User login
Antibiotic pretreatment may protect against liver ischemia/reperfusion (I/R) injury through altered gut microbiota, glutamine levels, and glutamine downstream products in circulation, according to a recent study in Cellular and Molecular Gastroenterology and Hepatology.
The findings show that , wrote Tianfei Lu, with the Abdominal Transplant Surgery Center at Ruijin Hospital and Shanghai Jiao Tong University, China, and colleagues.
“Potential therapies that target macrophage metabolism, including antibiotic therapies and novel immunometabolism modulators, can be exploited for the treatment of liver I/R injury,” the authors wrote.
Liver I/R injury is a common complication of liver resection, transplantation, trauma, and hemorrhagic shock. Previous studies have noted the important role of gut microbiota in liver disease progression, yet the mechanisms in liver I/R injury remain unknown.
The researchers pretreated mice with an antibiotic cocktail to modify the gut microbiome. They found that the pretreatment showed protective effects against hepatic I/R injury, with reductions in serum alanine aminotransferase (ALT), interleukin-1 beta, tumor necrosis factor–alpha, IL-6, IL-12b, and CXCL10.
Through histologic analysis of liver tissues, they also found that the area of necrosis, the degree of congestion and edema, and the presence of vacuole-like lesions were alleviated in the preconditioned mice. Inflammation and necrosis of the liver were also lower, according to both qualitative and quantitative data.
Then, through fecal microbiota transplantation into germ-free mice, they found that the protection from I/R injury was transferable. This finding indicated that the altered gut microbiome, rather than the antibiotic treatment itself, exerted the protective effect.
Because altered gut microbiota can cause changes in metabolites, the researchers used ultra-performance liquid chromatography coupled to tandem mass spectrometry to explore the changes of gut microbiota and metabolites in both feces and portal blood, as well as analyze the mechanisms underlying their protective effects in liver I/R injury.
The researchers found that glutamine and its downstream product called alpha-ketoglutarate (AKG) were present in higher concentrations in feces and blood in the mice with antibiotic pretreatment. Glutamate levels were significantly lower, indicating that glutamine is converted into AKG through glutamate after entering the blood.
In addition, there were increased levels of intermediate products of the tricarboxylic acid (TCA) cycle, as well as pyruvate produced by glycolysis. That led to an increase in M2 macrophages, which are responsible for anti-inflammatory processes and tissue repair.
The authors concluded that elevated glutamine levels in the intestine cause an increase in AKG levels in the blood, and AKG can promote M2 macrophage polarization by fueling the TCA cycle. In turn, the increased number of M2 macrophages can repair hepatic I/R injury.
Finally, the researchers tested oligomycin A, which can block the OXPHOS metabolic pathway and inhibit the mitochondrial ATP synthase. As expected, they wrote, the protective effect of antibiotic pretreatment reversed, M2 macrophages decreased, and serum ALT levels increased.
“The immunometabolism and polarization of macrophages play an important role in host homeostasis and the development of various diseases,” the authors wrote. “The relationship between antibiotics treatment, altered gut microbiota, and liver I/R injury are complex and worthy of further study.”
The study was supported by the China National Science and Technology Major Project, National Natural Science Foundation of China, and Natural Science Foundation exploration project of Zhejiang Province. The authors disclosed no conflicts.
In modern clinical practice, multiple conditions can cause ischemia and reperfusion injury to the liver, including surgical liver resection, liver transplantation, and physical trauma to the organ. Liver damage due to hypoxia is followed by reperfusion injury, resulting in a pre-proinflammatory environment. Liver resident macrophages called Kupffer cells are major mediators of this response, initiating a signaling cascade that leads to recruitment of neutrophils, natural killer cells, and circulating macrophages, which attack sinusoidal endothelial cells and hepatocytes.
In the current issue of CMGH, Lu and colleagues address the question of to what extent do the gut microbiome and its metabolite products, which reach the liver via the portal circulation, play a role in the severity of ischemia and reperfusion injury (Cell Mol Gastroenterol Hepatol. 2023 Jan 24. doi: 10.1016/j.jcmgh.2023.01.004). This topic is of clinical relevance, as the microbial load of the gut lumen can be easily reduced by several orders of magnitude using non-absorbed antibiotics. Thus, it is important to establish if pretreatment of patients scheduled for liver resection or transplantation might benefit from preprocedure antibiotic treatment.
Remarkably, Lu and colleagues find that antibiotic preconditioning significantly reduces ischemia and reperfusion injury in an animal model. Mechanistically, they linked the protective effects to a shift of macrophage polarization to the protective M phenotype, which is known to promote tissue repair. These findings suggest that the antibiotic preconditioning of patients who are undergoing procedures with significant ischemia and reperfusion injury should be evaluated in future clinical trials.
Klaus H. Kaestner, PhD, MS, is the Thomas and Evelyn Suor Butterworth Professor in Genetics and associate director of the Penn Diabetes Research Center at the University of Pennsylvania, Philadelphia. He has no relevant financial relationships.
