Bugs and drugs in inflammatory bowel disease

Important new themes are whether we can actually find a cure for inflammatory bowel disease and, in particular, whether there are common pathogenetic mechanisms leading to Crohn’s disease and ulcerative colitis. Are Crohn’s and ulcerative colitis infectious diseases? If the answer to that question is ‘yes,’ then eliminating that “pathogen” would turn off the immune response. Crohn’s disease and ulcerative colitis share common genetic origins with the majority of genes shared between both disorders. Indeed, 110 of the 163 confirmed loci in IBD are common between the two disorders ⁽Nature 2012;491:119–24).

In addition to there being many genes contributing even a small amount to the development of IBD, there are also some genetic pathways that have a far more impactful role in IBD. By studying very-early-onset IBD, we have discovered that the IL-10 receptor pathway is very important in controlling intestinal inflammation, such that if you have a mutation in the receptor for IL-10 it can lead to very-early-onset IBD. Children who are born with these disorders can be treated with a hematopoietic bone marrow transplant. At this year’s Digestive Disease Week (DDW⁾ in fact, there was the presentation of the ASTIC trial; it described patients having a prolonged remission after an autologous hematopoietic stem cell transplant.

One of the big advances that has been made in terms of the treatment of IBD is based on an understanding of the pathogenetic pathways; in particular, there has been an increase in the number of medications that are currently available to treat IBD from a variety of different avenues. There was a recent publication describing an anti-sense treatment against SMAD7 in restoring TGF-beta signaling that produced a very rapid and profound improvement in the clinical symptoms of Crohn’s disease. We await more data on that particular compound.

We now know that an antibody against P40, which is the common subunit between IL-12 and IL-23, is effective in the treatment of Crohn’s disease and is commercially available as ustekinumab. At this year’s DDW we heard about an antibody that is specific for anti-IL-23 since it only antagonizes the P19 subunit of the cytokine; it also shows great promise for treating IBD. At DDW 2014, vedolizumab had just obtained approval for the treatment of ulcerative colitis and Crohn’s disease and that has been a big advance in treating patients. On its heels are a variety of other compounds that work by a similar mechanism by inhibiting the trafficking of effector lymphocytes to the intestine; these include anti-beta7 strategies and anti-MAdCAM. Both of these have been shown to be more effective in ulcerative colitis than in Crohn’s disease, as has been a common theme.

The other important presentation that took place at DDW 2015 is the use of ozanimod to treat ulcerative colitis; again, this is an oral agent that has a very dramatic effect in treating ulcerative colitis in a very short period of time by inhibiting the exit of effector T cells from lymph nodes. This tells us about the host immune response. We can now sequence all the bacteria that are present in the gut and using that approach we have found broad patterns of decreased diversity in patients who have IBD, although we have not identified a particular pathogen or pathogens.

The laboratory of Dr. Richard Flavell used a strategy in which they identified bacteria that were IgA coated and reasoned that IgA-coated bacteria were more likely to be pathogens (Cell. 2014 Aug 28;158(5):1000-1010). Indeed, by giving mice these IgA-coated bacteria found in IBD patients, the mice were more likely to develop colitis than if you gave non–IgA-coated bacteria to the same mice.

Another very important observation was in a study that was published in Nature, which demonstrated that emulsifiers really changed the relationship between the host and the microbiome. In particular, the investigators found that interactions with the microbiota led to metabolic syndrome. They also found that with dietary emulsifiers there is encroachment of the epithelium because of a thinning of the mucous layer and the study animals were more susceptible to developing colitis. I think that this is a sign to our patients that it is better to avoid processed foods.

Dr. Abreu is professor of medicine, professor of microbiology and immunology, chief of the division of gastroenterology, the Martin Kalser Chair in gastroenterology, and the director, Crohn’s & Colitis Center at the University of Miami Miller School of Medicine. She consults for AbbVie, Focus Medical Communications, GSK, and many other biopharmaceutical companies. Her comments were made during the ASGE and AGA joint Presidential Plenary at the annual Digestive Disease Week.

