and a 30% increased likelihood among the non-Ashkenazi cohort.
The researchers also examined the two protective alleles, N551K and R1398H, in these further analyses. In the Ashkenazi cohort, N551K decreased the likelihood of Crohn’s by 33%, and it decreased the likelihood of Parkinson’s by 23% in non-Ashkenazi subjects (OR, 0.67 and 0.77, respectively).
In the Ashkenazi cohort, R1398H reduced the odds of Crohn’s by 29% and the odds of Parkinson’s by 16% (OR, 0.71 and 0.84, respectively). In the non-Ashkenazi cohort, the risk reduction was not significant.
Finally, they examined the effect of the mutations on macrophages isolated from four Crohn’s patients who carried the N2081D allele, as well as five patients with the two protective mutations N551K and R1398H and four patients with no mutation. When the macrophages were put in nutrient starvation, those from the N2081D carriers exhibited impaired resting acetylation of alpha-tubulin and poor response to cellular stress. Decreased alpha-tubulin acetylation is associated with poor protein transport through the cytoskeleton. “In contrast, the highest basal acetylation of alpha-tubulin was detected in macrophages of noncarriers and carriers of the protective N551K + R1398H mutations,” the investigators wrote.
“Our study strongly implicates the contribution of LRRK2 in Crohn’s disease risk,” they concluded. “The LRRK2 N2081D risk allele and the N551K/R1398H protective alleles, as well as numerous other variants within the LRRK2 locus, revealed shared genetic effects between Crohn’s and Parkinson’s risk, providing a potential biological basis for clinical co-occurrence. Our findings suggest that LRRK2 may be a useful target for developing drugs to treat Crohn’s disease.”
The research was supported by a variety of grants from the National Institutes of Health, the National Science Foundation, and various other foundations. Five of the authors reported consulting for various pharmaceutical companies or companies selling genetic information products. None of the other authors had relevant disclosures.
SOURCE: Hui K et al. Sci Transl Med. 2018. doi: 10.1126/scitranslmed.aai7795
FROM SCIENCE TRANSLATIONAL MEDICINE
Key clinical point:
Major finding: Variant N2081D in LRRK2 was associated with a 73% increased risk of Crohn’s.
Study details: The study comprised data from 30,269 patients and controls.
Disclosures: The research was supported by a variety of grants from the National Institutes of Health, the National Science Foundation, and various other foundations. Five of the authors reported consulting for various pharmaceutical companies or companies selling genetic information products. None of the other authors had relevant disclosures.
Source: Hui K et al. Sci Transl Med. 2018. doi: 10.1126/scitranslmed.aai7795
CMV colitis mortality rates similar in both immunocompetent and immunocompromised patients
Cytomegalovirus (CMV) colitis has mortality rates similar in immunocompetent patients to that in immunocompromised patients, according to Puo-Hsien Le, MD, and associates.
In a retrospective study, the investigators analyzed data from 42 immunocompetent patients and 27 patients who were immunocompromised because of HIV infection, solid organ or bone marrow transplantation, immunosuppressive drug use, chemotherapeutic agent use within 6 months, or other reasons. In-hospital mortality was 26.2% in immunocompetent patients and 25.9% in immunocompromised patients.
While diarrhea and melena were the first presenting symptom in a similar number of patients, immunocompetent patients were more likely to present with melena while immunocompromised patients were more likely to present with diarrhea. The number of days until diagnosis was the only independent predictor of in-hospital mortality according to the analysis, with patients who were diagnosed within 9 days of admittance having a significantly higher survival rate.
“Contrary to data published up to this point, we found that CMV colitis was not rare and that it could be fatal in immunocompetent hosts, especially those patients with advanced age, specific comorbidities associated with immune dysfunction, critical illness, or IBD. ... Being alert to the different presentations can greatly help make an accurate early diagnosis and materially improve survival for CMV colitis patients,” the investigators concluded.
Find the full study in Therapeutics and Clinical Risk Management (doi: 10.2147/TCRM.S151180).
Cytomegalovirus (CMV) colitis has mortality rates similar in immunocompetent patients to that in immunocompromised patients, according to Puo-Hsien Le, MD, and associates.
In a retrospective study, the investigators analyzed data from 42 immunocompetent patients and 27 patients who were immunocompromised because of HIV infection, solid organ or bone marrow transplantation, immunosuppressive drug use, chemotherapeutic agent use within 6 months, or other reasons. In-hospital mortality was 26.2% in immunocompetent patients and 25.9% in immunocompromised patients.
While diarrhea and melena were the first presenting symptom in a similar number of patients, immunocompetent patients were more likely to present with melena while immunocompromised patients were more likely to present with diarrhea. The number of days until diagnosis was the only independent predictor of in-hospital mortality according to the analysis, with patients who were diagnosed within 9 days of admittance having a significantly higher survival rate.
“Contrary to data published up to this point, we found that CMV colitis was not rare and that it could be fatal in immunocompetent hosts, especially those patients with advanced age, specific comorbidities associated with immune dysfunction, critical illness, or IBD. ... Being alert to the different presentations can greatly help make an accurate early diagnosis and materially improve survival for CMV colitis patients,” the investigators concluded.
Find the full study in Therapeutics and Clinical Risk Management (doi: 10.2147/TCRM.S151180).
Cytomegalovirus (CMV) colitis has mortality rates similar in immunocompetent patients to that in immunocompromised patients, according to Puo-Hsien Le, MD, and associates.
In a retrospective study, the investigators analyzed data from 42 immunocompetent patients and 27 patients who were immunocompromised because of HIV infection, solid organ or bone marrow transplantation, immunosuppressive drug use, chemotherapeutic agent use within 6 months, or other reasons. In-hospital mortality was 26.2% in immunocompetent patients and 25.9% in immunocompromised patients.
While diarrhea and melena were the first presenting symptom in a similar number of patients, immunocompetent patients were more likely to present with melena while immunocompromised patients were more likely to present with diarrhea. The number of days until diagnosis was the only independent predictor of in-hospital mortality according to the analysis, with patients who were diagnosed within 9 days of admittance having a significantly higher survival rate.
“Contrary to data published up to this point, we found that CMV colitis was not rare and that it could be fatal in immunocompetent hosts, especially those patients with advanced age, specific comorbidities associated with immune dysfunction, critical illness, or IBD. ... Being alert to the different presentations can greatly help make an accurate early diagnosis and materially improve survival for CMV colitis patients,” the investigators concluded.
Find the full study in Therapeutics and Clinical Risk Management (doi: 10.2147/TCRM.S151180).
FROM THERAPEUTICS AND CLINICAL RISK MANAGEMENT
FDA approves infliximab biosimilar Ixifi for all of Remicade’s indications
The Food and Drug Administration has approved Ixifi (infliximab-qbtx), a biosimilar of Remicade, the original infliximab product. Ixifi is the third infliximab biosimilar to be approved by the FDA, and it is approved for all the same indications as Remicade, according to an announcement from its manufacturer, Pfizer.
Ixifi and Remicade are approved for the treatment of rheumatoid arthritis in combination with methotrexate, Crohn’s disease, pediatric Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.
The most common adverse events associated with Ixifi are upper respiratory infections, sinusitis, pharyngitis, infusion-related reactions, headache, and abdominal pain.
The Food and Drug Administration has approved Ixifi (infliximab-qbtx), a biosimilar of Remicade, the original infliximab product. Ixifi is the third infliximab biosimilar to be approved by the FDA, and it is approved for all the same indications as Remicade, according to an announcement from its manufacturer, Pfizer.
Ixifi and Remicade are approved for the treatment of rheumatoid arthritis in combination with methotrexate, Crohn’s disease, pediatric Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.
The most common adverse events associated with Ixifi are upper respiratory infections, sinusitis, pharyngitis, infusion-related reactions, headache, and abdominal pain.
The Food and Drug Administration has approved Ixifi (infliximab-qbtx), a biosimilar of Remicade, the original infliximab product. Ixifi is the third infliximab biosimilar to be approved by the FDA, and it is approved for all the same indications as Remicade, according to an announcement from its manufacturer, Pfizer.
Ixifi and Remicade are approved for the treatment of rheumatoid arthritis in combination with methotrexate, Crohn’s disease, pediatric Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.
The most common adverse events associated with Ixifi are upper respiratory infections, sinusitis, pharyngitis, infusion-related reactions, headache, and abdominal pain.
Elevated antiphospholipid antibodies in celiac disease unrelated to gluten
Levels of antiphospholipid antibodies were significantly higher in adults with celiac disease compared with healthy controls, and gluten was not a factor, according to a study published in Digestive and Liver Disease (Dig Liver Dis. 2017. doi: 10.1016/j.dld.2017.11.018).
“In inflammatory bowel diseases active prophylaxis and treatment of thromboembolic complications is considered appropriate despite the increased risk of gastrointestinal bleeding,” wrote Outi Laine, MD, of Tampere University, Finland, and colleagues.
Results from previous studies suggest that thrombophilic autoantibodies are increased in celiac disease patients, but data are limited, the researchers wrote. In this study, the researchers measured antiphospholipid antibodies (cardiolipin IgG and M, prothrombin IgG, and aPS/PT IgG) in 179 adults with celiac disease (89 untreated, 90 on long-term gluten-free diets) and 91 nonceliac controls. Demographic characteristics were similar among the groups; the average age of the patients was 48 years in the untreated celiac disease group, 58 years in the treated group, and 45 years in the control group. In addition, the presentation of disease (gastrointestinal symptoms, malabsorption or anemia, and extraintestinal symptoms or screen-detected celiac disease) was similar among the groups.
Overall, the levels of antiphospholipid antibodies were significantly higher among celiac disease patients compared with controls 4.9 U/mL vs. 2.2 U/mL respectively, for anticardiolipin; 2.9 U/mL vs. 2.1 U/mL for antiprothrombin IgG, and 6.9 U/mL vs. 2.3 U/mL for antiphosphatidylserine-prothrombin. All three were higher among the untreated celiac disease patients compared with the treated patients.
“Treated patients with the highest levels of cardiolipin IgG and prothrombin IgG antibodies and aPS/PT were older than the newly diagnosed, untreated patients. This observation suggests that the formation of antibodies is not triggered by gluten but is related to the autoimmune-based celiac disease itself,” the researchers wrote.
