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

Treatments for NAFLD That Target gut Microbiota

Historically, the mainstay of treatment for patients with NAFLD has been lifestyle modification (eg, diet, exercise and weight loss) and the correction of underlying risk factors (eg, tight control of T2DM).[108] Most pharmacologic treatments for NAFLD are designed to improve insulin sensitivity (eg, metformin, thiazolidinediones liraglutide and sitagliptin), reduce oxidative stress (vitamin E, ursodeoxycholic acid and pentoxifylline) or downregulate fibrosis mechanisms (angiotensin receptor blockers).[125] Unfortunately, these medications have not demonstrated consistent improvement in liver fibrosis.[125–127] Alternatively, data are accumulating on the potential role of therapies that alter gut microbiota in the treatment of patients with NAFLD and NASH.

Prebiotics

Prebiotics are indigestible foods that promote the growth of beneficial GI bacteria through the fermentation of the prebiotic into SCFA.[128] Preclinical studies of prebiotics have shown improvement in biochemical and histologic markers of NAFLD.[129] One randomised trial (placebo crossover design) has been published to date.[130] In patients with biopsy-proven NASH (n = 7), prebiotic administration (ie, oligofructose 16 g/d) significantly reduced hepatic levels of aspartate aminotransferase (AST; P < 0.05 vs placebo) and nonsignificantly decreased TG concentrations compared with placebo after 8 weeks of treatment. However, a systematic review that included four clinical studies of patients with obesity-related NAFLD did not support the use of prebiotics, due to a lack of study quality.[131]

Probiotics

Probiotics are living microorganisms that are ingested and improve the mucosal integrity of the GI tract through alteration of the gut microbiota (via competitive colonisation and by acidification of the GI lumen).[128] To date, six double-blind, randomised controlled trials,[132–137] one open-label, randomised controlled trial[138] and one open-label, single-treatment trial[139] have examined the effect of probiotics in patients with NAFLD (Table 1). The studies have reported improvement in several biochemical markers (eg, alanine aminotransferase [ALT], AST and TNF-α). A systematic review that included three clinical studies examining the efficacy of probiotics in patients with NAFLD did not support their use in this patient population, due to a lack of high-quality studies.[131]

Unfortunately, few studies have examined the effect of probiotics on histologic markers of NAFLD and NASH. In a 2013 meta-analysis of randomised controlled trials, only four studies were available when patient inclusion was limited to those with histologically or radiologically diagnosed NAFLD.[140] However, Alisi et al[133] reported that obese children with histologically diagnosed NAFLD who received sachets of eight probiotic strains daily for 4 months (n = 22) had a significantly lower risk of "more severe" steatosis (vs "less severe" steatosis) compared with children who received placebo (n = 22).

Synbiotics

Synbiotics (or symbiotics) are a combination of both a prebiotic and a probiotic, and represent an emerging area of therapeutic research in NAFLD. Malaguarnera et al[141] evaluated 66 patients with histologically diagnosed NASH who were randomly assigned to receive 24 weeks of a synbiotic (Bifidobacterium longum plus a prebiotic [fructooligosaccharides]) or placebo. Both groups underwent lifestyle modification and a B vitamin regimen. Compared with the placebo arm, the active treatment arm had significantly lower TNF-α and C-reactive protein (CRP) levels, as well as histologic improvement (decreased hepatocellular injury, inflammation and steatosis) after treatment (P < 0.05).

In the largest double-blind, placebo-controlled trial to date, 80 patients with ultrasound-diagnosed NAFLD were randomly assigned to receive either a synbiotic (probiotics [Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus bulgaricus, Bifidobacterium breve, B longum and Streptococcus thermophilus] and fructooligosaccharides) or placebo for 8 weeks. At the end of the intervention period, patients who received synbiotics had significantly reduced steatosis (as measured by ultrasound) vs baseline, whereas no significant improvement was observed in patients who received placebo.[142] No significant differences in CRP, ALT or AST levels were observed between groups (adjusted for energy intake). In contrast, a study of 50 lean patients (ie, low or normal body mass index [BMI]) with NAFLD (patients had steatosis and elevated ALT) demonstrated significant reductions in fibrosis and hepatic steatosis, fasting blood sugar, TG levels and markers of inflammation after 28 weeks of synbiotic supplementation compared with placebo (P < 0.05).[143]

