NASH and the Gut Microbiome: Implications for New Therapies

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Nonalcoholic steatohepatitis (NASH) is an intermediary between nonalcoholic fatty liver disease (NAFLD) and cirrhosis. With the ongoing obesity epidemic and the accompanying metabolic syndrome, the global incidence and prevalence of NAFLD and NASH has been increasing. ¹ Therapeutic options for biopsy‐proven NASH are limited primarily to medical, endoscopic, and surgical weight loss, as well as NASH‐directed pharmacotherapy, such as vitamin E and pioglitazone. ¹ , ² , ³ The gut microbiome has emerged as an area of interest, with recent studies suggesting that disruptions in intestinal microbiota may contribute to the pathogenesis of inflammation‐mediated disorders such as obesity and inflammatory bowel disease. ⁴ , ⁵ , ⁶ , ⁷ , ⁸ Emerging data additionally suggest a potential causal relationship between changes in gut microbiota and NAFLD/NASH, although are primarily limited to animal studies. This review aims to summarize current evidence to support this relationship and discuss potential targets for novel NASH therapy.

Gut Microbiome and NASH

Altered gut epithelial permeability, choline metabolism, proinflammatory cytokines, gut microbiome dysbiosis, endogenous alcohol production, alterations in bile acid metabolism, and upregulation of hepatic toll‐like receptors (TLR) are among the proposed mechanisms in the bidirectional microbiome‐gut‐liver axis leading to the progression of NAFLD to NASH ⁴ , ⁵ , ⁹ , ¹⁰ (Fig. 1). Increased intestinal permeability may lead to bacterial translocation and upregulation of proinflammatory cytokines. Further inflammation and gut‐derived lipopolysaccharides (LPS) and endotoxins lead to gut microbiota dysregulation. ⁹ Studies have identified dysbiosis, specifically an abundance of Prevotella in NASH and obese patients. In a pediatric study, the composition of the microbiome in patients with NASH compared with obese and healthy patients was notable for increased Escherichia, which is the genus of ethanol producing bacteria. ¹¹ Other studies have also demonstrated an increase in ethanol levels in patients with NASH compared to obese individuals. The sustained presence of ethanol derived from gut bacteria may represent a source of reactive oxygen species increasing hepatic inflammation. ¹¹ Similarly, bacterial products lead to activation of TLRs, which cause inflammation and progression of NAFLD to NASH and subsequent fibrosis. ¹² , ¹³ Therefore, these proposed pathogenic mechanisms linking inflammation secondary to dysbiosis of the gut microbiome has led to targeted investigation of potential microbiome‐targeting therapeutic strategies for NASH.

FIG 1.

NASH and the gut microbiome: implications for new therapies.

Therapeutic Targets

Studies suggest that modulation of the intestinal microbiota via fecal microbiota transplant (FMT), probiotics, prebiotics antibiotics, and synbiotics can alter the gut microbiota and the pathogenesis leading to inflammation and the progression from NAFLD to NASH. ⁴ , ¹⁰ , ¹⁴ , ¹⁵ While mostly limited to animal models of NASH, some human studies and clinical trials are ongoing. The following microbiome‐targeted techniques (MTT) are attempts to bridge knowledge from pre‐clinical animal models into human subjects ⁴ , ¹⁵ (Table 1).

TABLE 1.

MTT

Modifiable Target	Therapy
Inflammation, insulin resistance, excess ethanol, increased phenylalanine	Isocaloric, carbohydrate‐restricted, high protein and high fat diet; high fiber diet
Dysbiosis	Probiotic (Lactobacillus, Bifodobacterium), Prebiotic (oligofructose, fructo‐oligosaccharides, isomalto‐oligosaccharides), Synbiotics
Antibiotics	Rifaximin, Cidomycin, Vancomycin + Neomycin + Metronidazole + Ampicillin
Alteration of gut microbiome or portal hypertension	FMT
Intestinal permeability and elevated bile acids	Obeticholic acid (farsenoid X receptor agonist), Elafibranor (dual peroxisome proliferator‐activated receptor‐alpha) agonist, ursodeoxycholic acid (UDCA)
Dysregulated lipogenesis	Butyrate (short chain fatty acid)
Choline deficiency	Choline
Elevated lipLPS level	Anti‐LPS immunoglobulin

