Rifaximin and sarcopenia in cirrhosis: Commentary on a promising but complex relationship

Abstract

We commend Worland et al for their work associating rifaximin-α use with improved muscle mass in individuals with liver cirrhosis. This observation adds momentum to the evolving gut-liver-muscle axis hypothesis. However, the retrospective design and lack of functional outcomes invite caution in interpretation. Mechanistically, rifaximin may exert benefit beyond ammonia reduction through modulation of systemic inflammation, tumor necrosis factor alpha suppression, and restoration of myocyte integrity. Additionally, concerns about long-term antimicrobial resistance must be acknowledged. Overall, this study represents a valuable first step, but its implications require validation in future, prospective, mechanistically informed clinical trials.

Key Words: Rifaximin; Sarcopenia; Cirrhosis; Myostatin; Gut-liver-muscle axis; Hyperammonemia; Tumor necrosis factor alpha

Core Tip: The study by Worland et al adds valuable data suggesting that rifaximin-α may improve muscle mass in people with cirrhosis. We highlight plausible mechanisms beyond ammonia reduction, such as cytokine suppression and microbiota modulation. However, concerns regarding resistance and the need for prospective validation merit discussion.

TO THE EDITOR

We commend Worland et al[1] for their recent publication in the World Journal of Hepatology reporting that rifaximin-α use is independently associated with improved skeletal muscle area in patients with cirrhosis and hepatic encephalopathy. This study is both timely and clinically significant, given the high prevalence and prognostic impact of sarcopenia in this population[2,3]. Importantly, their findings support the long-hypothesized role of the gut-liver-muscle axis, a framework corroborated by emerging data from both preclinical[4,5] and translational[6] studies. However, we believe several points warrant further clarification and discussion.

Mechanistic underpinnings

The proposed mechanism—primarily via ammonia-lowering—merits broader elaboration. While hyperammonemia contributes to muscle wasting through the upregulation of myostatin and suppression of mTOR signaling[4,7], rifaximin’s effects are likely multifaceted. Murata et al[5] demonstrated that rifaximin reduces pro-inflammatory cytokines and promotes mitochondrial biogenesis and IGF-1 signaling in skeletal muscle. Moreover, Han et al[7] showed that rifaximin therapy in cirrhotic rats reduced serum tumor necrosis factor alpha and myostatin levels, correlating with muscle fiber restoration[7]. These findings suggest that rifaximin’s therapeutic benefit may stem from both anti-inflammatory and metabolic modulation.

Translational gaps

Despite its robust analysis, the study’s retrospective design precludes causal inference. The absence of functional assessments, such as handgrip strength or validated quality of life instruments, limits our ability to judge the clinical relevance of the observed changes[8]. Furthermore, sarcopenia is influenced by factors including sex, etiology of liver disease, and nutritional status[2]. Subgroup analyses based on these parameters may have provided more profound insights. Recent evidence underscores the importance of tailoring sarcopenia treatment based on sex-specific and metabolic profiles[3].

Antimicrobial resistance concerns

Although rifaximin is considered minimally absorbed and low risk for systemic resistance, this assumption is increasingly challenged. Turner et al[9] reported that rifaximin exposure may select for Enterococcus faecium strains harboring rpoB mutations associated with daptomycin resistance. This is particularly concerning in patients with cirrhosis, who are frequently hospitalized and often immunocompromised. These observations reinforce the need for careful antimicrobial stewardship.

Clinical implications

The Baveno VII consensus has emphasized recompensation and reversibility in cirrhosis management[10], highlighting sarcopenia as a potentially modifiable factor. If rifaximin proves capable of preserving or restoring muscle mass, it may serve as a disease-modifying agent, especially in the pre-transplant population. Nevertheless, this potential must be confirmed through prospective, multicenter randomized controlled trials with standardized sarcopenia definitions and incorporation of functional and imaging biomarkers.

Conclusion

The study by Worland et al[1] initiates a valuable dialogue on the role of rifaximin in managing sarcopenia among patients with cirrhosis. While the hypothesis is biologically plausible, further rigorous investigation is essential. As hepatology advances toward precision medicine, mechanistic and controlled studies will be critical to delineate rifaximin’s full therapeutic profile.