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. 2023 Dec;15(2):2282789.
doi: 10.1080/19490976.2023.2282789. Epub 2023 Nov 27.

Loss of claudin-3 expression increases colitis risk by promoting Gut Dysbiosis

Rizwan Ahmad  1 , Balawant Kumar  1 , Ishwor Thapa  2 , Geoffrey A Talmon  3 , Jeffrey Salomon  4 , Amanda E Ramer-Tait  5 , Dhundy K Bastola  2 , Punita Dhawan  1   6 , Amar B Singh  1   6
Affiliations

Loss of claudin-3 expression increases colitis risk by promoting Gut Dysbiosis

Rizwan Ahmad et al. Gut Microbes. 2023 Dec.

Abstract

Dysregulation of both the gut barrier and microbiota (dysbiosis) promotes susceptibility to and severity of Inflammatory Bowel Diseases (IBD). Leaky gut and dysbiosis often coexist; however, potential interdependence and molecular regulation are not well understood. Robust expression of claudin-3 (CLDN3) characterizes the gut epithelium, and studies have demonstrated a positive association between CLDN3 expression and gut barrier maturity and integrity, including in response to probiotics. However, the exact status and causal role of CLDN3 in IBD and regulation of gut dysbiosis remain unknown. Analysis of mouse and human IBD cohorts helped examine CLDN3 expression in IBD. The causal role was determined by modeling CLDN3 loss of expression during experimental colitis. 16S sequencing and in silico analysis helped examine gut microbiota diversity between Cldn3KO and WT mice and potential host metabolic responses. Fecal microbiota transplant (FMT) studies were performed to assess the role of gut dysbiosis in the increased susceptibility of Cldn3KO mice to colitis. A significant decrease in CLDN3 expression characterized IBD and CLDN3 loss of expression promoted colitis. 16S sequencing analysis suggested gut microbiota changes in Cldn3KO mice that were capable of modulating fatty acid metabolism and oxidative stress response. FMT from naïve Cldn3KO mice promoted colitis susceptibility in recipient germ-free mice (GFM) compared with GFM-receiving microbiota from WT mice. Our data demonstrate a critical role of CLDN3 in maintaining normal gut microbiota and inflammatory responses, which can be harnessed to develop novel therapeutic opportunities for patients with IBD.

Keywords: Claudin; FMT; dysbiosis; germ-free mice and IBD; gut barrier.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Robust decrease in CLDN3 expression characterize IBD patients and mice subjected to colitis.
Figure 2.
Figure 2.
Cldn3KO mice are susceptible to colitis.
Figure 3.
Figure 3.
Deletion of Cldn3 expression exhibits deregulated inflammatory signaling.
Figure 4.
Figure 4.
Pseudo-germ-free (microbial depletion) Cldn3KO mice show reduced severity of DSS-colitis.
Figure 5.
Figure 5.
Loss of endogenous Cldn3 expression alters gut microbial composition.
Figure 6.
Figure 6.
Relative abundance of bacterial communities in Cldn3KO differ from WT.
Figure 7.
Figure 7.
Gut dysbiosis in Cldn3KO mice leads to altered host metabolism.
Figure 8.
Figure 8.
Fecal microbiota transplantation (FMT) from Cldn3KO mice to germ-free C57BL/6 mice induces susceptibility to DSS colitis.
Figure 9.
Figure 9.
Cldn3KO microbiota potentiates inflammatory signaling in intestinal epithelial cells.
Figure 10.
Figure 10.
Microbiome associated signaling is altered in IBD and corelates with CLDN3 expression.
Figure 11.
Figure 11.
Host-microbiome interactions in IBD patient cohort show overlap with Cldn3KO mice.
See this image and copyright information in PMC

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