FMT

Animal models of NASH have been shown to be responsive to FMT and early studies demonstrated that FMT from lean mice donors resulted in changes in gut microbiota of obese mice, thought to be mostly secondary to increased microbiota diversity. Two studies investigated small intestinal microbiota transfers from lean to obese individuals and noted improved insulin sensitivity in individuals with metabolic syndrome and there is an ongoing phase I clinical study (NCT02469272) studying FMT in NASH. ¹⁶ , ¹⁷ However, there are additional factors involved in the variable efficacy of FMT that limit its standardization including the strength and adaptability of host and donor characteristics. This is a rich and potentially promising area of research that will require high‐quality studies and controlled trials in patients with NASH. ⁵ , ⁹

Probiotics, Probiotics, and Synbiotics

Probiotics are bacteria known to have a beneficial impact on metabolism, prebiotics are indigestible fermented ingredients that selectively optimize the composition of the gut microbiota, and synbiotics are a combination of both pre‐ and probiotics. Lactobacillus and Bifodobacterium are two genera that have been shown to decrease inflammation and visceral fat accumulation and improve insulin resistance in animal models. ⁴ , ¹⁸ Clinical evidence appears to support these experimental findings, but data remain discordant due to the transient, changing nature of the gut microbiota and its relationship to diet. ¹⁹ Prebiotics such as oligofructose (OFS), fructooligosaccharides (FOS), and isomalto‐oligosaccharides (IMOs) have decreased LPS and cytokine levels, improved insulin resistance, decreased inflammatory and liver markers, and decreased steatohepatitis in mice and human studies. ⁴ Multiple human trials using synbiotics in patients with NAFLD or NASH have demonstrated significant improvements in hepatic steatosis and fibrosis compared to the placebo arms, although changes to serum markers of inflammation or liver injury remain variable. ⁵ , ²⁰ , ²¹ , ²² These findings signal the therapeutic potential of synbiotics in the treatment of NASH, but larger controlled human trials with histologic endpoints are needed to clarify its impact on NASH resolution, liver fibrosis, and clinical outcomes.

Antibiotics

Antibiotics represent another potential target, although the effects are believed to be multifactorial from alterations in the gut microbiota composition. Most studies demonstrating improvement in NAFLD were limited to animal models and used various antibiotic combinations. ⁴ The hypothesis is that antibiotics not only alter the composition of gut microbiota but also bile acid metabolism. In humans, the nonsystemic antibiotic rifaximin has been studied with mixed effect on liver enzymes, changes in microbiome composition, and bile acid and inflammatory marker levels. ⁵

Additional Targets

Based on the role of the microbiome in modulating metabolic processes in the gut‐liver access including hepatic lipogenesis and gluconeogenesis as well as intestinal permeability, additional targets have been identified, including short chain fatty acids (SCFA), bile acids, and anti‐lipopolysaccharides (anti‐LPS) metabolites. Butyrate, a SCFA, is a microbial metabolite formed during fermentation of nondigestible carbohydrates and sodium butyrate reduced inflammation and fat accumulation in the animal model of NAFLD. ⁴ Other agents under study included uresodeoxycholic acid (UDCA), the farnesoid X receptor (FXR) agonist ²³ obeticholic acid (OCA), and the dual peroxisome proliferator‐activated receptor‐alpha and ‐gamma agonist, elafibranor (ELA).

Future Directions

A microbiome‐based precision medicine approach to treating NASH remains an attractive but unproven concept at this time and will require additional human studies to further demonstrate a causal pathway between the gut microbiome and NASH within individuals. Nevertheless, the cumulative evidence strongly supports the hypothesis that gut dysbiosis represents an important precipitant for NASH pathogenesis in a subset of patients, for whom treatment of the offending pathogens and/or their metabolites and signaling molecules may be an appropriate therapeutic strategy in the future, and warrants further investigation in prospective controlled studies.