Conference Coverage

Microbiome – Impact on health and disease


 

The gut microbiota influences our biology through our mucosal immune system as well as by leading to the production of bioactive small molecules. I’ll describe how gut microbiota influences colon cancer, liver disease, the production of bioactive compounds, as well as the current status and future prospects of microbiota therapeutics.

Dr. Gary D. Wu, University of Pennsylvania, Philadelphia

Dr. Gary D. Wu

The gut microbiota may be a factor in colon cancer. Studies have shown that bacterial biofilms are associated with right-sided colon cancers in humans. More recently, a study has shown that mucosal biofilm formation is carcinogenic in an animal model, suggesting that such biofilms may play a role in the disease pathogenesis. From the standpoint of the liver, the microbiome may be a biomarker for diseases such as cirrhosis and fibrosis in patients with nonalcoholic steatohepatitis. Therapeutically, a recent study suggests that the function of gut microbiota can be altered by introducing an engineered Escherichia coli bacterial strain to treat hyperammonemia by modifying its metabolism to overproduce arginine, thereby sequestering ammonia produced by gut bacteria into the amino acids (Sci Transl Med. 2019 Jan 16;11[475]. doi: 10.1126/scitranslmed.aau7975). Drug metabolism also can be influenced by the gut microbiota and vice versa. For example, drugs such as metformin have effects on the composition of the gut microbiota in humans. In turn, the gut microbiota and its metabolites can have an influence on hepatic drug metabolism, thereby altering xenobiotic pharmacokinetics and pharmacodynamics.

The production of bioactive small molecules by bacterial metabolism is a topic of intense interest in the microbiome field. Such small molecules have been shown to act as antibiotics, neurotransmitters, immune modulators, and ligands for host receptors. Some of these small metabolites are generated through the dietary aromatic amino acids in which the bacterial enzymatic pathways are being elucidated. Such small molecules have a myriad of functions. For example, indole propionic acid, a bacterial metabolite of tryptophan, can activate the pregnane X receptor to fortify intestinal epithelial barrier function, a pathway that may have relevance to inflammatory bowel disease.

Probiotics that are found in dietary supplements represent our currently available strategy for the prevention and/or treatment of disease through the delivery of specific live microbes. However, there are limitations to their effectiveness since none have been approved for the prevention or treatment of any disease process. Via an intensive human subject study, (Cell. 2018 Sep 6;174[6]:1388-405) investigators have shown that the mucosally associated microbiota was a better biomarker for probiotic engraftment than stool was, where the response was very personalized. It’s possible that the personalized nature of probiotic engraftment may indicate that “one size may not fit all.” There will be a technical review and guideline document published by the American Gastroenterological Association early in 2020.

Currently, the only effective therapeutic modality for the treatment of a human disease by deeply altering the composition of the gut microbiota is the use of fecal microbiota transplantation (FMT) for the treatment of recurrent Clostridium difficile infection (CDI). However, there is now early evidence that FMT might have efficacy in the treatment of a disease other than recurrent CDI, namely ulcerative colitis. Although the short-term risks for FMT are low and quantifiable and long-term risks are largely hypothetical, there is a need for caution and regulation in the practice of FMT. Indeed, long-term engraftment of bacterial strains from the donor into the recipient has been demonstrated. Ultimately, as the science in the microbiota field moves forward together with product development, more sophisticated microbiota-based therapeutics will be generated. During this interim period, the AGA and partner national societies have developed an FMT National Registry to gather information on FMT practice, assess effectiveness as well as short- and long-term safety, and promote scientific investigation.

In conclusion, the field of gut microbiome research is very dynamic and exciting with tremendous opportunities at the intersection between fabulous science and technology, clinical practice, and federal regulation involving the practice of FMT, concurrent in a significant interest in intellectual property and business.

Dr. Wu is the Ferdinand G. Weisbrod Professor in Gastroenterology at the University of Pennsylvania, Philadelphia. He has received research funding from Seres Therapeutics, Intercept Pharmaceuticals, and Takeda; is on the scientific advisory board for Danone and Biocodex; and does consulting for Hitachi High-Technologies. Dr. Wu made these comments during the AGA Institute Presidential Plenary at the annual Digestive Disease Week®.

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