The study was not designed to assess the impact of antiphospholipid antibodies on thrombosis, the researchers noted. However, “To guide therapeutic decisions, the optimal predictive biomarkers for thromboembolic episodes in patients with celiac disease should be determined,” and future areas of research should include identifying patients at high risk for thromboembolic episodes, they said.
The researchers had no financial conflicts to disclose. The study was funded in part by organizations including the Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital, the Academy of Finland, and the Finnish Association of Hematology.
Levels of antiphospholipid antibodies were significantly higher in adults with celiac disease compared with healthy controls, and gluten was not a factor, according to a study published in Digestive and Liver Disease (Dig Liver Dis. 2017. doi: 10.1016/j.dld.2017.11.018).
“In inflammatory bowel diseases active prophylaxis and treatment of thromboembolic complications is considered appropriate despite the increased risk of gastrointestinal bleeding,” wrote Outi Laine, MD, of Tampere University, Finland, and colleagues.
Results from previous studies suggest that thrombophilic autoantibodies are increased in celiac disease patients, but data are limited, the researchers wrote. In this study, the researchers measured antiphospholipid antibodies (cardiolipin IgG and M, prothrombin IgG, and aPS/PT IgG) in 179 adults with celiac disease (89 untreated, 90 on long-term gluten-free diets) and 91 nonceliac controls. Demographic characteristics were similar among the groups; the average age of the patients was 48 years in the untreated celiac disease group, 58 years in the treated group, and 45 years in the control group. In addition, the presentation of disease (gastrointestinal symptoms, malabsorption or anemia, and extraintestinal symptoms or screen-detected celiac disease) was similar among the groups.
Overall, the levels of antiphospholipid antibodies were significantly higher among celiac disease patients compared with controls 4.9 U/mL vs. 2.2 U/mL respectively, for anticardiolipin; 2.9 U/mL vs. 2.1 U/mL for antiprothrombin IgG, and 6.9 U/mL vs. 2.3 U/mL for antiphosphatidylserine-prothrombin. All three were higher among the untreated celiac disease patients compared with the treated patients.
“Treated patients with the highest levels of cardiolipin IgG and prothrombin IgG antibodies and aPS/PT were older than the newly diagnosed, untreated patients. This observation suggests that the formation of antibodies is not triggered by gluten but is related to the autoimmune-based celiac disease itself,” the researchers wrote.
The study was not designed to assess the impact of antiphospholipid antibodies on thrombosis, the researchers noted. However, “To guide therapeutic decisions, the optimal predictive biomarkers for thromboembolic episodes in patients with celiac disease should be determined,” and future areas of research should include identifying patients at high risk for thromboembolic episodes, they said.
The researchers had no financial conflicts to disclose. The study was funded in part by organizations including the Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital, the Academy of Finland, and the Finnish Association of Hematology.
Levels of antiphospholipid antibodies were significantly higher in adults with celiac disease compared with healthy controls, and gluten was not a factor, according to a study published in Digestive and Liver Disease (Dig Liver Dis. 2017. doi: 10.1016/j.dld.2017.11.018).
“In inflammatory bowel diseases active prophylaxis and treatment of thromboembolic complications is considered appropriate despite the increased risk of gastrointestinal bleeding,” wrote Outi Laine, MD, of Tampere University, Finland, and colleagues.
Results from previous studies suggest that thrombophilic autoantibodies are increased in celiac disease patients, but data are limited, the researchers wrote. In this study, the researchers measured antiphospholipid antibodies (cardiolipin IgG and M, prothrombin IgG, and aPS/PT IgG) in 179 adults with celiac disease (89 untreated, 90 on long-term gluten-free diets) and 91 nonceliac controls. Demographic characteristics were similar among the groups; the average age of the patients was 48 years in the untreated celiac disease group, 58 years in the treated group, and 45 years in the control group. In addition, the presentation of disease (gastrointestinal symptoms, malabsorption or anemia, and extraintestinal symptoms or screen-detected celiac disease) was similar among the groups.
Overall, the levels of antiphospholipid antibodies were significantly higher among celiac disease patients compared with controls 4.9 U/mL vs. 2.2 U/mL respectively, for anticardiolipin; 2.9 U/mL vs. 2.1 U/mL for antiprothrombin IgG, and 6.9 U/mL vs. 2.3 U/mL for antiphosphatidylserine-prothrombin. All three were higher among the untreated celiac disease patients compared with the treated patients.
“Treated patients with the highest levels of cardiolipin IgG and prothrombin IgG antibodies and aPS/PT were older than the newly diagnosed, untreated patients. This observation suggests that the formation of antibodies is not triggered by gluten but is related to the autoimmune-based celiac disease itself,” the researchers wrote.
The study was not designed to assess the impact of antiphospholipid antibodies on thrombosis, the researchers noted. However, “To guide therapeutic decisions, the optimal predictive biomarkers for thromboembolic episodes in patients with celiac disease should be determined,” and future areas of research should include identifying patients at high risk for thromboembolic episodes, they said.
The researchers had no financial conflicts to disclose. The study was funded in part by organizations including the Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital, the Academy of Finland, and the Finnish Association of Hematology.
FROM DIGESTIVE AND LIVER DISEASE
Key clinical point: Antiphospholipid antibodies are elevated in celiac patients, and highest in those on a gluten-free diet.
Major finding: Levels among celiac patients vs. controls were 4.9 U/mL vs. 2.2 U/mL respectively, for anticardiolipin; 2.9 U/mL vs. 2.1 U/mL for antiprothrombin IgG, and 6.9 U/mL vs. 2.3 U/mL for antiphosphatidylserine-prothrombin.
Data source: Study of 179 adults with confirmed celiac disease and 91 controls.
Disclosures: The researchers had no financial conflicts to disclose. The study was funded in part by organizations including the Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital, the Academy of Finland, and the Finnish Association of Hematology.
Fecal microbiota transplants by oral capsule noninferior to colonoscopy
Fecal microbiota transplantation (FMT) using oral capsules as the delivery method has been shown to be noninferior to delivery using colonoscopy for the treatment of Clostridium difficile infection, but with a significantly lower price tag.
In an unblended noninferiority trial, published in the Nov. 28 issue of JAMA, 116 adults with at least three documented episodes of C. difficile infection were randomized to either 360 mL of fecal slurry delivered to the cecum via colonoscopy or to 40 capsules of processed fecal microbiota swallowed under direct observation.
Dina Kao, MD, of the department of medicine at the University of Alberta, Edmonton, and coauthors commented that the response rate with the capsules was higher than that seen in other studies of fecal microbiota capsules, which they suggested may partly be due to the larger amount of donor stool used in the study: 80-100 g, compared with 17 g and 25 g used in other studies.
“The higher efficacy observed in this study suggests a dose-dependent response to FMT, and a benefit of bowel lavage prior to FMT, because residual vancomycin was detected up to 8 days despite its discontinuation,” they wrote.
Both treatment modalities achieved similar quality of life improvements. Both groups reported major improvements in domains including physical and emotional health, physical and social functioning, and general health, with no significant differences between the two arms of the study.
The cost per treatment in the colonoscopy group was $874 per patient, compared with $308 per patient in the capsule group.
“Although colonoscopy delivery is more invasive, resource intensive, costly, and inconvenient for patients, it has the advantage of identifying alternative diagnoses,” the authors wrote. “Conversely, when FMT is given by oral capsules, it can be administered in an office setting, which could substantially reduce cost and wait time.”
Both groups also showed significantly improved gut microbiota diversity, which approached that of the donor just 1 week after administration of the treatment.
While 30% of patients characterized FMTs as “unpleasant, gross, or disgusting,” 79% of participants said the unpleasantness was the same or less than anticipated, and 97% said they would undergo the same treatment by the same delivery method again if needed.
However, significantly more patients in the capsule group described their experience as “not at all unpleasant,” compared with the colonoscopy group (66% vs. 44%; 95% CI, 3%-40%; P = .01).
There were no colonic perforations seen in the colonoscopy group, and no infectious complications relating to the treatment in either group. One patient in each group died of underlying cardiopulmonary illness that was unrelated to the treatment, and the rate of minor adverse events was 5.4% in the capsule group and 12.5% in the colonoscopy group.
The authors acknowledged that the lack of a placebo group in the study meant they were not able to measure the size of the effect of fecal microbiota transplantation by either route. One earlier trial had also shown a placebo response rate of 45%.
The study was funded by Alberta Health Services and the University of Alberta Hospital Foundation. Four authors declared grants and other funding from the study funder and the pharmaceutical industry.
The AGA Center for Gut Microbiome Research and Education serves as a virtual “home” for AGA activities related to the gut microbiome, including the AGA FMT National Registry, which will assess short- and long-term patient outcomes associated with FMT. Learn more at http://www.gastro.org/about/initiatives/aga-center-for-gut-microbiome-research-education.
Clostridium difficile infection costs the U.S. health care system an estimated $1.5 billion each year, with 450,000 cases reported annually, 20% of which involve a recurrence of the infection. Fecal microbiota transplantation is increasingly being used as a treatment, but more widespread adoption is limited partly by the logistical difficulties of delivery.
This study offers encouraging data on delivery of fecal microbiota transplants via capsule, which may reduce barriers to adoption of this treatment; however, there are still some questions to be answered about the treatment’s efficacy, such as the timing of delivery and the relative importance of stool components.
There are also other approaches that should be considered in future research on C. difficile infection, including the use of vancomycin tapers with and without “chasers” of fidaxomicin/rifaximin, the use of defined microbial communities, and the use of sterile, fecal-derived products, which may even supplant standard fecal microbial transplants in the future.
Krishna Rao, MD, Vincent B. Young, MD, PhD, and Preeti N. Malani, MD, are with the division of infectious diseases in the department of internal medicine at the University of Michigan, Ann Arbor. These comments are taken from an accompanying editorial (JAMA. 2017 Nov 28;381:1979-80. doi: 10.1001/jama.2017.17969). Dr. Young reported consulting fees from Vedanta, Merck, and Finch Therapeutics and grants from MedImmune. No other disclosures were reported.