In modern clinical practice, multiple conditions can cause ischemia and reperfusion injury to the liver, including surgical liver resection, liver transplantation, and physical trauma to the organ. Liver damage due to hypoxia is followed by reperfusion injury, resulting in a pre-proinflammatory environment. Liver resident macrophages called Kupffer cells are major mediators of this response, initiating a signaling cascade that leads to recruitment of neutrophils, natural killer cells, and circulating macrophages, which attack sinusoidal endothelial cells and hepatocytes.
In the current issue of CMGH, Lu and colleagues address the question of to what extent do the gut microbiome and its metabolite products, which reach the liver via the portal circulation, play a role in the severity of ischemia and reperfusion injury (Cell Mol Gastroenterol Hepatol. 2023 Jan 24. doi: 10.1016/j.jcmgh.2023.01.004). This topic is of clinical relevance, as the microbial load of the gut lumen can be easily reduced by several orders of magnitude using non-absorbed antibiotics. Thus, it is important to establish if pretreatment of patients scheduled for liver resection or transplantation might benefit from preprocedure antibiotic treatment.
Remarkably, Lu and colleagues find that antibiotic preconditioning significantly reduces ischemia and reperfusion injury in an animal model. Mechanistically, they linked the protective effects to a shift of macrophage polarization to the protective M phenotype, which is known to promote tissue repair. These findings suggest that the antibiotic preconditioning of patients who are undergoing procedures with significant ischemia and reperfusion injury should be evaluated in future clinical trials.
Klaus H. Kaestner, PhD, MS, is the Thomas and Evelyn Suor Butterworth Professor in Genetics and associate director of the Penn Diabetes Research Center at the University of Pennsylvania, Philadelphia. He has no relevant financial relationships.
In modern clinical practice, multiple conditions can cause ischemia and reperfusion injury to the liver, including surgical liver resection, liver transplantation, and physical trauma to the organ. Liver damage due to hypoxia is followed by reperfusion injury, resulting in a pre-proinflammatory environment. Liver resident macrophages called Kupffer cells are major mediators of this response, initiating a signaling cascade that leads to recruitment of neutrophils, natural killer cells, and circulating macrophages, which attack sinusoidal endothelial cells and hepatocytes.
In the current issue of CMGH, Lu and colleagues address the question of to what extent do the gut microbiome and its metabolite products, which reach the liver via the portal circulation, play a role in the severity of ischemia and reperfusion injury (Cell Mol Gastroenterol Hepatol. 2023 Jan 24. doi: 10.1016/j.jcmgh.2023.01.004). This topic is of clinical relevance, as the microbial load of the gut lumen can be easily reduced by several orders of magnitude using non-absorbed antibiotics. Thus, it is important to establish if pretreatment of patients scheduled for liver resection or transplantation might benefit from preprocedure antibiotic treatment.
Remarkably, Lu and colleagues find that antibiotic preconditioning significantly reduces ischemia and reperfusion injury in an animal model. Mechanistically, they linked the protective effects to a shift of macrophage polarization to the protective M phenotype, which is known to promote tissue repair. These findings suggest that the antibiotic preconditioning of patients who are undergoing procedures with significant ischemia and reperfusion injury should be evaluated in future clinical trials.
Klaus H. Kaestner, PhD, MS, is the Thomas and Evelyn Suor Butterworth Professor in Genetics and associate director of the Penn Diabetes Research Center at the University of Pennsylvania, Philadelphia. He has no relevant financial relationships.
Antibiotic pretreatment may protect against liver ischemia/reperfusion (I/R) injury through altered gut microbiota, glutamine levels, and glutamine downstream products in circulation, according to a recent study in Cellular and Molecular Gastroenterology and Hepatology.
The findings show that , wrote Tianfei Lu, with the Abdominal Transplant Surgery Center at Ruijin Hospital and Shanghai Jiao Tong University, China, and colleagues.
“Potential therapies that target macrophage metabolism, including antibiotic therapies and novel immunometabolism modulators, can be exploited for the treatment of liver I/R injury,” the authors wrote.
Liver I/R injury is a common complication of liver resection, transplantation, trauma, and hemorrhagic shock. Previous studies have noted the important role of gut microbiota in liver disease progression, yet the mechanisms in liver I/R injury remain unknown.
The researchers pretreated mice with an antibiotic cocktail to modify the gut microbiome. They found that the pretreatment showed protective effects against hepatic I/R injury, with reductions in serum alanine aminotransferase (ALT), interleukin-1 beta, tumor necrosis factor–alpha, IL-6, IL-12b, and CXCL10.
Through histologic analysis of liver tissues, they also found that the area of necrosis, the degree of congestion and edema, and the presence of vacuole-like lesions were alleviated in the preconditioned mice. Inflammation and necrosis of the liver were also lower, according to both qualitative and quantitative data.
Then, through fecal microbiota transplantation into germ-free mice, they found that the protection from I/R injury was transferable. This finding indicated that the altered gut microbiome, rather than the antibiotic treatment itself, exerted the protective effect.