Antibiotics

Several small trials, mostly in animal models, have analysed the effect of antibiotics on NAFLD. The mechanism of action for antibiotics is multifactorial and may include alterations in the gut microbiota composition, bacterial virulence and/or bacterial metabolic function,[128] although the specific pathway differs with each antibiotic. In a murine model, improvement in NAFLD was observed after the administration of an antibiotic cocktail (bacitracin, neomycin and streptomycin).[115] This improvement was hypothesised to be the result of alterations in gut microbiota and BA metabolism and reductions in intestinal FXR signalling, serum ceramides and fatty acid synthesis. Reduced levels of bile salt hydrolase, a bacterial enzyme that metabolises the BA, result in the retention of tauro-beta-muricholic acid in the ileum, which then inhibits FXR signalling within the intestinal wall, leading to decreased ceramide production.[115] Decreased ceramide production causes hepatic SREBP1C inhibition and decreased hepatic fatty acid accumulation. These findings were replicated in a rat study that showed alterations in the tissue BA profile, steroid biosynthesis and FXR signalling pathways after streptomycin and penicillin administration.[144] As in the previous study, elevated levels of tauro-beta-muricholic acid were observed, although this time in the liver.

Several human studies of antibiotics in NAFLD have assessed the effect of rifaximin, a nonsystemic antibiotic (Table 2).[145–147] Rifaximin is currently indicated in the United States to prevent overt hepatic encephalopathy recurrence and to treat travellers' diarrhoea and irritable bowel syndrome (IBS) with diarrhoea.[148,149] Although one may hypothesise that rifaximin exerts its effect by altering the composition of the gut microbiota, data have shown only modest changes in the components of the gut microbiome in patients with cirrhosis and hepatic encephalopathy after rifaximin treatment.[150] Additionally, preclinical studies have indicated that the efficacy of rifaximin may be attributable to its beneficial effects on host cell physiology and bacterial gene expression.[151–153]

Faecal Transplantation

Faecal transplantation has been used successfully in the treatment of patients with refractory and recurrent Clostridium difficile.[154,155] Although no human studies have examined the role of faecal transplantation for NAFLD, this strategy may be a potential avenue for exploration. In mouse models of NAFLD, animals that underwent a faecal transplantation from wild-type mice donors showed decreased hepatic gluconeogenesis[156] and reduced intestinal permeability[157] (Table 3). However, faecal transplantation is not without risks. For example, a 2015 case report documented that a previously lean patient with recurrent C difficile infection developed obesity after a faecal transplant from an obese donor.[158]

Both murine knockout studies[85,86] and population-based studies[19,88] have examined alterations in gut microbiota in both NAFLD/NASH and in non-NAFLD subjects with risk factors for NAFLD. In the murine model, faecal transplantation from human obese adult twins into germ-free lean mice resulted in the development of obesity in these mice,[159] indicating that dysbiosis may lead to the development of obesity even in the absence of poor diet or genetic predisposition.

Studies in humans indicate that even in healthy individuals who donate stool for a faecal microbiota transplant (FMT), faeces from a select few patients (called "super donors") may yield more FMT success than stool obtained from other healthy donors.[160,161] FMTs have been studied in the setting of C. difficile infection[162] and in chronic illnesses, such as IBD,[160,161] IBS,[163] constipation[164] and neurologic conditions.[165] Two separate studies assessing the efficacy of FMT in the treatment of IBD found that patients who had received stool transplants from a particular donor had a higher success rate in inducing clinical and endoscopic remission compared with patients who did not receive stool from the "super donors."[160,161] FMTs using stool obtained from lean donors transplanted into patients with metabolic syndrome led to a greater degree of improvement in peripheral insulin sensitivity compared with autologous FMT.[166,167] Thus far, the only factor that seems to predict a successful FMT is the diversity of gut microbiota in the donor; conversely, recipients who are able to increase their faecal microbiome diversity to a higher degree in response to FMT were more likely to have successful outcomes in treatment of the underlying disease.[168,169]

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