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

Xuelian Tang,Yuen Tian,Siran Zhu,Xiaohua Hou,Rong Lin,Weijun Wang,Wei Qian,Gaichao Hong,Caihan Duan,Chaoqun Han

doi:10.1186/s12929-021-00711-z

Abstract

Background and aimsPrevious 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.MethodsIntestinal 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.ResultsThe 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.ConclusionFut2 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.

Highlights

Inflammatory bowel disease (IBD) is a chronic inflammatory gastrointestinal disorder and a global public health concern [1, 2]
Fucosyltransferase 2 (Fut2) and α‐1,2‐fucosylation are down‐regulated in IBD patients and dextran sulfate sodium (DSS)‐induced colitis mice In comparison of heathy individuals, the expression of Fut2 gene was remarkably down-regulated in colon tissues of Ulcerative colitis (UC) (P = 0.036) and Crohn’s Disease (CD) patients (P = 0.031); Fut2 in all 5 CD patients and in 15 out of 16 UC patients was lower than one standard deviation of the controls (Fig. 1a)
The data above demonstrated that the expression of Fut2 and α-1,2fucosylation decreased in IBD patients and experimental colitis

Summary

Introduction

Inflammatory bowel disease (IBD) is a chronic inflammatory gastrointestinal disorder and a global public health concern [1, 2]. It is widely accepted that the etiology of IBD depends on dysregulation of immune responses interacting with gut microbiota and environmental. It has been newly reported that fucosyltransferase 2 (Fut2) non-secretor of state (individuals lacking a functional copy of Fut are known as non-secretors) is associated with Crohn’s Disease (CD) susceptibility [5, 6, 8], the mechanism remains unknown. Guntram et al [14] demonstrated that Salmonella expresses Std fimbriae in the gastrointestinal tract They demonstrated that Salmonella-triggered intestinal inflammation and colonization are dependent on Std-fucose interaction. These findings suggests potential regulatory effect of Fut on gut microbiota. Previous study disclosed Fucosyltransferase 2 (Fut2) gene as a IBD risk locus.

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