Important new themes are whether we can actually find a cure for inflammatory bowel disease and, in particular, whether there are common pathogenetic mechanisms leading to Crohn’s disease and ulcerative colitis. Are Crohn’s and ulcerative colitis infectious diseases? If the answer to that question is ‘yes,’ then eliminating that “pathogen” would turn off the immune response. Crohn’s disease and ulcerative colitis share common genetic origins with the majority of genes shared between both disorders. Indeed, 110 of the 163 confirmed loci in IBD are common between the two disorders ⁽Nature 2012;491:119–24).

In addition to there being many genes contributing even a small amount to the development of IBD, there are also some genetic pathways that have a far more impactful role in IBD. By studying very-early-onset IBD, we have discovered that the IL-10 receptor pathway is very important in controlling intestinal inflammation, such that if you have a mutation in the receptor for IL-10 it can lead to very-early-onset IBD. Children who are born with these disorders can be treated with a hematopoietic bone marrow transplant. At this year’s Digestive Disease Week (DDW⁾ in fact, there was the presentation of the ASTIC trial; it described patients having a prolonged remission after an autologous hematopoietic stem cell transplant.

One of the big advances that has been made in terms of the treatment of IBD is based on an understanding of the pathogenetic pathways; in particular, there has been an increase in the number of medications that are currently available to treat IBD from a variety of different avenues. There was a recent publication describing an anti-sense treatment against SMAD7 in restoring TGF-beta signaling that produced a very rapid and profound improvement in the clinical symptoms of Crohn’s disease. We await more data on that particular compound.

We now know that an antibody against P40, which is the common subunit between IL-12 and IL-23, is effective in the treatment of Crohn’s disease and is commercially available as ustekinumab. At this year’s DDW we heard about an antibody that is specific for anti-IL-23 since it only antagonizes the P19 subunit of the cytokine; it also shows great promise for treating IBD. At DDW 2014, vedolizumab had just obtained approval for the treatment of ulcerative colitis and Crohn’s disease and that has been a big advance in treating patients. On its heels are a variety of other compounds that work by a similar mechanism by inhibiting the trafficking of effector lymphocytes to the intestine; these include anti-beta7 strategies and anti-MAdCAM. Both of these have been shown to be more effective in ulcerative colitis than in Crohn’s disease, as has been a common theme.

The other important presentation that took place at DDW 2015 is the use of ozanimod to treat ulcerative colitis; again, this is an oral agent that has a very dramatic effect in treating ulcerative colitis in a very short period of time by inhibiting the exit of effector T cells from lymph nodes. This tells us about the host immune response. We can now sequence all the bacteria that are present in the gut and using that approach we have found broad patterns of decreased diversity in patients who have IBD, although we have not identified a particular pathogen or pathogens.

The laboratory of Dr. Richard Flavell used a strategy in which they identified bacteria that were IgA coated and reasoned that IgA-coated bacteria were more likely to be pathogens (Cell. 2014 Aug 28;158(5):1000-1010). Indeed, by giving mice these IgA-coated bacteria found in IBD patients, the mice were more likely to develop colitis than if you gave non–IgA-coated bacteria to the same mice.

Another very important observation was in a study that was published in Nature, which demonstrated that emulsifiers really changed the relationship between the host and the microbiome. In particular, the investigators found that interactions with the microbiota led to metabolic syndrome. They also found that with dietary emulsifiers there is encroachment of the epithelium because of a thinning of the mucous layer and the study animals were more susceptible to developing colitis. I think that this is a sign to our patients that it is better to avoid processed foods.

Dr. Abreu is professor of medicine, professor of microbiology and immunology, chief of the division of gastroenterology, the Martin Kalser Chair in gastroenterology, and the director, Crohn’s & Colitis Center at the University of Miami Miller School of Medicine. She consults for AbbVie, Focus Medical Communications, GSK, and many other biopharmaceutical companies. Her comments were made during the ASGE and AGA joint Presidential Plenary at the annual Digestive Disease Week.

Important new themes are whether we can actually find a cure for inflammatory bowel disease and, in particular, whether there are common pathogenetic mechanisms leading to Crohn’s disease and ulcerative colitis. Are Crohn’s and ulcerative colitis infectious diseases? If the answer to that question is ‘yes,’ then eliminating that “pathogen” would turn off the immune response. Crohn’s disease and ulcerative colitis share common genetic origins with the majority of genes shared between both disorders. Indeed, 110 of the 163 confirmed loci in IBD are common between the two disorders ⁽Nature 2012;491:119–24).

In addition to there being many genes contributing even a small amount to the development of IBD, there are also some genetic pathways that have a far more impactful role in IBD. By studying very-early-onset IBD, we have discovered that the IL-10 receptor pathway is very important in controlling intestinal inflammation, such that if you have a mutation in the receptor for IL-10 it can lead to very-early-onset IBD. Children who are born with these disorders can be treated with a hematopoietic bone marrow transplant. At this year’s Digestive Disease Week (DDW⁾ in fact, there was the presentation of the ASTIC trial; it described patients having a prolonged remission after an autologous hematopoietic stem cell transplant.

One of the big advances that has been made in terms of the treatment of IBD is based on an understanding of the pathogenetic pathways; in particular, there has been an increase in the number of medications that are currently available to treat IBD from a variety of different avenues. There was a recent publication describing an anti-sense treatment against SMAD7 in restoring TGF-beta signaling that produced a very rapid and profound improvement in the clinical symptoms of Crohn’s disease. We await more data on that particular compound.

We now know that an antibody against P40, which is the common subunit between IL-12 and IL-23, is effective in the treatment of Crohn’s disease and is commercially available as ustekinumab. At this year’s DDW we heard about an antibody that is specific for anti-IL-23 since it only antagonizes the P19 subunit of the cytokine; it also shows great promise for treating IBD. At DDW 2014, vedolizumab had just obtained approval for the treatment of ulcerative colitis and Crohn’s disease and that has been a big advance in treating patients. On its heels are a variety of other compounds that work by a similar mechanism by inhibiting the trafficking of effector lymphocytes to the intestine; these include anti-beta7 strategies and anti-MAdCAM. Both of these have been shown to be more effective in ulcerative colitis than in Crohn’s disease, as has been a common theme.

The other important presentation that took place at DDW 2015 is the use of ozanimod to treat ulcerative colitis; again, this is an oral agent that has a very dramatic effect in treating ulcerative colitis in a very short period of time by inhibiting the exit of effector T cells from lymph nodes. This tells us about the host immune response. We can now sequence all the bacteria that are present in the gut and using that approach we have found broad patterns of decreased diversity in patients who have IBD, although we have not identified a particular pathogen or pathogens.

The laboratory of Dr. Richard Flavell used a strategy in which they identified bacteria that were IgA coated and reasoned that IgA-coated bacteria were more likely to be pathogens (Cell. 2014 Aug 28;158(5):1000-1010). Indeed, by giving mice these IgA-coated bacteria found in IBD patients, the mice were more likely to develop colitis than if you gave non–IgA-coated bacteria to the same mice.

Another very important observation was in a study that was published in Nature, which demonstrated that emulsifiers really changed the relationship between the host and the microbiome. In particular, the investigators found that interactions with the microbiota led to metabolic syndrome. They also found that with dietary emulsifiers there is encroachment of the epithelium because of a thinning of the mucous layer and the study animals were more susceptible to developing colitis. I think that this is a sign to our patients that it is better to avoid processed foods.

Dr. Abreu is professor of medicine, professor of microbiology and immunology, chief of the division of gastroenterology, the Martin Kalser Chair in gastroenterology, and the director, Crohn’s & Colitis Center at the University of Miami Miller School of Medicine. She consults for AbbVie, Focus Medical Communications, GSK, and many other biopharmaceutical companies. Her comments were made during the ASGE and AGA joint Presidential Plenary at the annual Digestive Disease Week.