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Ultra-processed foods sourced 7-ketositosterol aggravates colitis through gut dysbiosis induced-PDLIM3 activation

ABSTRACT: Excessive ultra-processed foods (UPFs) consumption has been reported to increase the risk of inflammatory bowel disease (IBD). However, the specific mechanisms remain unclarified. As an important ingredient of UPFs, 7-ketositosterol (KS) is mainly synthesized from high-temperature heating oils. We find that KS intake is higher in IBD patients and related to disease activity. KS exacerbats colitis in a gut microbiota-dependent manner in mice, altering the gut microbiota composition, increasing the abundance of potential pathogenic bacteria, especially Staphylococcus_lentus (SL). Morevoer, SL aggravates DSS-induced colitis. Mechanically, KS up-regulates the expression of PDZ and LIM Domain 3 (PDLIM3). SL-derived lysin motif peptidoglycan-binding domain-containing protein (LPDP) interacts with PDLIM3, and activates p38MAPK/NF-κB signaling pathway. Furthermore, tubuloside B, selected by high-throughput screening, blocks the interaction of PDLIM3 and LPDP, and ameliorates SL-aggravated colitis. Our study reveals that KS exposure promotes colitis via gut microbiota and PDLIM3 interaction, providing evidence of IBD pathogenesis and potential therapeutic strategy for IBD treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE299083 | GEO | 2026/01/01

REPOSITORIES: GEO

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Project description:Background: The etiology of Inflammatory Bowel Disease (IBD) is unclear but involves both genetics and environmental factors, including the gut microbiota. Indeed, exacerbated activation of the gastrointestinal immune system toward the gut microbiota occurs in genetically susceptible hosts and under the influence of the environment. For instance, a majority of IBD susceptibility loci lie within genes involved in immune responses, such as caspase recruitment domain member 9 (Card9). However, the relative impacts of genotype versus microbiota on colitis susceptibility in the context of CARD9 deficiency remain unknown. Results: Card9 gene directly contributes to recovery from dextran sodium sulfate (DSS)-induced colitis by inducing the colonic expression of the cytokine IL-22 and the antimicrobial peptides Reg3 and Reg3 independently of the microbiota. On the other hand, Card9 is required for regulating the microbiota capacity to produce AhR ligands, which leads to the production of IL-22 in the colon, promoting recovery after colitis. In addition, cross-fostering experiments showed that five weeks after weaning, the microbiota transmitted from the nursing mother before weaning had a stronger impact on the tryptophan metabolism of the pups than the pups' own genotype. Conclusions: These results show the role of CARD9 and its effector IL-22 in mediating recovery from DSS-induced colitis in both microbiota-independent and microbiota-dependent manners. Card9 genotype modulates the microbiota metabolic capacity to produce AhR ligands, but this effect can be overridden by the implantation of a WT or healthy microbiota before weaning. It highlights the importance of the weaning reaction occurring between the immune system and microbiota for the host metabolism and immune functions throughout life. A better understanding of the impact of genetics on microbiota metabolism is key to developing efficient therapeutic strategies for patients suffering from complex inflammatory disorders.

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Ultra-processed foods sourced 7-ketositosterol aggravates colitis through gut dysbiosis induced-PDLIM3 activation

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