Synergistic effects of Clostridium butyricum and Akkermansia muciniphila-derived postbiotics ameliorate DSS-induced colitis and associated tumorigenesis through immunomodulation and microbiota regulation in mice

Inflammatory bowel disease (IBD) is a major precursor to colorectal cancer(CRC). Our previous study demonstrated that combined administration of the probioticsClostridium butyricum (CB) and Akkermansia muciniphila (AKK) significantly alleviated IBDand CRC symptoms in mice. Increasing evidence suggests that probiotic metabolites(postbiotics) offer significant advantages in disease prevention and treatment withoutthe stability and safety concerns associated with live bacterial therapies. To furtherexplore the therapeutic potential of CB- and AKK-fermented metabolites against IBD andCRC, we established a DSS-induced IBD model and DSS/AOM-induced CRC orthotopicmodels in mice and evaluated the effects of CB and AKK metabolites on alleviating IBDand CRC. The results revealed that the fermented metabolites of CB and AKK (designatedas SupCB and SupAKK, respectively) exhibited significant synergistic effects. Mixedfermented metabolites (designated as SupCBAKK) outperformed individual metabolites,significantly alleviating IBD and CRC symptoms by modulating immune responses,repairing the mucosal barrier, and ameliorating gut dysbiosis. Notably, SupCBAKKsynergized with the immune checkpoint inhibitor anti-PD-L1 (aPD-L1), enhancing tumorsensitivity to immunotherapy and amplifying antitumor immune responses. Thesefindings underscore the potential of SupCBAKK as a novel postbiotic formulation formitigating IBD and CRC progression and offer innovative strategies for developing CB-and AKK-based therapeutic interventions.