Short-chain fatty acid enrichment, TLR4/MyD88/p-JNK inhibition, and gut metabolic modulation: a triple mechanism by which the probiotic ameliorates colorectal cancer

Abstract

Abstract Chronic intestinal inflammation is a major risk factor for colorectal cancer (CRC). This study investigated the therapeutic potential of the probiotic Streptococcus thermophilus NCU074001 (ST) in a mouse model of colitis-associated CRC. ST supplementation reduced tumor number, preserved colon length, and alleviated clinical disease activity. ST suppressed pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and COX-2, while restoring the anti-inflammatory cytokine IL-10 and the tight junction proteins ZO-1 and Claudin-1, indicating potent anti-inflammatory and barrier-protective effects. ST treatment inhibited the TLR4/MyD88/p-JNK pathway, reduced the CD117+FcɛRI+ immune population, and expanded CD25⁺Foxp3⁺ regulatory T cells, thereby rebalancing host immunity. ST also induced a significant microbiome reprogramming, partially ameliorating dysbiosis, enriching beneficial short-chain fatty acid (SCFA)-producing genera ( Odoribacter and Lachnospiraceae_NK4A136_group ), reducing Escherichia-Shigella , and elevating SCFAs (butyrate, acetate, and propionate). A notable finding was that ST treatment correlated with reduced activity of proteolytic pathways ( L -lysine fermentation and creatinine degradation) and increased abundance of pathways related to methanol oxidation (PWY-7616) and decaprenyl phosphate biosynthesis (PWY-6383), both of which are associated with barrier function and colonization resistance. Such functional alterations have rarely been reported in probiotic‑CRC research. Correlation network analysis further identified two opposing regulatory axes, a pathogen-driven pro-inflammatory axis and a protective SCFA-mediated axis, indicating that ST actively redirects the host immunometabolic landscape toward a protective state. Collectively, these findings position ST as a promising next-generation probiotic capable of modulating inflammation, epithelial barrier function, and microbial metabolism to disrupt the cycle of inflammation-driven colorectal carcinogenesis.