Clostridium difficile infection costs the U.S. health care system an estimated $1.5 billion each year, with 450,000 cases reported annually, 20% of which involve a recurrence of the infection. Fecal microbiota transplantation is increasingly being used as a treatment, but more widespread adoption is limited partly by the logistical difficulties of delivery.
This study offers encouraging data on delivery of fecal microbiota transplants via capsule, which may reduce barriers to adoption of this treatment; however, there are still some questions to be answered about the treatment’s efficacy, such as the timing of delivery and the relative importance of stool components.
There are also other approaches that should be considered in future research on C. difficile infection, including the use of vancomycin tapers with and without “chasers” of fidaxomicin/rifaximin, the use of defined microbial communities, and the use of sterile, fecal-derived products, which may even supplant standard fecal microbial transplants in the future.
Krishna Rao, MD, Vincent B. Young, MD, PhD, and Preeti N. Malani, MD, are with the division of infectious diseases in the department of internal medicine at the University of Michigan, Ann Arbor. These comments are taken from an accompanying editorial (JAMA. 2017 Nov 28;381:1979-80. doi: 10.1001/jama.2017.17969). Dr. Young reported consulting fees from Vedanta, Merck, and Finch Therapeutics and grants from MedImmune. No other disclosures were reported.
Clostridium difficile infection costs the U.S. health care system an estimated $1.5 billion each year, with 450,000 cases reported annually, 20% of which involve a recurrence of the infection. Fecal microbiota transplantation is increasingly being used as a treatment, but more widespread adoption is limited partly by the logistical difficulties of delivery.
This study offers encouraging data on delivery of fecal microbiota transplants via capsule, which may reduce barriers to adoption of this treatment; however, there are still some questions to be answered about the treatment’s efficacy, such as the timing of delivery and the relative importance of stool components.
There are also other approaches that should be considered in future research on C. difficile infection, including the use of vancomycin tapers with and without “chasers” of fidaxomicin/rifaximin, the use of defined microbial communities, and the use of sterile, fecal-derived products, which may even supplant standard fecal microbial transplants in the future.
Krishna Rao, MD, Vincent B. Young, MD, PhD, and Preeti N. Malani, MD, are with the division of infectious diseases in the department of internal medicine at the University of Michigan, Ann Arbor. These comments are taken from an accompanying editorial (JAMA. 2017 Nov 28;381:1979-80. doi: 10.1001/jama.2017.17969). Dr. Young reported consulting fees from Vedanta, Merck, and Finch Therapeutics and grants from MedImmune. No other disclosures were reported.
Fecal microbiota transplantation (FMT) using oral capsules as the delivery method has been shown to be noninferior to delivery using colonoscopy for the treatment of Clostridium difficile infection, but with a significantly lower price tag.
In an unblended noninferiority trial, published in the Nov. 28 issue of JAMA, 116 adults with at least three documented episodes of C. difficile infection were randomized to either 360 mL of fecal slurry delivered to the cecum via colonoscopy or to 40 capsules of processed fecal microbiota swallowed under direct observation.
Dina Kao, MD, of the department of medicine at the University of Alberta, Edmonton, and coauthors commented that the response rate with the capsules was higher than that seen in other studies of fecal microbiota capsules, which they suggested may partly be due to the larger amount of donor stool used in the study: 80-100 g, compared with 17 g and 25 g used in other studies.
“The higher efficacy observed in this study suggests a dose-dependent response to FMT, and a benefit of bowel lavage prior to FMT, because residual vancomycin was detected up to 8 days despite its discontinuation,” they wrote.
Both treatment modalities achieved similar quality of life improvements. Both groups reported major improvements in domains including physical and emotional health, physical and social functioning, and general health, with no significant differences between the two arms of the study.
The cost per treatment in the colonoscopy group was $874 per patient, compared with $308 per patient in the capsule group.
“Although colonoscopy delivery is more invasive, resource intensive, costly, and inconvenient for patients, it has the advantage of identifying alternative diagnoses,” the authors wrote. “Conversely, when FMT is given by oral capsules, it can be administered in an office setting, which could substantially reduce cost and wait time.”
Both groups also showed significantly improved gut microbiota diversity, which approached that of the donor just 1 week after administration of the treatment.
While 30% of patients characterized FMTs as “unpleasant, gross, or disgusting,” 79% of participants said the unpleasantness was the same or less than anticipated, and 97% said they would undergo the same treatment by the same delivery method again if needed.
However, significantly more patients in the capsule group described their experience as “not at all unpleasant,” compared with the colonoscopy group (66% vs. 44%; 95% CI, 3%-40%; P = .01).
There were no colonic perforations seen in the colonoscopy group, and no infectious complications relating to the treatment in either group. One patient in each group died of underlying cardiopulmonary illness that was unrelated to the treatment, and the rate of minor adverse events was 5.4% in the capsule group and 12.5% in the colonoscopy group.
The authors acknowledged that the lack of a placebo group in the study meant they were not able to measure the size of the effect of fecal microbiota transplantation by either route. One earlier trial had also shown a placebo response rate of 45%.
The study was funded by Alberta Health Services and the University of Alberta Hospital Foundation. Four authors declared grants and other funding from the study funder and the pharmaceutical industry.
The AGA Center for Gut Microbiome Research and Education serves as a virtual “home” for AGA activities related to the gut microbiome, including the AGA FMT National Registry, which will assess short- and long-term patient outcomes associated with FMT. Learn more at http://www.gastro.org/about/initiatives/aga-center-for-gut-microbiome-research-education.
Fecal microbiota transplantation (FMT) using oral capsules as the delivery method has been shown to be noninferior to delivery using colonoscopy for the treatment of Clostridium difficile infection, but with a significantly lower price tag.
In an unblended noninferiority trial, published in the Nov. 28 issue of JAMA, 116 adults with at least three documented episodes of C. difficile infection were randomized to either 360 mL of fecal slurry delivered to the cecum via colonoscopy or to 40 capsules of processed fecal microbiota swallowed under direct observation.
Dina Kao, MD, of the department of medicine at the University of Alberta, Edmonton, and coauthors commented that the response rate with the capsules was higher than that seen in other studies of fecal microbiota capsules, which they suggested may partly be due to the larger amount of donor stool used in the study: 80-100 g, compared with 17 g and 25 g used in other studies.
“The higher efficacy observed in this study suggests a dose-dependent response to FMT, and a benefit of bowel lavage prior to FMT, because residual vancomycin was detected up to 8 days despite its discontinuation,” they wrote.
Both treatment modalities achieved similar quality of life improvements. Both groups reported major improvements in domains including physical and emotional health, physical and social functioning, and general health, with no significant differences between the two arms of the study.
The cost per treatment in the colonoscopy group was $874 per patient, compared with $308 per patient in the capsule group.
“Although colonoscopy delivery is more invasive, resource intensive, costly, and inconvenient for patients, it has the advantage of identifying alternative diagnoses,” the authors wrote. “Conversely, when FMT is given by oral capsules, it can be administered in an office setting, which could substantially reduce cost and wait time.”
Both groups also showed significantly improved gut microbiota diversity, which approached that of the donor just 1 week after administration of the treatment.
While 30% of patients characterized FMTs as “unpleasant, gross, or disgusting,” 79% of participants said the unpleasantness was the same or less than anticipated, and 97% said they would undergo the same treatment by the same delivery method again if needed.
However, significantly more patients in the capsule group described their experience as “not at all unpleasant,” compared with the colonoscopy group (66% vs. 44%; 95% CI, 3%-40%; P = .01).
There were no colonic perforations seen in the colonoscopy group, and no infectious complications relating to the treatment in either group. One patient in each group died of underlying cardiopulmonary illness that was unrelated to the treatment, and the rate of minor adverse events was 5.4% in the capsule group and 12.5% in the colonoscopy group.
The authors acknowledged that the lack of a placebo group in the study meant they were not able to measure the size of the effect of fecal microbiota transplantation by either route. One earlier trial had also shown a placebo response rate of 45%.
The study was funded by Alberta Health Services and the University of Alberta Hospital Foundation. Four authors declared grants and other funding from the study funder and the pharmaceutical industry.
The AGA Center for Gut Microbiome Research and Education serves as a virtual “home” for AGA activities related to the gut microbiome, including the AGA FMT National Registry, which will assess short- and long-term patient outcomes associated with FMT. Learn more at http://www.gastro.org/about/initiatives/aga-center-for-gut-microbiome-research-education.
FROM JAMA
Key clinical point: Delivering fecal microbiota transplants using oral capsules is noninferior to delivery via colonoscopy in the treatment of Clostridium difficile infection.
Major finding: The rates of resolution of recurrent C. difficile infection with fecal microbiota transplants are similar for delivery via oral capsule or via colonoscopy.
Data source: A randomized, unblended noninferiority trial in 116 adults with recurrent C. difficile infection.
Disclosures: The study was funded by Alberta Health Services and the University of Alberta Hospital Foundation. Four authors declared grants and other funding from the study funder and the pharmaceutical industry.
AGA Clinical Practice Update: Treatment of fecal incontinence and defecatory disorders
About 25% of patients with fecal incontinence benefit from conservative treatments, which merit a “rigorous trial” before considering surgery, experts write in a Clinical Practice Update in the December issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.08.023).
“A stepwise approach should be followed for management of fecal incontinence. In our experience, many incontinent patients who are considered refractory to conservative therapy have not received an optimal trial of conservative therapy,” states Adil E. Bharucha, MBBS, MD, of the Mayo Clinic and the Mayo Foundation in Rochester, Minn., and his associates.
Fecal incontinence affects 7%-15% of individuals and has potentially “devastating” implications for quality of life, the experts note. They recommend starting treatment by meticulously documenting bowel habits, triggers of incontinence, and treatment history. For fecal incontinence with diarrhea, they suggest eliminating caffeine and poorly absorbed dietary sugars, such as sorbitol and fructose, and adding loperamide, starting with one 2-mg tablet taken 30 minutes before breakfast and titrating up to a maximum of 16 mg per day. Other conservative therapeutic options for diarrhea include fiber supplementation, scheduled toileting, a bowel retraining program, anticholinergic agents, clonidine, and cholestyramine or colesevelam to correct bile salt malabsorption. Patients whose fecal incontinence involves constipation should start with laxatives and anorectal testing for evacuation disorders. Rectal cleansing with a small enema or tap water can help prevent stool leakage, the experts write.
