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 Gut Microbiome in Maintaining Homeostasis

Progressing along the human GI tract from the jejunum to the colon, the number and the diversity of bacteria increases,[27] and the predominant bacterial species change. In the upper GI tract (oesophagus and proximal small bowel), Streptococcus species predominate,[28,29] whereas in the colon, Firmicutes and Bacteroidetes are most prevalent.[20,21,30–32] These locational alterations likely reflect the overall functionality of the dominant species (eg, Firmicutes and Bacteroidetes convert dietary complex carbohydrates and insoluble oligosaccharides to short-chain fatty acids [SCFAs], which can be absorbed by the host within the intestines).[33]

The interconnection between the gut microbiome and the host is complex. The host provides both a suitable environment and nutrients for bacterial growth, and the host's diet, disease states and medications affect gut bacteria.[33] The gut microbiota can, in turn, affect host nutrient and drug metabolism, contribute to maintaining the mucosal barrier of the GI tract, affect mucosal immunity and contribute to disease states.[34] Bacteria in the GI tract synthesise host nutrients, such as vitamins and amino acids and conjugate primary bile acids (BAs) to form secondary BAs, such as deoxycholic acid and lithocholic acids.[35,36] The gut microbiota themselves derive sustenance mainly through the fermentation of dietary complex carbohydrates and indigestible oligosaccharides ingested by the host. Bacterial metabolism of these complex carbohydrates produces SCFAs (eg, butyrate, propionate and acetate), which the host can subsequently use as an energy source.[34,37,38] A study of 15 healthy women given diets with varying levels of choline for 2 months found that the composition of the gut microbiome assessed by pyrosequencing of 16S ribosomal RNA bacterial genes in stool samples was altered from baseline with varying levels of dietary choline.[39] Choline depletion was associated both with variations in the levels of Gammaproteobacteria and Erysipelotrichia and variations in amount of liver fat.[39] The investigators hypothesised that the tendency to develop hepatic steatosis with a choline-deficient diet could be predicted by a model based on bacterial levels, presence of a single nucleotide polymorphism affecting choline metabolism and change in hepatic steatosis.[39]

Alterations in either the number or function of the tight junctions found on the GI epithelium can result in increased intestinal permeability, allowing for passage of antigens and microbes into systemic circulation. A growing body of research indicates that BA metabolism via epidermal growth factor signalling may affect these tight junctions.[40,41] Deoxycholic acid and chenodeoxycholic acid have been shown to interact with and phosphorylate the endothelial growth factor receptor, ultimately resulting in tight junction rearrangement (through alterations in occludin, a structural protein found in tight junctions) and increased paracellular permeability.[41] Interestingly, lithocholic acid has been shown to increase the integrity of tight junctions and to attenuate the production of reactive oxygen species, tumour necrosis factor alpha (TNF-α), interleukin-1β and interferon-γ.[42]

Gut microbiota play a key immunomodulatory role, interacting closely with macrophages, dendritic cells, gut-associated lymphoid tissues, B cells and T cells.[43] For example, a healthy gut microbiome is integral to the proper development and function of T regulatory cells through a variety of cellular signalling mechanisms,[44–47] such as Clostridium butyricuminducing transforming growth factor-β1 expression via toll-like receptor (TLR)-2 activation.[48] Bacteria in the GI tract also participate in maintaining intestinal villous function[34] and preventing intestinal epithelial cell apoptosis.[49] In addition, alteration of the gut microbiota appears to have a role in intestinal disease (eg, inflammatory bowel disease [IBD][50,51]) and extraintestinal disease (eg, obesity,[52,53] diabetes[43,52,53] and chronic liver disease[54,55]). Furthermore, accumulating evidence supporting the role of the gut microbiota in drug metabolism (and corresponding effects on efficacy or adverse events) suggests that assessing microbiome activity could impact pharmaceutical drug development.[56,57]

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