Decoding the diet-gut-liver axis: links between dietary pattern adherence, gut microbiome, and hepatic health

medRxiv

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly becoming the leading cause of chronic liver disease and confers substantial cardiometabolic burden. Diet quality and gut microbiota composition have been implicated in MASLD development; however, the interplay among diet, gut microbiota, and hepatic health remains insufficiently characterized. Here, in 9,616 deeply phenotyped middle-aged participants (mean age 52 years) from the Human Phenotype Project, we investigated how five dietary quality indices capturing complementary dimensions of healthy eating, including plant-based (hPDI), Mediterranean-style (AMED), anti-inflammatory (rDII), anti-hyperinsulinemic (rEDIH), and overall quality (AHEI), relate to gut microbial composition and liver steatosis. Dietary pattern scores were derived from two-week continuous diet logs, gut microbiota was characterized by shotgun metagenomic sequencing, and hepatic health was assessed by both ultrasound-derived metrics and prevalent MASLD status. Adherence to each of the five healthy dietary patterns was inversely associated with MASLD prevalence and positively associated with liver speed of sound (SoS), an ultrasound-derived metric that correlates inversely with hepatic fat content. Across all five dietary patterns, greater adherence was consistently associated with 138 gut microbial species, including inverse associations with Flavonifractor plautii, Dysosmobacter welbionis, Ruthenibacterium lactatiformans, Bilophila wadsworthia, and Phocea massiliensis. These five species were also associated with lower liver SoS and higher odds of prevalent MASLD, emerging as potential mediators of the diet–liver relationship in cross-sectional mediation analyses after adjustment for body mass index (BMI). This study identifies candidate microbial targets for future interventional studies investigating dietary strategies for MASLD prevention.

Authors 9

1. Keyong Deng Aachen Department of Clinical Epidemiology

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands;

2. Quinten R. Ducarmon Aachen

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center, Leiden, the Netherlands;

3. Anastasia Godneva

   Weizmann Institute of Science

   Affiliation as printed

   Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel;

4. Zheqing Zhang

   Southern Medical University

   Affiliation as printed

   Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangdong, China;

5. Astrid van Hylckama Vlieg Aachen Department of Clinical Epidemiology

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands;

6. Frits Richard Rosendaal Aachen Department of Clinical Epidemiology

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands;

7. Georg Zeller Aachen

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center, Leiden, the Netherlands;

8. Eran Segal

   Mohamed bin Zayed University of Artificial Intelligence · Weizmann Institute of Science

   Affiliation as printed

   Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel; Mohamed bin Zayed University of Artificial Intelligence, Abu Dhabi, UAE

9. Ruifang Li‐Gao corresponding Aachen Department of Clinical Epidemiology

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands;