HBOT alleviates diet-induced MASH by reprograming gut microbiota and liver metabolism in mice

Background: Hyperbaric oxygen therapy (HBOT) has been validated as a potential treatment for metabolic dysfunction, but its effect on metabolic dysfunction-associated steatohepatitis (MASH) has not been well elucidated. This study aims to determine the effect of HBOT on diet-induced MASH in mice. Method: HBOT (2.2 ATA, 60 min per day for 4 weeks) was administrated in mice fed with 12-week high-fat, highcholesterol (HFHC) and 4-week methionine- and choline-deficient (MCD) diets to explore the therapeutic effects on MASH. 16S rRNA sequencing, oral broad-spectrum antibiotic cocktail (Abx) administration and non-targeted metabolomics were employed to further investigate the modulatory effect of HBOT on gut microbiota and liver metabolism. Results: Dyslipidemia, liver dysfunction, hepatic steatosis, inflammation and fibrosis were markedly attenuated by HBOT intervention in HFHC-fed mice. In parallel, HBOT showed similar therapeutic effects in MCD-fed mice. Furthermore, 16S rRNA sequencing revealed that the MASH-associated community diversity reduction of gut microbiota was reversed by HBOT, which also improved gut dysbiosis and increased the relative level of beneficial bacteria, such as Alloprevotella and Akkermansia. Removal of gut microbiota by Abx obviously abolished the therapeutic effect of HBOT. Additionally, HBOT significantly changed liver metabolism and ameliorated the changes of sphingolipids, which were significantly correlated with gut microbiota changes. Conclusion: In summary, HBOT protects against diet-induced steatohepatitis in mice by remodeling the gut microbiota and improving the liver metabolic profile, indicating promising therapy for MASH.