Tingtao Chen

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.

The limitations of current rheumatoid arthritis (RA) therapies, including substantial adverse effects and economic burden, necessitate the development of safer, cost-effective adjunct treatments. Probiotic-based interventions targeting the gut-joint axis hold therapeutic promise, yet their precise mechanisms of action remain incompletely understood. This study investigated the therapeutic efficacy and underlying mechanisms of W. coagulans NCU-33 in a collagen-induced arthritis (CIA) mouse model. Intervention with NCU-33 significantly attenuated clinical arthritic scores, joint swelling, and histopathological damage. Mechanistically, NCU-33 exerted a coordinated, multi-pronged effect: in joint tissue, it suppressed TLR2/MyD88/NF-κB signaling, reducing pro-inflammatory cytokines TNF-α and IL-6; systemically, it modulated Notch signaling in splenic lymphocytes, thereby rectifying the pathogenic Th17/Treg imbalance; and in the gut, it restructured the microbiota by enriching beneficial Lactobacillus spp., which enhanced intestinal barrier integrity and elevated short-chain fatty acid levels. In summary, W. coagulans NCU-33 ameliorates experimental arthritis through an integrated, multi-target mechanism that concurrently regulates local inflammation, systemic immune homeostasis, and gut ecosystem equilibrium. These findings provide robust preclinical evidence supporting the clinical development of W. coagulans NCU-33 as a novel, mechanism-driven probiotic therapy for RA via modulation of the gut-joint axis.

Emerging research has revealed a diverse microbiota in the high myopia (HM) conjunctival sac, highlighting the therapeutic potential of modulating this community to influence disease outcomes. However, current research on targeted modulation of this microbiota for myopia intervention lacks in‐depth investigation and definitive conclusions regarding its efficacy and underlying mechanisms. In this study, high‐throughput sequencing and culturomics were first used to screen the conjunctival sac microbiota of healthy people, identifying Lactobacillus mucosae MM‐1 as a potential probiotic for myopia control. Then, animal studies further confirmed that L. mucosae MM‐1 significantly attenuated lens‐induced myopia, improved COL1A1 expression and scleral integrity and elevated Lactobacillus abundance. Furthermore, untargeted metabolomics analysis suggested that indole‐3‐lactic acid (ILA) may be a key substance for L. mucosae MM‐1 to exert its effects for myopia control. Mechanistically, pharmacological ILA supplementation supports the involvement of AHR in TGF‐β/Smad pathway inhibition, accompanied by altered COL1A1 and α‐SMA expression and attenuation of lens‐induced myopia in mice. Therefore, these findings suggest that L. mucosae MM‐1 may attenuate lens‐induced myopia in mice, at least in part, through ILA‐mediated regulation of the TGF‐β/Smad pathway, and offer a theoretical foundation for future therapeutic strategies based on conjunctival sac microbiome manipulation.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most prevalent chronic liver disease worldwide but lacks effective therapies. Gut micro