Gut Microbiota Interactions in Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis, and its global rise parallels the obesity and diabetes pandemics. Central to its pathogenesis is the gut-liver axis, whereby intestinal microbes and their metabolites influence hepatic lipid metabolism, inflammation and fibrogenesis. Alterations in microbial composition, or dysbiosis, can increase intestinal permeability, permitting bacterial products such as lipopolysaccharide to reach the liver via the portal vein and trigger inflammatory cascades. Microbial fermentation yields short-chain fatty acids (SCFAs) that modulate energy homeostasis, gut barrier integrity and immune responses, while other microbial-derived mediators such as ethanol, bile acids and extracellular vesicles shape hepatocellular signalling. Interventions that reshape the microbiota—antimicrobial phages, probiotics, dietary modulation or faecal microbiota transplantation—have shown promise in preclinical and early clinical studies, underscoring the microbiota’s potential as both biomarker and therapeutic target in NAFLD management.

Research from Nature Portfolio

Phage therapy targeting high alcohol-producing Klebsiella pneumoniae has been demonstrated in a mouse model of steatohepatitis. Specific bacteriophages reduced hepatic dysfunction, attenuated inflammatory cytokine expression and corrected lipid-metabolism gene profiles without broad disruption of the gut community, suggesting a precision antimicrobial approach can mitigate microbial-driven liver injury.

Fecal microbiota transplantation in a high-fat diet-induced model of steatohepatitis reversed dysbiosis by enriching beneficial taxa such as Christensenellaceae and Lactobacillus, increased butyrate levels and restored intestinal tight junction proteins. These changes reduced endotoxaemia, hepatic lipid accumulation and pro-inflammatory cytokines, indicating that community-level microbial modulation can ameliorate diet-induced liver inflammation.

In nonobese individuals with NAFLD, comparative analysis of faecal microbiota revealed lower microbial diversity, a shift towards Bacteroidetes over Firmicutes, reduced SCFA-producing genera and an association between these alterations and indices of liver biochemistry. This seminal work established dysbiosis as an independent correlate of NAFLD severity even in the absence of obesity, highlighting the microbiome’s diagnostic and mechanistic importance.

Gut Microbiota Interactions in Non-Alcoholic Fatty Liver Disease publication trend

The graph below shows the total number of articles in gut microbiota interactions in non-alcoholic fatty liver disease across all publications each year (not limited to Nature Index journals).

Technical terms

Dysbiosis: Imbalance in the gut microbial community associated with disease.

Gut-liver axis: Bidirectional communication pathway linking intestinal microbes, their products and the liver via the portal circulation and immune signalling.

Short-chain fatty acids (SCFAs): Microbial fermentation products (acetate, propionate, butyrate) that influence energy metabolism, barrier integrity and inflammation.

Intestinal permeability: Degree to which the gut mucosal barrier allows passage of microbes and their products into the bloodstream.

Non-alcoholic steatohepatitis (NASH): Progressive form of NAFLD characterised by hepatic inflammation, hepatocyte injury and variable fibrosis.

References

1. Assessment of the functional state of gut microbiota in patients with metabolic-associated fatty liver disease in combination with type 2 diabetes mellitus. Gastroenterology (2024).
2. Enhanced mitochondrial activity reshapes a gut microbiota profile that delays NASH progression. Hepatology (2023).
3. Bacteriophage targeting microbiota alleviates non-alcoholic fatty liver disease induced by high alcohol-producing Klebsiella pneumoniae. Nature Communications (2023).
4. Total fecal microbiota transplantation alleviates high-fat diet-induced steatohepatitis in mice via beneficial regulation of gut microbiota. Scientific Reports (2017).
5. Altered Fecal Microbiota Correlates with Liver Biochemistry in Nonobese Patients with Non-alcoholic Fatty Liver Disease. Scientific Reports (2016).
6. Lactobacillus plantarum ameliorates NASH-related inflammation by upregulating l-arginine production. Experimental & Molecular Medicine (2023).