Review Article

Emerging Role of the Gut Microbiome in the Progression of Nonalcoholic Fatty Liver Disease and Potential Therapeutic Implications

Saumya Jayakumar; Rohit Loomba

Disclosures

Aliment Pharmacol Ther. 2019;50(2):144-158. 

In This Article

Role of the gut Microbiome in Differentiating NAFL From NASH and Advanced Fibrosis

Although animal studies have linked gut dysbiosis to the severity of hepatic inflammation and/or fibrosis, the findings of preclinical studies do not necessarily translate to humans; however, few human studies have examined this connection in the NAFLD setting.[110,111] In a study comparing the gut microbiomes of 50 patients (healthy controls, patients with NAFL/simple steatosis and patients with NASH), patients with NASH had lower levels of Bacteroidetes and higher levels of Clostridium coccoides compared with both healthy controls and patients with NAFL (P < 0.05).[110] In another study, examining the taxonomic composition of gut microbiota using 16S ribosomal RNA gene sequencing with stool samples from 57 patients with biopsy-proven NAFLD, 30 patients had F0/1 fibrosis stage disease and 27 patients had advanced fibrosis (defined as ≥ F2 fibrosis stage).[111] Ten patients with F0/1 stage and 25 patients with ≥ F2 stage had NASH. Patients with NASH had higher levels of Bacteroides and a lower abundance of Prevotella compared with patients without NASH. In comparison to patients with F0/1 fibrosis stage, patients with advanced fibrosis (≥F2 fibrosis stage) had increased levels of Bacteroides and Ruminococcus and lower levels of Prevotella. A multivariate analysis revealed that NASH was associated with increased Bacteroides, whereas findings of increased Ruminococcus were associated with advanced fibrosis.

Loomba et al[19] characterised the gut microbiome of patients with biopsy-proven NAFLD using whole-genome shotgun sequencing for stool samples. Of 86 patients in the study, 72 had early fibrosis (F0/2) and the remaining 14 patients had F3/4 fibrosis. The median abundance for species in patients with early fibrosis was 2.5% Eubacterium rectale and 1.7% Bacteroides vulgatus, while E coli (1.0%) and B vulgatus (2.2% were predominant in patients with advanced fibrosis. Interestingly, a statistically significant increase in Proteobacteria levels was apparent as patients progressed to advanced fibrosis. Given that the increase in E coli levels preceded any clinical measures of fibrosis, they postulated that dysbiosis precedes the development of portal hypertension. However, larger studies are needed to determine if this finding is simply a correlation, or if a causal association is possible.

Exposure of liver Kupffer cells to bacterial LPS results in a release of proinflammatory cytokines through activating pathways that involve TLRs, myeloid differentiation factor 88 and NFκB,[100,112,113] which may activate stellate cells and fibrogenesis. These factors are integral in the promotion of inflammation and the progression of fibrosis to cirrhosis in many diseases, such as viral hepatitis, biliary liver disease and NAFLD.[112,114] In addition, a case-control/cross-sectional study has shown that trimethylamine-N-oxide, the liver product of a bacterial metabolite of choline, is associated with hepatic steatosis and inflammation.[87]

Neither of these studies had any subgroup analysis of patients with and without insulin resistance or other confounding variables that may also affect gut microbiota.[19,110,111] However, there may be a future role for the gut microbiome to be used as a non-invasive marker to determine the presence of NASH and advanced fibrosis. However, further studies, with larger cohorts, are needed before this marker can be recommended for diagnosis and prognosis of NASH. Thus, while additional studies are warranted to validate the promise of gut microbial profiling, the gut microbiome in these patient populations may one day serve as an emerging tool for non-invasive diagnosis of disease severity and monitoring progression.

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