Gut microbes, diet, and genetics as drivers of metabolic liver disease: a narrative review outlining implications for precision medicine

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly increasing in prevalence, impacting over a third of the global population. The advanced form of MASLD, Metabolic dysfunction-associated steatohepatitis (MASH), is on track to become the number one indication for liver transplant. FDA-approved pharmacological agents are limited for MASH, despite over 400 ongoing clinical trials, with only a single drug (resmetirom) currently on the market. This is likely due to the heterogeneous nature of disease pathophysiology, which involves interactions between highly individualized genetic and environmental factors. To apply precision medicine approaches that overcome interpersonal variability, in-depth insights into interactions between genetics, nutrition, and the gut microbiome are needed, given that each have emerged as dynamic contributors to MASLD and MASH pathogenesis. Here, we discuss the associations and molecular underpinnings of several of these factors individually and outline their interactions in the context of both patient-based studies and preclinical animal model systems. Finally, we highlight gaps in knowledge that will require further investigation to aid in successfully implementing precision medicine to prevent and alleviate MASLD and MASH.

Keywords: Genetics; Gut microbiome; MASH; MASLD; Nutrition; Precision medicine.

Figure 1.. Genetics and environmental factors, including diet and gut microbes, converge to drive MASLD/MASH development and progression in an individualized manner.

Genetic variants either protect against or predispose individuals to develop metabolic disruptions that contribute to MASLD/MASH pathogenesis. Dietary substrates, including simple sugars, saturated fat, and cholesterol can promote MASLD/MASH, while others, such as fiber and unsaturated fatty acids, can protect against disease. Alterations in the gut microbiome driven by dietary intake and host genetics are key mediators of gut-liver cross-communication, which can be beneficial or detrimental to the gut-liver axis. These three factors are tightly interconnected, contributing in unique ways to disease processes, underscoring the importance of precision nutrition interventions. Abbreviations include SCFA: short-chain fatty acid, LPS: lipopolysaccharide, PUFA: polyunsaturated fatty acid, MUFA: monounsaturated fatty acid. Supported by evidence from *human studies; ^†rodent studies; ^#in vitro studies.

Figure 2.. Interactions between genetics, nutrition, and gut microbiota influence MASLD and MASH pathogenesis: TLR4 signaling as a model for protective vs. disease-enhancing effects.

The relationship between genetic variation, gut microbiota, and dietary components highlights the complex relationship between highly individualized disease drivers. Host genetics may modulate and select for specific gut microbes. Dietary substrates, including lipids, simple sugars, and fiber differentially shift gut microbiota composition and may drive competition between microbial community members in a context-dependent manner. Saturated fatty acids (SFA) can increase postprandial lipopolysaccharide (LPS) while simple sugars may directly disrupt gut barrier function. The TLR4 D299G mutation dampens activation and signaling in downstream pathways, which may confer protection against MASLD/MASH, even in the face of gut microbiota dysbiosis. However, Individuals without the D299G mutation or with other disease enhancing SNPs may exhibit enhanced TLR4 expression and activation, contributing to disease onset and progression. On the other hand, monounsaturated fatty acids (MUFA) and dietary fiber may promote the expansion of beneficial Gram + microbes that inhibit the expansion of Gram- microbes and protect against gut barrier damage via the production of short-chain fatty acids (SCFA), subsequently diminishing TLR4 activation.