Prebiotic xylo-oligosaccharides for alleviation of hepatic steatosis: results from a four-month dietary intervention and determinants of response

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ABSTRACT A common complexity from increasing rates of overweight is metabolic dysfunction associated steatotic liver disease (MASLD) which can develop into more severe conditions such as fibrosis or hepatocellular carcinoma. The gut and its microbial flora interact with the liver through the gut-liver axis and supporting healthy composition and metabolism of the microbiota can benefit metabolic health. We have previously shown in animals that a xylo-oligosaccharide (XOS) prebiotic can drive beneficial gut flora and ameliorate hepatic steatosis- our current objective is to validate these results in humans. Forty-two adults (mean age 53.7, mean BMI 33.5) ingested a prebiotic dose of XOS daily for four months. Liver fat was quantified with MRI and body composition was measured. Standard clinical measurements and untargeted metabolomes were analyzed from serum. Microbiota composition, metagenome and metabolites were analyzed from fecal samples. A subgroup analysis was conducted between non-steatotic individuals, non-responders, and responders. The XOS supplementation caused decreases in detrimental amino acid degradation products (AADPs) isovalerate, isobutyrate, and phenylacetate in the gut while serum metabolome remained stable. A decrease in liver fat during the prebiotic was accompanied by a decrease in visceral fat. In a prediction analysis, this response was driven by higher initial ratio of Bacteroides to Faecalibacterium , higher fecal AADPs, and higher serum amino acids. Non-responders had metabolomic signatures of advanced steatosis, possibly impeding effects from XOS. In overweight individuals with early hepatic steatosis, XOS may correct fermentation imbalances in the gut and decrease production of harmful metabolites, which may benefit hepatic health. IMPORTANCE Pre- and probiotics are emerging, yet unknown, avenues of treatment for metabolism-associated steatotic liver disease. In overweight humans, a xylo-oligosaccharide (XOS) prebiotic induced shifts in gut bacteria and their metabolites. High proteolytic activity in the gut was predictive of hepatic response to XOS, which may serve the development of personalized treatment of fatty liver.

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