The gut microbiome and liver cancer: mechanisms and clinical translation

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Abstract

Increasing evidence suggests that the gut microbiota are important modulators of chronic liver disease progression and the development of hepatocellular carcinoma. In this Review, Yu and Schwabe discuss the mechanisms by which the gut microbiota promote hepatocarcinogenesis, and explore therapeutic interventions with clinical potential.

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Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.

Seth Rakoff-Nahoum, Justin Paglino, Fatima Eslami-Varzaneh … (2004)

Toll-like receptors (TLRs) play a crucial role in host defense against microbial infection. The microbial ligands recognized by TLRs are not unique to pathogens, however, and are produced by both pathogenic and commensal microorganisms. It is thought that an inflammatory response to commensal bacteria is avoided due to sequestration of microflora by surface epithelia. Here, we show that commensal bacteria are recognized by TLRs under normal steady-state conditions, and this interaction plays a crucial role in the maintenance of intestinal epithelial homeostasis. Furthermore, we find that activation of TLRs by commensal microflora is critical for the protection against gut injury and associated mortality. These findings reveal a novel function of TLRs-control of intestinal epithelial homeostasis and protection from injury-and provide a new perspective on the evolution of host-microbial interactions.

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The role of the gut microbiota in NAFLD.

Christopher Leung, Leni R Rivera, John Furness … (2016)

NAFLD is now the most common cause of liver disease in Western countries. This Review explores the links between NAFLD, the metabolic syndrome, dysbiosis, poor diet and gut health. Animal studies in which the gut microbiota are manipulated, and observational studies in patients with NAFLD, have provided considerable evidence that dysbiosis contributes to the pathogenesis of NAFLD. Dysbiosis increases gut permeability to bacterial products and increases hepatic exposure to injurious substances that increase hepatic inflammation and fibrosis. Dysbiosis, combined with poor diet, also changes luminal metabolism of food substrates, such as increased production of certain short-chain fatty acids and alcohol, and depletion of choline. Changes to the microbiome can also cause dysmotility, gut inflammation and other immunological changes in the gut that might contribute to liver injury. Evidence also suggests that certain food components and lifestyle factors, which are known to influence the severity of NAFLD, do so at least in part by changing the gut microbiota. Improved methods of analysis of the gut microbiome, and greater understanding of interactions between dysbiosis, diet, environmental factors and their effects on the gut-liver axis should improve the treatment of this common liver disease and its associated disorders.

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Gut microbiota profiling of pediatric NAFLD and obese patients unveiled by an integrated meta-omics based approach.

Federica Del Chierico, Valerio Nobili, Pamela Vernocchi … (2017)

There is evidence that non-alcoholic fatty liver disease (NAFLD) is affected by gut microbiota. Therefore, we investigated its modifications in paediatric NAFLD patients using targeted-metagenomics (MG) and metabolomics (MB). Stools were collected from 61 consecutive patients diagnosed with NAFL, NASH, or obesity and 54 healthy subjects (CTRLs), matched in a case-control fashion. Operational taxonomic units were pyrosequenced targeting 16S ribosomal RNA and volatile organic compounds (VOCs) determined by solid-phase micro-extraction GC-MS. The α-diversity was highest in CTRLs followed by obese, NASH, NAFL patients and β-diversity distinguished between patients and CTRLs, but not NAFL and NASH. Compared to CTRLs, in NAFLD patients Actinobacteria were significantly increased and Bacteroidetes reduced. There were no significant differences amongst NAFL, NASH, and obese groups. Overall NAFLD patients had increased levels of Bradyrhizobium, Anaerococcus, Peptoniphilus, Propionibacterium acnes, Dorea, Ruminococcus and reduced proportions of Oscillospira and Rikenellaceae compared to CTRLs. After reducing MG and MB data dimensionality, multivariate analyses indicated Oscillospira decrease in NAFL and NASH groups, and Ruminococcus, Blautia, and Dorea increase in NASH patients compared to CTRLs. Of the 292 VOCs, 26 were up- and 2 down-regulated in NAFLD patients. Multivariate analyses found that combination of Oscillospira, Rickenellaceae, Parabacteroides, Bacteroides fragilis, Sutterella, Lachnospiraceae, 4-methyl-2-pentanone, 1-butanol, and 2-butanone could discriminate NAFLD patients from CTRLs. Univariate analyses found significantly lower levels of Oscillospira and higher levels of 1-pentanol and 2-butanone in NAFL compared to CTRLs. In NASH, lower levels of Oscillospira were associated with higher abundance of Dorea, Ruminococcus and higher levels of 2-butanone, 4-methyl-2-pentanone compared to CTRLs.