If these conservative measures fail to improve fecal incontinence, they recommend anorectal manometry to test for anal weakness, reduced or increased rectal sensation, and impaired rectal balloon expulsion, all of which can improve with biofeedback therapy to retrain the pelvic floor. If biofeedback fails, consider perianal bulking agents, such as intra-anal injection of dextranomer, the experts suggest. Sacral nerve stimulation might be indicated if moderate or severe fecal incontinence does not respond to at least 3 months of conservative treatment. However, the experts do not recommend percutaneous tibial nerve stimulation, which failed to outperform sham stimulation in a 12-week, double-blind, multicenter trial (Lancet. 2015;386:1640-8). Surgery is indicated for fecal incontinence associated with major anatomic defects, such as rectovaginal fistula, full-thickness rectal prolapse, fistula in ano, or cloaca-like deformity. Additionally, sphincteroplasty is an option for postpartum women with fecal incontinence, patients with recent sphincter injuries, and patients with sphincter damage and fecal incontinence fecal incontinence that fails to improve with conservative and biofeedback therapy, perianal bulking injection, and sacral nerve stimulation, according to the clinical practice update.
Barrier devices should be offered if fecal incontinence fails conservative treatments and surgery, or if surgery is not an option. Most anal plugs are “poorly tolerated,” with two exceptions – a Food and Drug Administration–approved device from Renew Medical and a vaginal insert and pressure-regulated pump from Pelvalon. Colostomy might be indicated if patients with severe fecal incontinence fail conservative treatment and or are not candidates for barrier devices, minimally invasive surgeries, and sphincteroplasty.
If severe fecal incontinence that is refractory to or contraindicated for all these interventions, the experts suggest considering artificial anal sphincter repair by dynamic graciloplasty. Surgery also is indicated to repair major anatomic defects such as rectovaginal fistula, full-thickness rectal prolapse, fistula in ano, or cloaca-like deformity, they noted. A magnetic anal sphincter device is a possibility for patients with medically refractory severe fecal incontinence who have failed or are not candidates for barrier devices, perianal bulking injection, sacral nerve stimulation, sphincteroplasty, or a colostomy. However, the study that led to FDA approval of a magnetic anal sphincter device included only 35 patients, and 7 (20%) had the device removed because of infection, erosion, or inefficacy. Another patient required a stoma in order to be able to defecate, and a total of 40% had moderate or severe complications when pain and bleeding were also considered, the experts noted.
Biofeedback is the preferred treatment for defecatory disorders – that is, chronic constipation or constipation-predominant irritable bowel syndrome with impaired rectal evacuation, according to the clinical practice update. The experts recommend against sacral nerve stimulation, anteretrograde colonic enemas, and stapled transanal rectal resection for patients with defecatory disorders. Surgical treatment typically is reserved for the small minority of patients with considerable pelvic organ or rectal prolapse, they note.
The National Institutes of Health Sciences provided funding. The authors reported having no conflicts of interest.
About 25% of patients with fecal incontinence benefit from conservative treatments, which merit a “rigorous trial” before considering surgery, experts write in a Clinical Practice Update in the December issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.08.023).
“A stepwise approach should be followed for management of fecal incontinence. In our experience, many incontinent patients who are considered refractory to conservative therapy have not received an optimal trial of conservative therapy,” states Adil E. Bharucha, MBBS, MD, of the Mayo Clinic and the Mayo Foundation in Rochester, Minn., and his associates.
Fecal incontinence affects 7%-15% of individuals and has potentially “devastating” implications for quality of life, the experts note. They recommend starting treatment by meticulously documenting bowel habits, triggers of incontinence, and treatment history. For fecal incontinence with diarrhea, they suggest eliminating caffeine and poorly absorbed dietary sugars, such as sorbitol and fructose, and adding loperamide, starting with one 2-mg tablet taken 30 minutes before breakfast and titrating up to a maximum of 16 mg per day. Other conservative therapeutic options for diarrhea include fiber supplementation, scheduled toileting, a bowel retraining program, anticholinergic agents, clonidine, and cholestyramine or colesevelam to correct bile salt malabsorption. Patients whose fecal incontinence involves constipation should start with laxatives and anorectal testing for evacuation disorders. Rectal cleansing with a small enema or tap water can help prevent stool leakage, the experts write.
If these conservative measures fail to improve fecal incontinence, they recommend anorectal manometry to test for anal weakness, reduced or increased rectal sensation, and impaired rectal balloon expulsion, all of which can improve with biofeedback therapy to retrain the pelvic floor. If biofeedback fails, consider perianal bulking agents, such as intra-anal injection of dextranomer, the experts suggest. Sacral nerve stimulation might be indicated if moderate or severe fecal incontinence does not respond to at least 3 months of conservative treatment. However, the experts do not recommend percutaneous tibial nerve stimulation, which failed to outperform sham stimulation in a 12-week, double-blind, multicenter trial (Lancet. 2015;386:1640-8). Surgery is indicated for fecal incontinence associated with major anatomic defects, such as rectovaginal fistula, full-thickness rectal prolapse, fistula in ano, or cloaca-like deformity. Additionally, sphincteroplasty is an option for postpartum women with fecal incontinence, patients with recent sphincter injuries, and patients with sphincter damage and fecal incontinence fecal incontinence that fails to improve with conservative and biofeedback therapy, perianal bulking injection, and sacral nerve stimulation, according to the clinical practice update.
Barrier devices should be offered if fecal incontinence fails conservative treatments and surgery, or if surgery is not an option. Most anal plugs are “poorly tolerated,” with two exceptions – a Food and Drug Administration–approved device from Renew Medical and a vaginal insert and pressure-regulated pump from Pelvalon. Colostomy might be indicated if patients with severe fecal incontinence fail conservative treatment and or are not candidates for barrier devices, minimally invasive surgeries, and sphincteroplasty.
If severe fecal incontinence that is refractory to or contraindicated for all these interventions, the experts suggest considering artificial anal sphincter repair by dynamic graciloplasty. Surgery also is indicated to repair major anatomic defects such as rectovaginal fistula, full-thickness rectal prolapse, fistula in ano, or cloaca-like deformity, they noted. A magnetic anal sphincter device is a possibility for patients with medically refractory severe fecal incontinence who have failed or are not candidates for barrier devices, perianal bulking injection, sacral nerve stimulation, sphincteroplasty, or a colostomy. However, the study that led to FDA approval of a magnetic anal sphincter device included only 35 patients, and 7 (20%) had the device removed because of infection, erosion, or inefficacy. Another patient required a stoma in order to be able to defecate, and a total of 40% had moderate or severe complications when pain and bleeding were also considered, the experts noted.
Biofeedback is the preferred treatment for defecatory disorders – that is, chronic constipation or constipation-predominant irritable bowel syndrome with impaired rectal evacuation, according to the clinical practice update. The experts recommend against sacral nerve stimulation, anteretrograde colonic enemas, and stapled transanal rectal resection for patients with defecatory disorders. Surgical treatment typically is reserved for the small minority of patients with considerable pelvic organ or rectal prolapse, they note.
The National Institutes of Health Sciences provided funding. The authors reported having no conflicts of interest.
About 25% of patients with fecal incontinence benefit from conservative treatments, which merit a “rigorous trial” before considering surgery, experts write in a Clinical Practice Update in the December issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.08.023).
“A stepwise approach should be followed for management of fecal incontinence. In our experience, many incontinent patients who are considered refractory to conservative therapy have not received an optimal trial of conservative therapy,” states Adil E. Bharucha, MBBS, MD, of the Mayo Clinic and the Mayo Foundation in Rochester, Minn., and his associates.
Fecal incontinence affects 7%-15% of individuals and has potentially “devastating” implications for quality of life, the experts note. They recommend starting treatment by meticulously documenting bowel habits, triggers of incontinence, and treatment history. For fecal incontinence with diarrhea, they suggest eliminating caffeine and poorly absorbed dietary sugars, such as sorbitol and fructose, and adding loperamide, starting with one 2-mg tablet taken 30 minutes before breakfast and titrating up to a maximum of 16 mg per day. Other conservative therapeutic options for diarrhea include fiber supplementation, scheduled toileting, a bowel retraining program, anticholinergic agents, clonidine, and cholestyramine or colesevelam to correct bile salt malabsorption. Patients whose fecal incontinence involves constipation should start with laxatives and anorectal testing for evacuation disorders. Rectal cleansing with a small enema or tap water can help prevent stool leakage, the experts write.
If these conservative measures fail to improve fecal incontinence, they recommend anorectal manometry to test for anal weakness, reduced or increased rectal sensation, and impaired rectal balloon expulsion, all of which can improve with biofeedback therapy to retrain the pelvic floor. If biofeedback fails, consider perianal bulking agents, such as intra-anal injection of dextranomer, the experts suggest. Sacral nerve stimulation might be indicated if moderate or severe fecal incontinence does not respond to at least 3 months of conservative treatment. However, the experts do not recommend percutaneous tibial nerve stimulation, which failed to outperform sham stimulation in a 12-week, double-blind, multicenter trial (Lancet. 2015;386:1640-8). Surgery is indicated for fecal incontinence associated with major anatomic defects, such as rectovaginal fistula, full-thickness rectal prolapse, fistula in ano, or cloaca-like deformity. Additionally, sphincteroplasty is an option for postpartum women with fecal incontinence, patients with recent sphincter injuries, and patients with sphincter damage and fecal incontinence fecal incontinence that fails to improve with conservative and biofeedback therapy, perianal bulking injection, and sacral nerve stimulation, according to the clinical practice update.
Barrier devices should be offered if fecal incontinence fails conservative treatments and surgery, or if surgery is not an option. Most anal plugs are “poorly tolerated,” with two exceptions – a Food and Drug Administration–approved device from Renew Medical and a vaginal insert and pressure-regulated pump from Pelvalon. Colostomy might be indicated if patients with severe fecal incontinence fail conservative treatment and or are not candidates for barrier devices, minimally invasive surgeries, and sphincteroplasty.
