Editorial: Rifaximin and the Gut–Liver–Brain Axis—Progress and Prudence. Authors' Reply

We thank the authors for their thoughtful Editorial on our randomised trial of rifaximin in covert hepatic encephalopathy (CHE) [1]. We fully agree that our findings should be interpreted as evidence of progress, while maintaining appropriate prudence regarding long‐term outcomes, antimicrobial stewardship, and the complexity of the gut–liver–brain axis.

Our study was designed to address an important clinical gap: CHE is common, clinically meaningful, and frequently underdiagnosed, despite its association with impaired daily functioning and progression to overt hepatic encephalopathy. In this context, the improvement in Stroop test performance after 12 weeks of rifaximin provides prospective randomised evidence that cognitive dysfunction in CHE is modifiable. Importantly, the reduction in cirrhosis‐related adverse events, including falls and accidents, suggests that treatment of CHE may have clinical relevance beyond psychometric improvement [2].

We also appreciate the Editorial's emphasis on the ammonia‐independent effects observed in our trial. Although ammonia remains central to the pathophysiology of hepatic encephalopathy, the absence of a parallel change in ammonia levels supports the concept that rifaximin may exert benefits through broader modulation of the gut–liver–brain axis. The observed reduction in specific taxa, including the Eubacterium brachy group, without major shifts in overall microbial diversity, is consistent with rifaximin acting less as a conventional bactericidal antibiotic and more as a functional modulator of microbial ecology, intestinal barrier integrity, and gut‐derived inflammation. These findings are consistent with previous studies demonstrating that rifaximin modulates microbial function and reduces gut‐derived inflammation rather than inducing broad changes in microbial composition [3, 4].

We recognise several limitations. The open‐label design, 12‐week duration, and use of 16S rRNA sequencing limit our ability to assess long‐term clinical efficacy, microbial function, and antimicrobial resistance. Future studies should therefore incorporate blinded designs, longer follow‐up, metagenomic or metabolomic analyses, and clinically robust endpoints, including prevention of first overt hepatic encephalopathy, hospitalisation, falls, and quality‐of‐life deterioration.

At the same time, our findings support the practical value of identifying and treating CHE in patients with cirrhosis. Rifaximin was well tolerated, and no signal of increased clinically significant infection was observed during the trial. We agree that enthusiasm for gut‐targeted therapy must be balanced by careful surveillance for resistance and by appropriate patient selection.

In summary, our study adds prospective randomised evidence that rifaximin improves cognitive performance and may reduce clinically relevant adverse events in CHE. We hope these results will stimulate larger, blinded, mechanistically informed trials to define the optimal role of rifaximin and other gut‐directed therapies across the spectrum of hepatic encephalopathy.

The authors' declarations of personal and financial interests are unchanged from those in the original article [2].

Author Contributions

Hiroki Inada: writing – review and editing, writing – original draft. Yasuhito Tanaka: writing – review and editing.

Funding

The authors have nothing to report.

Linked Articles

This article is linked to Inada et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70809 and https://doi.org/10.1111/apt.70712.

Inada H. and Tanaka Y., “Editorial: Rifaximin and the Gut–Liver–Brain Axis—Progress and Prudence. Authors' Reply,” Alimentary Pharmacology & Therapeutics 64, no. 5 (2026): 683–684, 10.1111/apt.70834.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.