The gut-liver axis and gut microbiota in health and liver disease - PubMed (original) (raw)

Review

The gut-liver axis and gut microbiota in health and liver disease

Cynthia L Hsu et al. Nat Rev Microbiol. 2023 Nov.

Abstract

The trillions of microorganisms in the human intestine are important regulators of health, and disruptions in the gut microbial communities can cause disease. The gut, liver and immune system have a symbiotic relationship with these microorganisms. Environmental factors, such as high-fat diets and alcohol consumption, can disrupt and alter microbial communities. This dysbiosis can lead to dysfunction of the intestinal barrier, translocation of microbial components to the liver and development or progression of liver disease. Changes in metabolites produced by gut microorganisms can also contribute to liver disease. In this Review, we discuss the importance of the gut microbiota in maintenance of health and the alterations in microbial mediators that contribute to liver disease. We present strategies for modulation of the intestinal microbiota and/or their metabolites as potential treatments for liver disease.

PubMed Disclaimer

Conflict of interest statement

Competing interests

B.S. has been consulting for Ambys Medicines, Ferring Research Institute, Gelesis, HOST Therabiomics, Intercept Pharmaceuticals, Mabwell Therapeutics, Patara Pharmaceuticals and Takeda. B.S. is founder of Nterica Bio. UC San Diego has filed several patents with B.S. as inventor. B.S.’s institution UC San Diego has received research support from Artizan Biosciences, Axial Biotherapeutics, BiomX, CymaBay Therapeutics, NGM Biopharmaceuticals, Prodigy Biotech and Synlogic Operating Company. C.H. declares no competing interests.

Figures

Fig. 1.. The gut–liver axis.

The liver produces bile, which is composed of cholesterol, phospholipids, proteins, bicarbonate, and bile acids that have been conjugated by the liver to taurine or glycine (yellow box). Bile is directed into the proximal small intestine via the bile ducts, where it aids in lipid digestion and absorption. In the colon, gut bacteria convert primary bile acids into secondary bile acids via dihydroxylation, and eventually both primary and secondary bile acids are reabsorbed back into the liver via the portal circulation (blue box). The portal circulation also carries absorbed nutrients, lipids, microbial products such as lipopolisaccharide, and microbial metabolites such as short-chain fatty acids (SCFAs) back to the liver. Toxic metabolites such as acetaldehyde and inflammatory cytokines produced by the liver then continue into the systemic circulation (red box). IgA, immunoglobulin A; SCFAs, small-chain fatty acids; MAMPs, microbe-associated molecular patterns; VLDLs, very low-density lipoproteins; TMAO, trimethylamine N-oxide.

Fig. 2.. Barrier systems against translocation of microorganisms.

There are multiple layers of defense that prevent translocation of gut bacteria into the systemic circulation. The intestinal epithelium is the first interface, as it separates the bacteria in the gut lumen from the lamina propria below. A mucus layer (green), composed of mucins produced by goblet cells, separates the bacteria from the underlying intestinal epithelial cells. In the lamina propria (beige), whole bacteria that cross the intestinal epithelium are phagocytosed by macrophages and neutrophils. Plasma cells produce immunoglobulin A (IgA), which binds to pIgR, a receptor on enterocytes, for transport across the epithelium and secretion into the mucus layer, where this secretory IgA binds and neutralizes harmful pathobionts and pathogens. M cells in the intestinal epithelium relay microbial antigens to dendritic cells, which activate Type 3 innate lymphoid cells (ILC3) (via interleukin 23 (IL-23)) to produce interleukin 22 (IL-22). IL-22 ultimately signals Paneth cells and intestinal epithelial cells (IEC) to secrete antimicrobial molecules into the mucus layer. Short-chain fatty acids (SCFAs), produced by bacterial microbial degradation of fiber, are an energy source for enterocytes and enhance the antimicrobial activity of macrophages. Another physical barrier against bacterial translocation is the gut vascular barrier (inset box). Tight junctions and adherens junctions on endothelial cells regulate the permeability of the gut vascular barrier, allowing passage of nutrients and small molecules into the enteral circulation but restricting the passage of viable bacteria and microbial antigens. Finally, gut microorganisms that do translocate into the enteral circulation will face the liver barrier via the portal vein. In the liver, blood from the portal vein flows into the central vein via sinusoids (grey), which are lined with liver sinusoidal endothelial cells that release chemokines in response to microorganisms and microbial products. This creates a chemokine gradient that recruits Kupffer cells to the periportal zone, where they can neutralize translocated microorganims. LPS, lipopolysaccharide.

Fig. 3.. Gut microbiomes differ with etiology of liver disease.

Non-alcoholic liver disease and alcohol-associated liver disease are associated with different changes in the composition of bacteria, fungi, viruses, and metabolites in the gut. Liver disease progression to cirrhosis and subsequent hepatocarcinogenesis (development of hepatocellular carcinoma) are associated with further changes in the gut microbiome and metabolites. The red boxes represent bacteria, blue boxes metabolites, yellow boxes fungi, and grey boxes viruses.

Fig. 4.. Targeted approaches for treatment of liver disease.

Fecal microbiota transplantation (FMT) involves transplantation of the entire gut microbial community. More targeted treatment approaches include use of bacteriophages (phages) to target specific bacterial strains that produce toxic metabolites, genetically engineered bacteria to produce beneficial metabolites, and supplementation of beneficial microbially produced metabolites or postbiotics.

References

1. Mazagova M et al. Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB J 29, 1043–1055, doi:fj.14–259515 [pii] 10.1096/fj.14-259515 (2015). - DOI - PMC - PubMed
1. Henao-Mejia J et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185, doi: 10.1038/nature10809 nature10809 [pii] (2012). - DOI - PMC - PubMed
2. First paper to report transmissibility of experimental NASH into mice by fecal microbiota transplantion.
1. Llopis M et al. Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease. Gut 65, 830–839, doi:gutjnl-2015–310585 [pii] 10.1136/gutjnl-2015-310585 (2016). - DOI - PubMed
2. First paper to report transmissibility of experimental ALD in gnotobiotic mice.
1. Philips CA, Ahamed R, Rajesh S, Abduljaleel JKP & Augustine P Long-term Outcomes of Stool Transplant in Alcohol-associated Hepatitis-Analysis of Clinical Outcomes, Relapse, Gut Microbiota and Comparisons with Standard Care. J Clin Exp Hepatol 12, 1124–1132, doi: 10.1016/j.jceh.2022.01.001 (2022). - DOI - PMC - PubMed
1. Qin J et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65, doi: 10.1038/nature08821 nature08821 [pii] (2010). - DOI - PMC - PubMed

The gut-liver axis and gut microbiota in health and liver disease - PubMed (original) (raw)