Association of Gut Microbiota and Metabolites With Disease Progression in Children With Biliary Atresia

Accumulating evidence implicates metabolites produced by gut microbes as crucial mediators of diet-induced host-microbial cross-talk. Here, we review emerging data suggesting that microbial tryptophan catabolites resulting from proteolysis are influencing host health. These metabolites are suggested to activate the immune system through binding to the aryl hydrocarbon receptor (AHR), enhance the intestinal epithelial barrier, stimulate gastrointestinal motility, as well as secretion of gut hormones, exert anti-inflammatory, anti-oxidative or toxic effects in systemic circulation, and putatively modulate gut microbial composition. Tryptophan catabolites thus affect various physiological processes and may contribute to intestinal and systemic homeostasis in health and disease.

Liver cirrhosis occurs as a consequence of many chronic liver diseases that are prevalent worldwide. Here we characterize the gut microbiome in liver cirrhosis by comparing 98 patients and 83 healthy control individuals. We build a reference gene set for the cohort containing 2.69 million genes, 36.1% of which are novel. Quantitative metagenomics reveals 75,245 genes that differ in abundance between the patients and healthy individuals (false discovery rate < 0.0001) and can be grouped into 66 clusters representing cognate bacterial species; 28 are enriched in patients and 38 in control individuals. Most (54%) of the patient-enriched, taxonomically assigned species are of buccal origin, suggesting an invasion of the gut from the mouth in liver cirrhosis. Biomarkers specific to liver cirrhosis at gene and function levels are revealed by a comparison with those for type 2 diabetes and inflammatory bowel disease. On the basis of only 15 biomarkers, a highly accurate patient discrimination index is created and validated on an independent cohort. Thus microbiota-targeted biomarkers may be a powerful tool for diagnosis of different diseases.

In the past decade, an exciting realization has been that diverse liver diseases, ranging from non-alcoholic steatohepatitis, alcoholic steatohepatitis, and cirrhosis, to hepatocellular carcinoma, are not unrelated but fall along a spectrum. Recent work on the biology of the gut-liver communication axis has assisted in understanding the basic biology of both alcoholic and nonalcoholic fatty liver disease. Of immense importance is the massive advancement in understanding of the role of the microbiome, driven by high-throughput DNA sequencing and improved computational techniques that allow the complexity of the microbiome to be interrogated, together with improved experimental designs. Here, we review the gut-liver communications of these various forms of liver disease, explore the molecular, genetic and microbiome relationships, discuss prospects for exploiting the microbiome to determine the stage of liver disease, and to predict the effects of pharmaceutical, dietary, and other interventions at a population and individual level. We conclude that although much remains to be done in understanding the relationship between the microbiome and liver disease, rapid progress towards clinical applications is being made, especially in study designs that complement human intervention studies with mechanistic work in mice that have been humanized in multiple respects, including the genetic, immunological and microbiome characteristics of individual patients. These “avatar mice” may be especially useful for guiding new microbiome-based or microbiome-informed therapies.