If severe fecal incontinence that is refractory to or contraindicated for all these interventions, the experts suggest considering artificial anal sphincter repair by dynamic graciloplasty. Surgery also is indicated to repair major anatomic defects such as rectovaginal fistula, full-thickness rectal prolapse, fistula in ano, or cloaca-like deformity, they noted. A magnetic anal sphincter device is a possibility for patients with medically refractory severe fecal incontinence who have failed or are not candidates for barrier devices, perianal bulking injection, sacral nerve stimulation, sphincteroplasty, or a colostomy. However, the study that led to FDA approval of a magnetic anal sphincter device included only 35 patients, and 7 (20%) had the device removed because of infection, erosion, or inefficacy. Another patient required a stoma in order to be able to defecate, and a total of 40% had moderate or severe complications when pain and bleeding were also considered, the experts noted.
Biofeedback is the preferred treatment for defecatory disorders – that is, chronic constipation or constipation-predominant irritable bowel syndrome with impaired rectal evacuation, according to the clinical practice update. The experts recommend against sacral nerve stimulation, anteretrograde colonic enemas, and stapled transanal rectal resection for patients with defecatory disorders. Surgical treatment typically is reserved for the small minority of patients with considerable pelvic organ or rectal prolapse, they note.
The National Institutes of Health Sciences provided funding. The authors reported having no conflicts of interest.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Biologics during pregnancy did not affect infant vaccine response
The use of biologic therapy during pregnancy did not lower antibody titers among infants vaccinated against Haemophilus influenzae B (HiB) or tetanus toxin, according to the results of a study of 179 mothers reported in the January issue of Clinical Gastroenterology and Hepatology (2017. doi: 10.1016/j.cgh.2017.08.041).
Additionally, there was no link between median infliximab concentration in uterine cord blood and antibody titers among infants aged 7 months and older, wrote Dawn B. Beaulieu, MD, with her associates. “In a limited cohort of exposed infants given the rotavirus vaccine, there was no association with significant adverse reactions,” they also reported.
Experts now recommend against live vaccinations for infants who may have detectable concentrations of biologics, but it remained unclear whether these infants can mount adequate responses to inactive vaccines. Therefore, the researchers analyzed data from the Pregnancy in IBD and Neonatal Outcomes (PIANO) registry collected between 2007 and 2016 and surveyed women about their infants’ vaccination history. They also quantified antibodies in serum samples from infants aged 7 months and older and analyzed measured concentrations of biologics in cord blood.
Among 179 mothers with IBD, most had inactive (77%) or mild disease activity (18%) during pregnancy, the researchers said. Eleven (6%) mothers were not on immunosuppressives while pregnant, 15 (8%) were on an immunomodulator, and the rest were on biologic monotherapy (65%) or a biologic plus an immunomodulator (21%). A total of 46 infants had available HiB titer data, of whom 38 were potentially exposed to biologics; among 49 infants with available tetanus titers, 41 were potentially exposed. In all, 71% of exposed infants had protective levels of antibodies against HiB, and 80% had protective titers to tetanus toxoid. Proportions among unexposed infants were 50% and 75%, respectively. Proportions of protective antibody titers did not significantly differ between groups even after excluding infants whose mothers received certolizumab pegol, which has negligible rates of placental transfer.
A total of 39 infants received live rotavirus vaccine despite having detectable levels of biologics in cord blood at birth. Seven developed mild vaccine reactions consisting of fever (six infants) or diarrhea (one infant). This proportion (18%) resembles that from a large study (N Engl J Med. 2006;354:23-33) of healthy infants who were vaccinated against rotavirus, the researchers noted. “Despite our data suggesting a lack of severe side effects with the rotavirus vaccine in these infants, in the absence of robust evidence, one should continue to avoid live vaccines in infants born to mothers on biologic therapy (excluding certolizumab) during the first year of life or until drug clearance is confirmed,” they suggested. “With the growing availability of tests, one conceivably could test serum drug concentration in infants, and, if undetectable, consider live vaccination at that time, if appropriate for the vaccine, particularly in infants most likely to benefit from such vaccines.”
The Crohn’s and Colitis Foundation provided funding. Dr. Beaulieu disclosed a consulting relationship with AbbVie, and four coinvestigators also reported ties to pharmaceutical companies.
The use of biologic therapy during pregnancy did not lower antibody titers among infants vaccinated against Haemophilus influenzae B (HiB) or tetanus toxin, according to the results of a study of 179 mothers reported in the January issue of Clinical Gastroenterology and Hepatology (2017. doi: 10.1016/j.cgh.2017.08.041).
Additionally, there was no link between median infliximab concentration in uterine cord blood and antibody titers among infants aged 7 months and older, wrote Dawn B. Beaulieu, MD, with her associates. “In a limited cohort of exposed infants given the rotavirus vaccine, there was no association with significant adverse reactions,” they also reported.
Experts now recommend against live vaccinations for infants who may have detectable concentrations of biologics, but it remained unclear whether these infants can mount adequate responses to inactive vaccines. Therefore, the researchers analyzed data from the Pregnancy in IBD and Neonatal Outcomes (PIANO) registry collected between 2007 and 2016 and surveyed women about their infants’ vaccination history. They also quantified antibodies in serum samples from infants aged 7 months and older and analyzed measured concentrations of biologics in cord blood.
Among 179 mothers with IBD, most had inactive (77%) or mild disease activity (18%) during pregnancy, the researchers said. Eleven (6%) mothers were not on immunosuppressives while pregnant, 15 (8%) were on an immunomodulator, and the rest were on biologic monotherapy (65%) or a biologic plus an immunomodulator (21%). A total of 46 infants had available HiB titer data, of whom 38 were potentially exposed to biologics; among 49 infants with available tetanus titers, 41 were potentially exposed. In all, 71% of exposed infants had protective levels of antibodies against HiB, and 80% had protective titers to tetanus toxoid. Proportions among unexposed infants were 50% and 75%, respectively. Proportions of protective antibody titers did not significantly differ between groups even after excluding infants whose mothers received certolizumab pegol, which has negligible rates of placental transfer.
A total of 39 infants received live rotavirus vaccine despite having detectable levels of biologics in cord blood at birth. Seven developed mild vaccine reactions consisting of fever (six infants) or diarrhea (one infant). This proportion (18%) resembles that from a large study (N Engl J Med. 2006;354:23-33) of healthy infants who were vaccinated against rotavirus, the researchers noted. “Despite our data suggesting a lack of severe side effects with the rotavirus vaccine in these infants, in the absence of robust evidence, one should continue to avoid live vaccines in infants born to mothers on biologic therapy (excluding certolizumab) during the first year of life or until drug clearance is confirmed,” they suggested. “With the growing availability of tests, one conceivably could test serum drug concentration in infants, and, if undetectable, consider live vaccination at that time, if appropriate for the vaccine, particularly in infants most likely to benefit from such vaccines.”
The Crohn’s and Colitis Foundation provided funding. Dr. Beaulieu disclosed a consulting relationship with AbbVie, and four coinvestigators also reported ties to pharmaceutical companies.
The use of biologic therapy during pregnancy did not lower antibody titers among infants vaccinated against Haemophilus influenzae B (HiB) or tetanus toxin, according to the results of a study of 179 mothers reported in the January issue of Clinical Gastroenterology and Hepatology (2017. doi: 10.1016/j.cgh.2017.08.041).
Additionally, there was no link between median infliximab concentration in uterine cord blood and antibody titers among infants aged 7 months and older, wrote Dawn B. Beaulieu, MD, with her associates. “In a limited cohort of exposed infants given the rotavirus vaccine, there was no association with significant adverse reactions,” they also reported.
Experts now recommend against live vaccinations for infants who may have detectable concentrations of biologics, but it remained unclear whether these infants can mount adequate responses to inactive vaccines. Therefore, the researchers analyzed data from the Pregnancy in IBD and Neonatal Outcomes (PIANO) registry collected between 2007 and 2016 and surveyed women about their infants’ vaccination history. They also quantified antibodies in serum samples from infants aged 7 months and older and analyzed measured concentrations of biologics in cord blood.
Among 179 mothers with IBD, most had inactive (77%) or mild disease activity (18%) during pregnancy, the researchers said. Eleven (6%) mothers were not on immunosuppressives while pregnant, 15 (8%) were on an immunomodulator, and the rest were on biologic monotherapy (65%) or a biologic plus an immunomodulator (21%). A total of 46 infants had available HiB titer data, of whom 38 were potentially exposed to biologics; among 49 infants with available tetanus titers, 41 were potentially exposed. In all, 71% of exposed infants had protective levels of antibodies against HiB, and 80% had protective titers to tetanus toxoid. Proportions among unexposed infants were 50% and 75%, respectively. Proportions of protective antibody titers did not significantly differ between groups even after excluding infants whose mothers received certolizumab pegol, which has negligible rates of placental transfer.
A total of 39 infants received live rotavirus vaccine despite having detectable levels of biologics in cord blood at birth. Seven developed mild vaccine reactions consisting of fever (six infants) or diarrhea (one infant). This proportion (18%) resembles that from a large study (N Engl J Med. 2006;354:23-33) of healthy infants who were vaccinated against rotavirus, the researchers noted. “Despite our data suggesting a lack of severe side effects with the rotavirus vaccine in these infants, in the absence of robust evidence, one should continue to avoid live vaccines in infants born to mothers on biologic therapy (excluding certolizumab) during the first year of life or until drug clearance is confirmed,” they suggested. “With the growing availability of tests, one conceivably could test serum drug concentration in infants, and, if undetectable, consider live vaccination at that time, if appropriate for the vaccine, particularly in infants most likely to benefit from such vaccines.”
The Crohn’s and Colitis Foundation provided funding. Dr. Beaulieu disclosed a consulting relationship with AbbVie, and four coinvestigators also reported ties to pharmaceutical companies.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: In utero biologic exposure did not prevent immune response to Haemophilus influenzae B and tetanus vaccines during infancy.
Major finding: Proportions of protective antibody titers did not significantly differ among groups.
Data source: A prospective study of 179 mothers with IBD and their infants.
Disclosures: The Crohn’s and Colitis Foundation provided funding. Dr. Beaulieu disclosed a consulting relationship with AbbVie, and four coinvestigators also reported ties to pharmaceutical companies.
Low tryptophan levels linked to IBD
Patients with inflammatory bowel disease (IBD) had significantly lower serum levels of the essential amino acid tryptophan than healthy controls in a large study reported in the December issue of Gastroenterology (doi: 10.1053/j.gastro.2017.08.028).
Serum tryptophan levels also correlated inversely with both disease activity and C-reactive protein levels in patients with IBD, reported Susanna Nikolaus, MD, of University Hospital Schleswig-Holstein, Kiel, Germany, with her associates. “Tryptophan deficiency could contribute to development of IBD. Studies are needed to determine whether modification of intestinal tryptophan pathways affects [its] severity,” they wrote.
Several small case series have reported low levels of tryptophan in IBD and other autoimmune disorders, the investigators noted. Removing tryptophan from the diet has been found to increase susceptibility to colitis in mice, and supplementing with tryptophan or some of its metabolites has the opposite effect. For this study, the researchers used high-performance liquid chromatography to quantify tryptophan levels in serum samples from 535 consecutive patients with IBD and 100 matched controls. They used mass spectrometry to measure metabolites of tryptophan, enzyme-linked immunosorbent assay to measure interleukin-22 (IL-22) levels, and 16S rDNA amplicon sequencing to correlate tryptophan levels with fecal microbiota species. Finally, they used real-time polymerase chain reaction to measure levels of mRNA encoding tryptophan metabolites in colonic biopsy specimens.
Serum tryptophan levels were significantly lower in patients with IBD than controls (P = 5.3 x 10–6). The difference was starker in patients with Crohn’s disease (P = 1.1 x 10–10 vs. controls) compared with those with ulcerative colitis (P = 2.8 x 10–3 vs. controls), the investigators noted. Serum tryptophan levels also correlated inversely with disease activity in patients with Crohn’s disease (P = .01), while patients with ulcerative colitis showed a similar but nonsignificant trend (P = .07). Low tryptophan levels were associated with marked, statistically significant increases in C-reactive protein levels in both Crohn’s disease and ulcerative colitis. Tryptophan level also correlated inversely with leukocyte count, although the trend was less pronounced (P = .04).IBD was associated with several aberrations in the tryptophan kynurenine pathway, which is the primary means of catabolizing the amino acid. For example, compared with controls, patients with active IBD had significantly lower levels of mRNA encoding tryptophan 2,3-dioxygenase-2 (TDO2, a key enzyme in the kynurenine pathway) and solute carrier family 6 member 19 (SLC6A19, also called B0AT1, a neutral amino acid transporter). Patients with IBD also had significantly higher levels of indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the initial, rate-limiting oxidation of tryptophan to kynurenine. Accordingly, patients with IBD had a significantly higher ratio of kynurenine to tryptophan than did controls, and this abnormality was associated with disease activity, especially in Crohn’s disease (P = .03).
Patients with IBD who had relatively higher tryptophan levels also tended to have more diverse gut microbiota than did patients with lower serum tryptophan levels, although differences among groups were not statistically significant, the investigators said. Serum concentration of IL-22 also correlated with disease activity in patients with IBD, and infliximab responders had a “significant and sustained increase” of tryptophan levels over time, compared with nonresponders.
Potsdam dietary questionnaires found no link between disease activity and dietary consumption of tryptophan, the researchers said. Additionally, they found no links between serum tryptophan levels and age, smoking status, or disease complications, such as fistulae or abscess formation.The investigators acknowledged grant support from the DFG Excellence Cluster “Inflammation at Interfaces” and BMBF e-med SYSINFLAME and H2020 SysCID. One coinvestigator reported employment by CONARIS Research Institute AG, which helps develop drugs with inflammatory indications. The other investigators had no conflicts of interest.
In this interesting study, Nikolaus et al. found an association of decreased serum tryptophan in patients with inflammatory bowel disease (IBD), compared with control subjects. The authors also found an inverse correlation of serum tryptophan levels in patients with C-reactive protein in both ulcerative colitis and Crohn's disease and with active disease as defined by clinical disease activity scores in Crohn's disease. A validated food-frequency questionnaire found no difference in tryptophan consumption based on disease activity in a subset of patients, decreasing the likelihood that this association is secondary to altered dietary intake only and may be related to other mechanisms.
Sara Horst, MD, MPH, is an assistant professor, division of gastroenterology, hepatology & nutrition, Inflammatory Bowel Disease Center, Vanderbilt University Medical Center, Nashville, Tenn. She had no relevant conflicts of interest.
In this interesting study, Nikolaus et al. found an association of decreased serum tryptophan in patients with inflammatory bowel disease (IBD), compared with control subjects. The authors also found an inverse correlation of serum tryptophan levels in patients with C-reactive protein in both ulcerative colitis and Crohn's disease and with active disease as defined by clinical disease activity scores in Crohn's disease. A validated food-frequency questionnaire found no difference in tryptophan consumption based on disease activity in a subset of patients, decreasing the likelihood that this association is secondary to altered dietary intake only and may be related to other mechanisms.
Sara Horst, MD, MPH, is an assistant professor, division of gastroenterology, hepatology & nutrition, Inflammatory Bowel Disease Center, Vanderbilt University Medical Center, Nashville, Tenn. She had no relevant conflicts of interest.
In this interesting study, Nikolaus et al. found an association of decreased serum tryptophan in patients with inflammatory bowel disease (IBD), compared with control subjects. The authors also found an inverse correlation of serum tryptophan levels in patients with C-reactive protein in both ulcerative colitis and Crohn's disease and with active disease as defined by clinical disease activity scores in Crohn's disease. A validated food-frequency questionnaire found no difference in tryptophan consumption based on disease activity in a subset of patients, decreasing the likelihood that this association is secondary to altered dietary intake only and may be related to other mechanisms.
Sara Horst, MD, MPH, is an assistant professor, division of gastroenterology, hepatology & nutrition, Inflammatory Bowel Disease Center, Vanderbilt University Medical Center, Nashville, Tenn. She had no relevant conflicts of interest.
Patients with inflammatory bowel disease (IBD) had significantly lower serum levels of the essential amino acid tryptophan than healthy controls in a large study reported in the December issue of Gastroenterology (doi: 10.1053/j.gastro.2017.08.028).
Serum tryptophan levels also correlated inversely with both disease activity and C-reactive protein levels in patients with IBD, reported Susanna Nikolaus, MD, of University Hospital Schleswig-Holstein, Kiel, Germany, with her associates. “Tryptophan deficiency could contribute to development of IBD. Studies are needed to determine whether modification of intestinal tryptophan pathways affects [its] severity,” they wrote.
Several small case series have reported low levels of tryptophan in IBD and other autoimmune disorders, the investigators noted. Removing tryptophan from the diet has been found to increase susceptibility to colitis in mice, and supplementing with tryptophan or some of its metabolites has the opposite effect. For this study, the researchers used high-performance liquid chromatography to quantify tryptophan levels in serum samples from 535 consecutive patients with IBD and 100 matched controls. They used mass spectrometry to measure metabolites of tryptophan, enzyme-linked immunosorbent assay to measure interleukin-22 (IL-22) levels, and 16S rDNA amplicon sequencing to correlate tryptophan levels with fecal microbiota species. Finally, they used real-time polymerase chain reaction to measure levels of mRNA encoding tryptophan metabolites in colonic biopsy specimens.
Serum tryptophan levels were significantly lower in patients with IBD than controls (P = 5.3 x 10–6). The difference was starker in patients with Crohn’s disease (P = 1.1 x 10–10 vs. controls) compared with those with ulcerative colitis (P = 2.8 x 10–3 vs. controls), the investigators noted. Serum tryptophan levels also correlated inversely with disease activity in patients with Crohn’s disease (P = .01), while patients with ulcerative colitis showed a similar but nonsignificant trend (P = .07). Low tryptophan levels were associated with marked, statistically significant increases in C-reactive protein levels in both Crohn’s disease and ulcerative colitis. Tryptophan level also correlated inversely with leukocyte count, although the trend was less pronounced (P = .04).IBD was associated with several aberrations in the tryptophan kynurenine pathway, which is the primary means of catabolizing the amino acid. For example, compared with controls, patients with active IBD had significantly lower levels of mRNA encoding tryptophan 2,3-dioxygenase-2 (TDO2, a key enzyme in the kynurenine pathway) and solute carrier family 6 member 19 (SLC6A19, also called B0AT1, a neutral amino acid transporter). Patients with IBD also had significantly higher levels of indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the initial, rate-limiting oxidation of tryptophan to kynurenine. Accordingly, patients with IBD had a significantly higher ratio of kynurenine to tryptophan than did controls, and this abnormality was associated with disease activity, especially in Crohn’s disease (P = .03).
Patients with IBD who had relatively higher tryptophan levels also tended to have more diverse gut microbiota than did patients with lower serum tryptophan levels, although differences among groups were not statistically significant, the investigators said. Serum concentration of IL-22 also correlated with disease activity in patients with IBD, and infliximab responders had a “significant and sustained increase” of tryptophan levels over time, compared with nonresponders.
Potsdam dietary questionnaires found no link between disease activity and dietary consumption of tryptophan, the researchers said. Additionally, they found no links between serum tryptophan levels and age, smoking status, or disease complications, such as fistulae or abscess formation.The investigators acknowledged grant support from the DFG Excellence Cluster “Inflammation at Interfaces” and BMBF e-med SYSINFLAME and H2020 SysCID. One coinvestigator reported employment by CONARIS Research Institute AG, which helps develop drugs with inflammatory indications. The other investigators had no conflicts of interest.
Patients with inflammatory bowel disease (IBD) had significantly lower serum levels of the essential amino acid tryptophan than healthy controls in a large study reported in the December issue of Gastroenterology (doi: 10.1053/j.gastro.2017.08.028).
Serum tryptophan levels also correlated inversely with both disease activity and C-reactive protein levels in patients with IBD, reported Susanna Nikolaus, MD, of University Hospital Schleswig-Holstein, Kiel, Germany, with her associates. “Tryptophan deficiency could contribute to development of IBD. Studies are needed to determine whether modification of intestinal tryptophan pathways affects [its] severity,” they wrote.
