C. butyricum Combined With Resmetirom Provides Therapeutic Benefits in MASH Associated With Gut–Liver–Brain Axis Modulation

Abstract

Background and Aims

Resmetirom has emerged as a major advance in MASH pharmacotherapy as the first approved liver-targeted THR-β agonist; however, variable therapeutic efficacy and adverse responses may limit its clinical benefits. This study investigated whether C. butyricum could provide additional therapeutic benefits when combined with resmetirom and attenuate nausea/vomiting-like responses in association with changes across the gut–liver–brain axis.

Methods

In this study, we established a high-fat diet-induced MASH mouse model and administered C. butyricum, resmetirom, or their combination. Comprehensive biochemical, histological, molecular, 16S rRNA sequencing-based microbiome profiling, and gut–brain axis-related analyses were performed to evaluate the effects of combination therapy on hepatic metabolism, inflammation, fibrosis, intestinal barrier integrity, gut microbiota remodelling, microbial metabolites, and resmetirom-associated adverse responses.

Results

Combined treatment with C. butyricum and resmetirom produced additional therapeutic benefits compared with either monotherapy, markedly improving hepatic steatosis, lipid accumulation, insulin resistance, inflammation, oxidative stress, and fibrosis in MASH mice. At the molecular level, combination treatment was associated with increased hepatic THR-β expression and coordinated changes in AMPK-related lipid metabolism, NRF2/HO-1 antioxidant, and TLR4/MyD88/NF-κB inflammatory markers. Furthermore, combination therapy restored intestinal barrier integrity, alleviated MASH-associated gut microbial dysbiosis, increased beneficial bacterial taxa, and increased faecal butyrate levels. Notably, C. butyricum attenuated resmetirom-induced nausea/vomiting-like responses, accompanied by reduced colonic and cerebral 5-HT/SP signalling, decreased brain Htr3a and Tacr1 mRNA expression, and suppressed neuronal FOS activation. Faecal butyrate levels were inversely associated with hepatic lipid burden and brain 5-HT/SP levels.

Conclusions

C. butyricum combined with resmetirom provides additional therapeutic benefits and attenuates nausea/vomiting-like responses in MASH, accompanied by coordinated changes across the gut–liver–brain axis. This combination strategy provides a potential microbiota-based adjunctive approach for optimizing the therapeutic benefits of resmetirom in MASH.