Gut microbiota-mediated lysophosphatidylcholine generation promotes colitis in intestinal epithelium-specific Fut2 deficiency

Abstract

Background and aims Previous study disclosed Fucosyltransferase 2 (Fut2) gene as a IBD risk locus. This study aimed to explore the mechanism of Fut2 in IBD susceptibility and to propose a new strategy for the treatment of IBD. Methods Intestinal epithelium-specific Fut2 knockout (Fut2△IEC) mice was used. Colitis was induced by dextran sulfate sodium (DSS). The composition and diversity of gut microbiota were assessed via 16S rRNA analysis and the metabolomic findings was obtained from mice feces via metabolite profiling. The fecal microbiota transplantation (FMT) experiment was performed to confirm the association of gut microbiota and LPC. WT mice were treated with Lysophosphatidylcholine (LPC) to verify its impact on colitis. Results The expression of Fut2 and α-1,2-fucosylation in colonic tissues were decreased in patients with UC (UC vs. control, P = 0.036) and CD (CD vs. control, P = 0.031). When treated with DSS, in comparison to WT mice, more severe intestinal inflammation and destructive barrier functions in Fut2△IEC mice was noted. Lower gut microbiota diversity was observed in Fut2△IEC mice compared with WT mice (p < 0.001). When exposed to DSS, gut bacterial diversity and composition altered obviously in Fut2△IEC mice and the fecal concentration of LPC was increased. FMT experiment revealed that mice received the fecal microbiota from Fut2△IEC mice exhibited more severe colitis and higher fecal LPC concentration. Correlation analysis showed that the concentration of LPC was positively correlated with four bacteria—Escherichia, Bilophila, Enterorhabdus and Gordonibacter. Furthermore, LPC was proved to promote the release of pro-inflammatory cytokines and damage epithelial barrier in vitro and in vivo. Conclusion Fut2 and α-1,2-fucosylation in colon were decreased not only in CD but also in UC patients. Gut microbiota in Fut2△IEC mice is altered structurally and functionally, promoting generation of LPC which was proved to promote inflammation and damage epithelial barrier.

Fat of the Gut: Epithelial Phospholipids in Inflammatory Bowel Diseases

“…As a result of PC hydrolysis, LPC and fatty acids such as arachidonic acid are formed [ 126 ]. Although LPC may be toxic to the intestinal mucosa, the data on the role of arachidonic acid in IBD is more complex [ 127 , 128 ]. Although it was reported to have an ameliorating effect on the intestine [ 129 , 130 ], it was also shown to activate inflammatory pathways, which may contribute to the enhancement of colitis [ 131 , 132 ].…”

The barrier and beyond: Roles of intestinal mucus and mucin-type O-glycosylation in resistance and tolerance defense strategies guiding host-microbe symbiosis

“…Braun and colleagues have shown this susceptibly is linked to altered microbiota composition and energy metabolism, and increased inflammatory tone of the colon, although mechanisms are unclear. 86 This may be linked to increased lysophosphatidylcholine production by microbes belonging the genera Escherichia, Bilophila, Enterorhabdus , and Gordonibacter in the absence of gut epithelial Fut2, which enhanced proinflammatory cytokine production and susceptibility to DSS colitis 87 ( Figure 3A ). Sonnenburg and colleagues have shown the influence of fucosylation is dependent on diet, as the microbiota changes induced by fucose deficiency were only apparent in agricultural vs. fiber-free diets.…”

Gastrointestinal microbiome and Helicobacter pylori: Eradicate, leave it as it is, or take a personalized benefit–risk approach?

“…A recent study showed that patients with ulcerative colitis and Crohn’s disease had decreased FUT2 expression and α1,2-fucosylation in the colon[ 41 ]. In addition, Fut2 deficiency in the intestinal epithelium exacerbated colitis in epithelium-specific Fut2 knockout ( Fut2 △IEC ) mice, promoted the release of proinflammatory cytokines, and aggravated epithelial barrier damage[ 41 ].…”

“…A recent study showed that patients with ulcerative colitis and Crohn’s disease had decreased FUT2 expression and α1,2-fucosylation in the colon[ 41 ]. In addition, Fut2 deficiency in the intestinal epithelium exacerbated colitis in epithelium-specific Fut2 knockout ( Fut2 △IEC ) mice, promoted the release of proinflammatory cytokines, and aggravated epithelial barrier damage[ 41 ]. The authors demonstrated for the first time that epithelium-specific Fut2 deficiency increased susceptibility to IBD through modulation of the gut microbiome and microbiota-mediated lysophosphatidylcholine generation.…”

“…The authors demonstrated for the first time that epithelium-specific Fut2 deficiency increased susceptibility to IBD through modulation of the gut microbiome and microbiota-mediated lysophosphatidylcholine generation. Lysophosphatidylcholine may have deleterious effects on the colon by promoting the release of proinflammatory cytokines, damaging the tight junctions and epithelial barrier in the colon epithelium, and exacerbating colonic inflammation in Fut2 ΔIEC mice[ 41 ].…”