Several small case series have reported low levels of tryptophan in IBD and other autoimmune disorders, the investigators noted. Removing tryptophan from the diet has been found to increase susceptibility to colitis in mice, and supplementing with tryptophan or some of its metabolites has the opposite effect. For this study, the researchers used high-performance liquid chromatography to quantify tryptophan levels in serum samples from 535 consecutive patients with IBD and 100 matched controls. They used mass spectrometry to measure metabolites of tryptophan, enzyme-linked immunosorbent assay to measure interleukin-22 (IL-22) levels, and 16S rDNA amplicon sequencing to correlate tryptophan levels with fecal microbiota species. Finally, they used real-time polymerase chain reaction to measure levels of mRNA encoding tryptophan metabolites in colonic biopsy specimens.
Serum tryptophan levels were significantly lower in patients with IBD than controls (P = 5.3 x 10–6). The difference was starker in patients with Crohn’s disease (P = 1.1 x 10–10 vs. controls) compared with those with ulcerative colitis (P = 2.8 x 10–3 vs. controls), the investigators noted. Serum tryptophan levels also correlated inversely with disease activity in patients with Crohn’s disease (P = .01), while patients with ulcerative colitis showed a similar but nonsignificant trend (P = .07). Low tryptophan levels were associated with marked, statistically significant increases in C-reactive protein levels in both Crohn’s disease and ulcerative colitis. Tryptophan level also correlated inversely with leukocyte count, although the trend was less pronounced (P = .04).IBD was associated with several aberrations in the tryptophan kynurenine pathway, which is the primary means of catabolizing the amino acid. For example, compared with controls, patients with active IBD had significantly lower levels of mRNA encoding tryptophan 2,3-dioxygenase-2 (TDO2, a key enzyme in the kynurenine pathway) and solute carrier family 6 member 19 (SLC6A19, also called B0AT1, a neutral amino acid transporter). Patients with IBD also had significantly higher levels of indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the initial, rate-limiting oxidation of tryptophan to kynurenine. Accordingly, patients with IBD had a significantly higher ratio of kynurenine to tryptophan than did controls, and this abnormality was associated with disease activity, especially in Crohn’s disease (P = .03).
Patients with IBD who had relatively higher tryptophan levels also tended to have more diverse gut microbiota than did patients with lower serum tryptophan levels, although differences among groups were not statistically significant, the investigators said. Serum concentration of IL-22 also correlated with disease activity in patients with IBD, and infliximab responders had a “significant and sustained increase” of tryptophan levels over time, compared with nonresponders.
Potsdam dietary questionnaires found no link between disease activity and dietary consumption of tryptophan, the researchers said. Additionally, they found no links between serum tryptophan levels and age, smoking status, or disease complications, such as fistulae or abscess formation.The investigators acknowledged grant support from the DFG Excellence Cluster “Inflammation at Interfaces” and BMBF e-med SYSINFLAME and H2020 SysCID. One coinvestigator reported employment by CONARIS Research Institute AG, which helps develop drugs with inflammatory indications. The other investigators had no conflicts of interest.
FROM GASTROENTEROLOGY
Key clinical point: Patients with inflammatory bowel disease had significantly lower serum tryptophan levels than healthy controls.
Major finding: Serum tryptophan levels also correlated inversely with disease activity and C-reactive protein levels in patients with IBD.
Data source: An analysis of serum samples from 535 consecutive patients with IBD and 100 matched controls.
Disclosures: The investigators acknowledged grant support from the DFG Excellence Cluster “Inflammation at Interfaces” and BMBF e-med SYSINFLAME and H2020 SysCID. One coinvestigator reported employment by CONARIS Research Institute AG, which helps develop therapies with inflammatory indications. The other investigators had no conflicts of interest.
Early evidence shows that surgery can alter gut microbiome
SAN DIEGO – Surgery appears to stimulate abrupt changes in both the skin and gut microbiome, which in some patients may increase the risk of surgical site infections and anastomotic leaks. With that knowledge, researchers are exploring the very first steps toward a presurgical microbiome optimization protocol, Heidi Nelson, MD, FACS, said at the annual clinical congress of the American College of Surgeons.
It’s very early in the journey, said Dr. Nelson, the Fred C. Andersen Professor of Surgery at Mayo Clinic, Rochester. Minn. And it won’t be a straightforward path: The human microbiome appears to be nearly as individually unique as the human fingerprint, so presurgical protocols might have to be individually tailored to each patient.
Dr. Nelson comoderated a session exploring this topic with John Alverdy, MD, FACS, of the University of Chicago. The panel discussed human and animal studies suggesting that the stress of surgery, when combined with subclinical ischemia and any baseline physiologic stress (chronic illness or radiation, for example) can cause some commensals to begin producing collagenase – a change that endangers even surgically sound anastomoses.
“It’s well known that bacteria can change their function in response to host stress,” said Dr. Shogan, a colorectal surgeon at the University of Chicago. “They recognize these factors and change their entire function. In our work, we found that Enterococcus began to express a tissue-destroying phenotype in response to subclinical ischemia related to surgery.”
The pathogenic flip doesn’t occur unless there are a couple of predisposing factors, he theorized. “There have to be multiple stresses involved. These could include smoking, steroids, obesity, and prior exposure to radiation – all things that we commonly see in our colorectal surgery patients. But when the right situation developed, we can see a proliferation of collagen-destroying bacteria that predispose to leaks.”
The skin microbiome is altered as well, with areas around abdominal incisions beginning to express gut flora, which increase the risk of a surgical site infection, said Andrew Yeh, MD, a general surgery resident at the University of Pittsburgh.
He presented data on 28 colorectal surgery patients, detailing perioperative changes in the chest and abdominal skin microbiome. All of the subjects were adults undergoing colon resection who had not been on any antibiotics at least 1 month before surgery. Skin sampling was performed before and after opening, with additional postoperative skin samples taken daily while the patient was in the hospital recovering. Dr. Yeh had DNA/RNA data on 431 samples taken from this group.
“We saw increases in Staphylococcus and Bacteroides on the skin – normally part of the gut microflora – in relative abundance, while Corynebacterium, a normal constituent of the skin microbiome, had decreased.”
These are all very early observations, though, and the surgical community is nowhere near being able to make any specific presurgical recommendations to optimize the microbiome, or postsurgical recommendations to manage it, said Neil Hyman, MD, FACS, professor of surgery at the University of Chicago.
While it does appear that good bacteria “gone bad” are associated with anastomotic leaks, he agreed that the right constellation of factors has to be in place for this to happen, including “the right bacteria [Enterococcus], the right virulence genes [collagenase], the right activating cures [long operation, blood loss], and the wrong microbiome [altered by smoking, chemotherapy, radiation, or other chronic stressors].”
“I think it’s safe to say that developing collagenase-producing bacteria at an anastomosis site is a bad thing, but the individual genetic makeup of every patient makes any one-size-fits-all protocol approach to treatment really problematic,” Dr. Hyman said.
None of the presenters had any financial disclosures.
[email protected]
On Twitter @Alz_Gal
SAN DIEGO – Surgery appears to stimulate abrupt changes in both the skin and gut microbiome, which in some patients may increase the risk of surgical site infections and anastomotic leaks. With that knowledge, researchers are exploring the very first steps toward a presurgical microbiome optimization protocol, Heidi Nelson, MD, FACS, said at the annual clinical congress of the American College of Surgeons.
It’s very early in the journey, said Dr. Nelson, the Fred C. Andersen Professor of Surgery at Mayo Clinic, Rochester. Minn. And it won’t be a straightforward path: The human microbiome appears to be nearly as individually unique as the human fingerprint, so presurgical protocols might have to be individually tailored to each patient.
Dr. Nelson comoderated a session exploring this topic with John Alverdy, MD, FACS, of the University of Chicago. The panel discussed human and animal studies suggesting that the stress of surgery, when combined with subclinical ischemia and any baseline physiologic stress (chronic illness or radiation, for example) can cause some commensals to begin producing collagenase – a change that endangers even surgically sound anastomoses.
“It’s well known that bacteria can change their function in response to host stress,” said Dr. Shogan, a colorectal surgeon at the University of Chicago. “They recognize these factors and change their entire function. In our work, we found that Enterococcus began to express a tissue-destroying phenotype in response to subclinical ischemia related to surgery.”
The pathogenic flip doesn’t occur unless there are a couple of predisposing factors, he theorized. “There have to be multiple stresses involved. These could include smoking, steroids, obesity, and prior exposure to radiation – all things that we commonly see in our colorectal surgery patients. But when the right situation developed, we can see a proliferation of collagen-destroying bacteria that predispose to leaks.”
The skin microbiome is altered as well, with areas around abdominal incisions beginning to express gut flora, which increase the risk of a surgical site infection, said Andrew Yeh, MD, a general surgery resident at the University of Pittsburgh.
He presented data on 28 colorectal surgery patients, detailing perioperative changes in the chest and abdominal skin microbiome. All of the subjects were adults undergoing colon resection who had not been on any antibiotics at least 1 month before surgery. Skin sampling was performed before and after opening, with additional postoperative skin samples taken daily while the patient was in the hospital recovering. Dr. Yeh had DNA/RNA data on 431 samples taken from this group.
“We saw increases in Staphylococcus and Bacteroides on the skin – normally part of the gut microflora – in relative abundance, while Corynebacterium, a normal constituent of the skin microbiome, had decreased.”
These are all very early observations, though, and the surgical community is nowhere near being able to make any specific presurgical recommendations to optimize the microbiome, or postsurgical recommendations to manage it, said Neil Hyman, MD, FACS, professor of surgery at the University of Chicago.
While it does appear that good bacteria “gone bad” are associated with anastomotic leaks, he agreed that the right constellation of factors has to be in place for this to happen, including “the right bacteria [Enterococcus], the right virulence genes [collagenase], the right activating cures [long operation, blood loss], and the wrong microbiome [altered by smoking, chemotherapy, radiation, or other chronic stressors].”
“I think it’s safe to say that developing collagenase-producing bacteria at an anastomosis site is a bad thing, but the individual genetic makeup of every patient makes any one-size-fits-all protocol approach to treatment really problematic,” Dr. Hyman said.
