From dysbiosis to MASLD: The central role of the gut microbiota

Metabolic dysfunction–associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, yet treatment options remain limited.^[1] Recent studies indicate that MASLD is associated with impaired pathophysiological mechanisms within the gut–liver axis, including increased intestinal permeability and consequent oxidative stress. These findings suggest that interventions targeting the gastrointestinal microbiota or restoring intestinal barrier integrity may attenuate downstream hepatic inflammation.^[2]

In this context, we read with great interest the study by Celik et al.,^[3] which investigated the effects of rifaximin—an intestinal decontaminant used in the management of hepatic encephalopathy—in an experimental model of fructose-induced MASLD. In fructose-fed mice, rifaximin exerted significant anti-inflammatory and antioxidant effects. The authors also discussed that these changes might be associated with improvements in the intestinal microflora and reductions in inflammatory parameters. Unfortunately, the authors did not include an analysis of the intestinal microbiota; therefore, it is difficult to determine whether rifaximin exerts its effects primarily through barrier-related or microbiome-mediated mechanisms, or via alternative or direct anti-inflammatory pathways. On the other hand, such an effect is plausible under rifaximin treatment. Previous mouse model studies have reported rifaximin-induced shifts in the gut microbiota, notably characterized by an increased abundance of Lactobacillus.^[4] Moreover, Wan et al.^[5] provided a mechanistic explanation for this variability by demonstrating that, in methionine–choline-deficient diet–induced MASH, rifaximin ameliorated steatosis, inflammation, and fibrosis, apparently through a specific microbiome–bile acid–host signaling axis.

Gut-microbiome–associated disturbances in bile acid metabolism have also been linked to abnormalities in lipid metabolism and the development of MASLD. Bile acids play a key regulatory role by activating the farnesoid X receptor (FXR), which in turn modulates pathways involved in lipid metabolic control.^[6] In a mouse model, treatment with rifaximin appeared to reduce levels of the secondary bile acid deoxycholic acid rather than affecting primary bile acids, and this reduction was associated with alterations in the gut microbiome. Because deoxycholic acid directly activates FXR, mice receiving rifaximin showed improvements in MASH, suggesting that microbiome-mediated changes in bile acid composition may contribute to the therapeutic effect.^[7]

The gut microbiota is implicated not only in MASH pathophysiology but also in the development of hepatocellular carcinoma (HCC). Comparative analyses have demonstrated a progressive reduction in the relative abundance of Bacteroidetes and, to a lesser extent, Actinobacteria across disease stages, from healthy controls to MASH and MASH-associated HCC.^[8] Increasing evidence indicates stage-specific alterations in intestinal microbiota composition associated with liver disease severity, supporting the exploration of microbiota-targeted therapeutic strategies such as probiotics, antimicrobial agents, and fecal microbiota transplantation.^[9] Clinical studies, however, demonstrate heterogeneous effects of rifaximin, with improvements in hepatic inflammation and fibrosis mainly observed in long-term rather than short-term interventions, suggesting that sustained modulation of the intestinal microbiota may be required to achieve meaningful benefits.^[10,11] Taken together, the long-term effects of rifaximin on gut microbiota composition and liver health remain insufficiently understood, and the mechanisms mediating fibrotic and inflammatory activation require further investigation. The effects of rifaximin are summarized in Figure 1.

Figure 1.

Effects of rifaximin on gut microbiota regulation and metabolic dysfunction–associated steatohepatitis (MASH).

Over recent years, substantial progress has been made in the field of MASLD, beginning with the establishment of an updated disease classification,^[12] followed by the conditional and full approval of the first pharmacological therapies for MASH, including resmetirom and semaglutide.^[13] In this evolving therapeutic landscape, the gut microbiota and associated bile acid metabolism are expected to assume an increasingly important role. As knowledge continues to expand, microbiota-targeted strategies may enable modification of disease trajectories and potentially allow prevention at early stages. In this regard, Celik et al.^[3] demonstrated in a well-designed mouse model that rifaximin ameliorated steatohepatitis, with biochemical improvements translating into consistent histopathological findings, thereby contributing to the existing body of evidence. However, the effects of rifaximin on the human microbiota—particularly whether these changes occur on an individual or generalizable level—and its long-term impact on metabolic and liver health remain insufficiently understood and require further investigation. In particular, integrative studies bridging experimental models and clinical research, while comprehensively addressing the multifaceted effects of rifaximin, are still lacking and represent an important priority for future research.

Conflict of Interest

The authors have no conflict of interest to declare.

Financial Disclosure

The authors declared that this study has received no financial support.

Use of AI for Writing Assistance

We did not use any artificial intelligence-assisted technologies in the preparation of this manuscript.

Author Contributions

Concept: EK, AC; Supervision: AC; Funding: AC; Analysis and/or Interpretation: MK, EK; Literature Search: MK, EK, AC; Writing: MK, EK, AC; Critical Reviews: EK, AC.

Peer-review

Externally peer-reviewed.