Because altered gut microbiota can cause changes in metabolites, the researchers used ultra-performance liquid chromatography coupled to tandem mass spectrometry to explore the changes of gut microbiota and metabolites in both feces and portal blood, as well as analyze the mechanisms underlying their protective effects in liver I/R injury.
The researchers found that glutamine and its downstream product called alpha-ketoglutarate (AKG) were present in higher concentrations in feces and blood in the mice with antibiotic pretreatment. Glutamate levels were significantly lower, indicating that glutamine is converted into AKG through glutamate after entering the blood.
In addition, there were increased levels of intermediate products of the tricarboxylic acid (TCA) cycle, as well as pyruvate produced by glycolysis. That led to an increase in M2 macrophages, which are responsible for anti-inflammatory processes and tissue repair.
The authors concluded that elevated glutamine levels in the intestine cause an increase in AKG levels in the blood, and AKG can promote M2 macrophage polarization by fueling the TCA cycle. In turn, the increased number of M2 macrophages can repair hepatic I/R injury.
Finally, the researchers tested oligomycin A, which can block the OXPHOS metabolic pathway and inhibit the mitochondrial ATP synthase. As expected, they wrote, the protective effect of antibiotic pretreatment reversed, M2 macrophages decreased, and serum ALT levels increased.
“The immunometabolism and polarization of macrophages play an important role in host homeostasis and the development of various diseases,” the authors wrote. “The relationship between antibiotics treatment, altered gut microbiota, and liver I/R injury are complex and worthy of further study.”
The study was supported by the China National Science and Technology Major Project, National Natural Science Foundation of China, and Natural Science Foundation exploration project of Zhejiang Province. The authors disclosed no conflicts.
Antibiotic pretreatment may protect against liver ischemia/reperfusion (I/R) injury through altered gut microbiota, glutamine levels, and glutamine downstream products in circulation, according to a recent study in Cellular and Molecular Gastroenterology and Hepatology.
The findings show that , wrote Tianfei Lu, with the Abdominal Transplant Surgery Center at Ruijin Hospital and Shanghai Jiao Tong University, China, and colleagues.
“Potential therapies that target macrophage metabolism, including antibiotic therapies and novel immunometabolism modulators, can be exploited for the treatment of liver I/R injury,” the authors wrote.
Liver I/R injury is a common complication of liver resection, transplantation, trauma, and hemorrhagic shock. Previous studies have noted the important role of gut microbiota in liver disease progression, yet the mechanisms in liver I/R injury remain unknown.
The researchers pretreated mice with an antibiotic cocktail to modify the gut microbiome. They found that the pretreatment showed protective effects against hepatic I/R injury, with reductions in serum alanine aminotransferase (ALT), interleukin-1 beta, tumor necrosis factor–alpha, IL-6, IL-12b, and CXCL10.
Through histologic analysis of liver tissues, they also found that the area of necrosis, the degree of congestion and edema, and the presence of vacuole-like lesions were alleviated in the preconditioned mice. Inflammation and necrosis of the liver were also lower, according to both qualitative and quantitative data.
Then, through fecal microbiota transplantation into germ-free mice, they found that the protection from I/R injury was transferable. This finding indicated that the altered gut microbiome, rather than the antibiotic treatment itself, exerted the protective effect.
Because altered gut microbiota can cause changes in metabolites, the researchers used ultra-performance liquid chromatography coupled to tandem mass spectrometry to explore the changes of gut microbiota and metabolites in both feces and portal blood, as well as analyze the mechanisms underlying their protective effects in liver I/R injury.
The researchers found that glutamine and its downstream product called alpha-ketoglutarate (AKG) were present in higher concentrations in feces and blood in the mice with antibiotic pretreatment. Glutamate levels were significantly lower, indicating that glutamine is converted into AKG through glutamate after entering the blood.
In addition, there were increased levels of intermediate products of the tricarboxylic acid (TCA) cycle, as well as pyruvate produced by glycolysis. That led to an increase in M2 macrophages, which are responsible for anti-inflammatory processes and tissue repair.
The authors concluded that elevated glutamine levels in the intestine cause an increase in AKG levels in the blood, and AKG can promote M2 macrophage polarization by fueling the TCA cycle. In turn, the increased number of M2 macrophages can repair hepatic I/R injury.
Finally, the researchers tested oligomycin A, which can block the OXPHOS metabolic pathway and inhibit the mitochondrial ATP synthase. As expected, they wrote, the protective effect of antibiotic pretreatment reversed, M2 macrophages decreased, and serum ALT levels increased.
“The immunometabolism and polarization of macrophages play an important role in host homeostasis and the development of various diseases,” the authors wrote. “The relationship between antibiotics treatment, altered gut microbiota, and liver I/R injury are complex and worthy of further study.”
The study was supported by the China National Science and Technology Major Project, National Natural Science Foundation of China, and Natural Science Foundation exploration project of Zhejiang Province. The authors disclosed no conflicts.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY