Project description:Gut dysbiosis is closely involved in the pathogenesis of inflammatory bowel disease (IBD). However, it remains unclear whether IBD-associated gut dysbiosis plays a primary role in disease manifestation or is merely secondary to intestinal inflammation. Here, we established a humanized gnotobiotic (hGB) mouse system to assess the functional role of gut dysbiosis associated with two types of IBD - Crohn's disease (CD) and ulcerative colitis (UC). In order to explore the functional impact of dysbiotic microbiota in IBD patients on host immune responses, we analyzed gene expression profiles in colonic mucosa of hGB mice colonized with healty (HC), CD, and UC microbiota.
Project description: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.
Project description:While fermentable oligo- and di-, mono-saccharides and polyols (FODMAPs) have been implicated in exacerbating inflammatory bowel disease (IBD) symptoms, the exact influence of FODMAPs on gut microbiota and inflammation is unclear. Here, we show that sorbitol, a polyol, exacerbates colitis in mice induced by dextran sodium sulfate (DSS). Sorbitol increases the expression of inflammatory genes including Il1b in the colon, associated with M1 macrophage-related genes elevated in IBD patients. Indeed, sorbitol treatment leads to a higher proportion of M1 macrophages in the colon, worsening colitis, which is reversed in IL-1β-deficient mice and mitigated with antibiotic treatment. Sorbitol alters the composition of gut microbiota and metabolites, with Prevotellaceae and tryptamine positively correlated with colonic M1 macrophages. Tryptamine stimulation enhances M1 macrophage polarization. Taken together, polyol consumption activates intestinal macrophages by altering the gut microbiome, which in turn promotes intestinal inflammation.
Project description:- Background: Optimized diets during the first period of life may be most effective for improving gut and overall health. Here, we set up an interdisciplinary research pipeline to evaluate gut health benefits of early life nutrition ingredients through advanced integration of in vitro and modeling technologies that represent the infant gut environment. - Methods: In our InTESTine platform (TM), biopts of piglet gut tissue (Jejunum or Colon) were exposed (0-6h) to various infant/piglet-formula-milk based food matrices (-/+ prebiotics; -/+ predigestion by infant/piglet fecal microbiome). RNA expression of the piglet gut tissue biopts was measured by RNAseq. - Results: To be published in various papers. - Conclusion: To be published in various papers.
Project description:Cadaverine is a polyamine produced by the gut microbiota with links to health and disease, notably inflammatory bowel disease (IBD). Here, we show that cadaverine shapes monocyte-macrophage immunometabolism in a context- and concentration-dependent fashion to impact macrophage functionality. At baseline, cadaverine is taken up via L-lysine transporters and activates the thioredoxin system, while during inflammation, cadaverine signals through aconitate decarboxylase 1 (Acod1)-itaconate. Both pathways induce activation of transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), which supports mitochondrial respiration and promotes immunoregulatory macrophage polarization. Conversely, under higher concentrations, cadaverine acts via histamine 4 receptor, leading to glycolysis-driven inflammation and pro-inflammatory functions in macrophages. Likewise, cadaverine exhibits paradoxical effects in experimental colitis, either protective or detrimental, evoking opposite fates on macrophages depending on levels dictated by Enterobacteriaceae. In IBD patients, elevated cadaverine correlated with higher flare risk. Our findings implicate cadaverine as a microbiota-derived metabolite manipulating macrophage energy metabolism with consequences in intestinal inflammation and implications for IBD pathogenesis.