Dietary iron intake is closely related to the incidence of colorectal cancer. However, the interactions among dietary iron, gut microbiota, and epithelial cells in promoting tumorigenesis have rarely been discussed. Here, we report that gut microbiota plays a crucial role in promoting colorectal tumorigenesis in multiple mice models under excessive dietary iron intake. Gut microbiota modulated by excessive dietary iron are pathogenic, irritating the permeability of the gut barrier and causing leakage of lumen bacteria. Mechanistically, epithelial cells released more secretory leukocyte protease inhibitor (SLPI) to combat the leaked bacteria and limit inflammation. The upregulated SLPI acted as a pro-tumorigenic factor and promoted colorectal tumorigenesis by activating the MAPK signaling pathway. Moreover, excessive dietary iron significantly depleted Akkermansiaceae in the gut microbiota; while supplementation with Akkermansia muciniphila could successfully attenuate the tumorigenic effect from excessive dietary iron. Overall, excessive dietary iron perturbs diet – microbiome–epithelium interactions, which contributes to intestinal tumor initiation.
Background:Mesenteric adipose tissue (MAT) in Crohn's disease (CD) is associated with transmural in ammation. Extended mesenteric excision can reduce surgical recurrence and improve long-term outcomes. These ndings indicate that MAT plays an important role in the pathogenesis of CD. Bacterial translocation has been reported to occur in CD-MAT, but the mechanisms by which translocated bacteria lead to intestinal colitis remain unclear. This study aimed to characterize CD-MAT-speci c bacteria and explore their roles in promoting intestinal in ammation. MethodsWe utilized 16S rRNA gene sequencing and culture-omics to characterize the translocated viable bacteria in MAT from CD. The pro-in ammatory role of the identi ed candidate bacteria was examined using a coculture assay in vitro and in a colitis mouse model in vivo. The type VI secretion system (T6SS) is thought to promote the pro-in ammatory effect, and a CRISPR interference system was employed to knockdown a core gene expression in T6SS. ResultsWe report that members of Enterobacteriaceae were enriched in CD-MAT compared with non-CD controls.Viable Klebsiella variicola in Enterobacteriaceae was identi ed exclusively in CD-MAT, which induces a pro-in ammatory response in vitro and exacerbates colitis in mice. This is the rst evidence that colitogenic K. variicola exists in the mesenteric tissue. Active T6SS was found in the K. variicola genome, which could impair the intestinal barrier by inhibiting the ZO-1 expression. Dysfunction of T6SS alleviated the inhibitory effect of K. variicola on ZO-1 expression and attenuated colitis in mice. Importantly, we validated that K. variicola and T6SS were enriched in the gut microbiome of patients with CD, further con rming that they are closely related to the occurrence of CD. ConclusionsCD mesenteric adipose tissue-derived K. variicola can disrupt the intestinal barrier and promote intestinal colitis induced by T6SS.
Background: Mesenteric adipose tissue (MAT) in Crohn’s disease (CD) is associated with transmural inflammation. Extended mesenteric excision can reduce surgical recurrence and improve long-term outcomes. These findings indicate that MAT plays an important role in the pathogenesis of CD. Bacterial translocation has been reported to occur in CD-MAT, but the mechanisms by which translocated bacteria lead to intestinal colitis remain unclear. This study aimed to characterize CD-MAT-specific bacteria and explore their roles in promoting intestinal inflammation. Methods We utilized 16S rRNA gene sequencing and culture-omics to characterize the translocated viable bacteria in MAT from CD. The pro-inflammatory role of the identified candidate bacteria was examined using a co-culture assay in vitro and in a colitis mouse model in vivo. The type VI secretion system (T6SS) is thought to promote the pro-inflammatory effect, and a CRISPR interference system was employed to knockdown a core gene expression in T6SS. Results We report that members of Enterobacteriaceae were enriched in CD-MAT compared with non-CD controls. Viable Klebsiella variicola in Enterobacteriaceae was identified exclusively in CD-MAT, which induces a pro-inflammatory response in vitro and exacerbates colitis in mice. This is the first evidence that colitogenic K. variicola exists in the mesenteric tissue. Active T6SS was found in the K. variicola genome, which could impair the intestinal barrier by inhibiting the ZO-1 expression. Dysfunction of T6SS alleviated the inhibitory effect of K. variicola on ZO-1 expression and attenuated colitis in mice. Importantly, we validated that K. variicola and T6SS were enriched in the gut microbiome of patients with CD, further confirming that they are closely related to the occurrence of CD. Conclusions CD mesenteric adipose tissue-derived K. variicola can disrupt the intestinal barrier and promote intestinal colitis induced by T6SS.
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