None of the presenters had any financial disclosures.
[email protected]
On Twitter @Alz_Gal
SAN DIEGO – Surgery appears to stimulate abrupt changes in both the skin and gut microbiome, which in some patients may increase the risk of surgical site infections and anastomotic leaks. With that knowledge, researchers are exploring the very first steps toward a presurgical microbiome optimization protocol, Heidi Nelson, MD, FACS, said at the annual clinical congress of the American College of Surgeons.
It’s very early in the journey, said Dr. Nelson, the Fred C. Andersen Professor of Surgery at Mayo Clinic, Rochester. Minn. And it won’t be a straightforward path: The human microbiome appears to be nearly as individually unique as the human fingerprint, so presurgical protocols might have to be individually tailored to each patient.
Dr. Nelson comoderated a session exploring this topic with John Alverdy, MD, FACS, of the University of Chicago. The panel discussed human and animal studies suggesting that the stress of surgery, when combined with subclinical ischemia and any baseline physiologic stress (chronic illness or radiation, for example) can cause some commensals to begin producing collagenase – a change that endangers even surgically sound anastomoses.
“It’s well known that bacteria can change their function in response to host stress,” said Dr. Shogan, a colorectal surgeon at the University of Chicago. “They recognize these factors and change their entire function. In our work, we found that Enterococcus began to express a tissue-destroying phenotype in response to subclinical ischemia related to surgery.”
The pathogenic flip doesn’t occur unless there are a couple of predisposing factors, he theorized. “There have to be multiple stresses involved. These could include smoking, steroids, obesity, and prior exposure to radiation – all things that we commonly see in our colorectal surgery patients. But when the right situation developed, we can see a proliferation of collagen-destroying bacteria that predispose to leaks.”
The skin microbiome is altered as well, with areas around abdominal incisions beginning to express gut flora, which increase the risk of a surgical site infection, said Andrew Yeh, MD, a general surgery resident at the University of Pittsburgh.
He presented data on 28 colorectal surgery patients, detailing perioperative changes in the chest and abdominal skin microbiome. All of the subjects were adults undergoing colon resection who had not been on any antibiotics at least 1 month before surgery. Skin sampling was performed before and after opening, with additional postoperative skin samples taken daily while the patient was in the hospital recovering. Dr. Yeh had DNA/RNA data on 431 samples taken from this group.
“We saw increases in Staphylococcus and Bacteroides on the skin – normally part of the gut microflora – in relative abundance, while Corynebacterium, a normal constituent of the skin microbiome, had decreased.”
These are all very early observations, though, and the surgical community is nowhere near being able to make any specific presurgical recommendations to optimize the microbiome, or postsurgical recommendations to manage it, said Neil Hyman, MD, FACS, professor of surgery at the University of Chicago.
While it does appear that good bacteria “gone bad” are associated with anastomotic leaks, he agreed that the right constellation of factors has to be in place for this to happen, including “the right bacteria [Enterococcus], the right virulence genes [collagenase], the right activating cures [long operation, blood loss], and the wrong microbiome [altered by smoking, chemotherapy, radiation, or other chronic stressors].”
“I think it’s safe to say that developing collagenase-producing bacteria at an anastomosis site is a bad thing, but the individual genetic makeup of every patient makes any one-size-fits-all protocol approach to treatment really problematic,” Dr. Hyman said.
None of the presenters had any financial disclosures.
[email protected]
On Twitter @Alz_Gal
EXPERT ANALYSIS FROM THE ACS CLINICAL CONGRESS
Meta-analysis confirms probiotics’ pediatric safety and efficacy
ORLANDO – Probiotics are safe and effective for treating functional abdominal pain in children, based on findings from a meta-analysis of 11 randomized studies with a total of 790 patients.
“We think there is pretty strong evidence” for the efficacy of probiotics, and “by any analysis you can throw at them probiotics are safe,” Gordon Morris, MD, said at the World Congress of Gastroenterology at ACG 2017. “The evidence is of moderate and high quality,” added Dr. Morris, a pediatric gastroenterologist at the University of Central Lancashire in Preston, England.
The most widely studied probiotic in the analysis was Lactobacillus reuteri, used in six of the studies with a total of 405 randomized patients. The next most commonly studied agent was Lactobacillus rhamnosus GG, the focus of four studies and tested in a total of 270 randomized patients. Both microbes showed statistically significant and clinically meaningful levels of pain reduction when compared with placebo in subgroup analyses, said Dr. Morris, who performed the meta-analysis as a Cochrane Review Groups systematic review.
“The pain score reductions we saw [with these two strains] could certainly have an impact. I think it matters clinically,” he explained. “Severity of pain is most important to patients.”
Both L. reuteri and L. rhamnosus GG have received “generally regarded as safe” designations from the Food and Drug Administration.
Based on these findings, “I don’t think we can justify, especially with these two main strains, any further basic efficacy studies,” Dr. Morris said. The primary focus for future clinical assessments of these probiotics should be long-term efficacy and safety and whether patients have rebound pain on withdrawal from probiotic use, he added.
The meta-analysis used studies that compared probiotics against placebo in children aged 4-18 years who received treatment for 4-16 weeks. The full analysis showed an average 0.57-unit reduction in pain scores across all 11 studies included, with an average 0.61-unit reduction using L. reuteri and an average 0.75-unit reduction using L. rhamnosus GG. All three between-group differences were statistically significant. Safety data came from eight of the included studies, and they collectively showed absolutely no safety difference between actively treated and control patients.
Dr. Morris noted that the mechanism by which probiotic bacilli relieve abdominal pain remains unclear, but suggested that both prokinetic and anti-inflammatory effects might be involved.
[email protected]
On Twitter @mitchelzoler
ORLANDO – Probiotics are safe and effective for treating functional abdominal pain in children, based on findings from a meta-analysis of 11 randomized studies with a total of 790 patients.
“We think there is pretty strong evidence” for the efficacy of probiotics, and “by any analysis you can throw at them probiotics are safe,” Gordon Morris, MD, said at the World Congress of Gastroenterology at ACG 2017. “The evidence is of moderate and high quality,” added Dr. Morris, a pediatric gastroenterologist at the University of Central Lancashire in Preston, England.
The most widely studied probiotic in the analysis was Lactobacillus reuteri, used in six of the studies with a total of 405 randomized patients. The next most commonly studied agent was Lactobacillus rhamnosus GG, the focus of four studies and tested in a total of 270 randomized patients. Both microbes showed statistically significant and clinically meaningful levels of pain reduction when compared with placebo in subgroup analyses, said Dr. Morris, who performed the meta-analysis as a Cochrane Review Groups systematic review.
“The pain score reductions we saw [with these two strains] could certainly have an impact. I think it matters clinically,” he explained. “Severity of pain is most important to patients.”
Both L. reuteri and L. rhamnosus GG have received “generally regarded as safe” designations from the Food and Drug Administration.
Based on these findings, “I don’t think we can justify, especially with these two main strains, any further basic efficacy studies,” Dr. Morris said. The primary focus for future clinical assessments of these probiotics should be long-term efficacy and safety and whether patients have rebound pain on withdrawal from probiotic use, he added.
The meta-analysis used studies that compared probiotics against placebo in children aged 4-18 years who received treatment for 4-16 weeks. The full analysis showed an average 0.57-unit reduction in pain scores across all 11 studies included, with an average 0.61-unit reduction using L. reuteri and an average 0.75-unit reduction using L. rhamnosus GG. All three between-group differences were statistically significant. Safety data came from eight of the included studies, and they collectively showed absolutely no safety difference between actively treated and control patients.
Dr. Morris noted that the mechanism by which probiotic bacilli relieve abdominal pain remains unclear, but suggested that both prokinetic and anti-inflammatory effects might be involved.
[email protected]
On Twitter @mitchelzoler
ORLANDO – Probiotics are safe and effective for treating functional abdominal pain in children, based on findings from a meta-analysis of 11 randomized studies with a total of 790 patients.
“We think there is pretty strong evidence” for the efficacy of probiotics, and “by any analysis you can throw at them probiotics are safe,” Gordon Morris, MD, said at the World Congress of Gastroenterology at ACG 2017. “The evidence is of moderate and high quality,” added Dr. Morris, a pediatric gastroenterologist at the University of Central Lancashire in Preston, England.
The most widely studied probiotic in the analysis was Lactobacillus reuteri, used in six of the studies with a total of 405 randomized patients. The next most commonly studied agent was Lactobacillus rhamnosus GG, the focus of four studies and tested in a total of 270 randomized patients. Both microbes showed statistically significant and clinically meaningful levels of pain reduction when compared with placebo in subgroup analyses, said Dr. Morris, who performed the meta-analysis as a Cochrane Review Groups systematic review.
“The pain score reductions we saw [with these two strains] could certainly have an impact. I think it matters clinically,” he explained. “Severity of pain is most important to patients.”
Both L. reuteri and L. rhamnosus GG have received “generally regarded as safe” designations from the Food and Drug Administration.
Based on these findings, “I don’t think we can justify, especially with these two main strains, any further basic efficacy studies,” Dr. Morris said. The primary focus for future clinical assessments of these probiotics should be long-term efficacy and safety and whether patients have rebound pain on withdrawal from probiotic use, he added.
The meta-analysis used studies that compared probiotics against placebo in children aged 4-18 years who received treatment for 4-16 weeks. The full analysis showed an average 0.57-unit reduction in pain scores across all 11 studies included, with an average 0.61-unit reduction using L. reuteri and an average 0.75-unit reduction using L. rhamnosus GG. All three between-group differences were statistically significant. Safety data came from eight of the included studies, and they collectively showed absolutely no safety difference between actively treated and control patients.
Dr. Morris noted that the mechanism by which probiotic bacilli relieve abdominal pain remains unclear, but suggested that both prokinetic and anti-inflammatory effects might be involved.
[email protected]
On Twitter @mitchelzoler
AT THE WORLD CONGRESS OF GASTROENTEROLOGY
Key clinical point:
Major finding: Probiotic treatment led to an average 0.57-unit reduction in pain intensity compared with placebo controls.
Data source: A Cochrane Group meta-analysis of 11 studies with 790 patients.
Disclosures: Dr. Morris had no disclosures.