Peroxisome proliferator-activated receptor-γ as the gatekeeper of tight junction in Clostridioides difficile infection

Yi-Hsin Lai; Tai-Chieh Wu; Bo-Yang Tsai; Yuan-Pin Hung; Hsiao-Ju Lin; Yau-Sheng Tsai; Wen-Chien Ko; Pei-Jane Tsai

doi:10.3389/fmicb.2022.986457

Peroxisome proliferator-activated receptor-γ as the gatekeeper of tight junction in Clostridioides difficile infection

Front Microbiol. 2022 Nov 11:13:986457. doi: 10.3389/fmicb.2022.986457. eCollection 2022.

Authors

Yi-Hsin Lai¹, Tai-Chieh Wu², Bo-Yang Tsai¹, Yuan-Pin Hung^{3

4

5}, Hsiao-Ju Lin^{4

6}, Yau-Sheng Tsai^{6

7}, Wen-Chien Ko^{4

5}, Pei-Jane Tsai^{1

2

8

9}

Affiliations

¹ Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
² Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
³ Departments of Internal Medicine, Tainan Hospital, Ministry of Health & Welfare, Tainan, Taiwan.
⁴ Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁵ Department of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁶ Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan.
⁷ Clinical Medicine Research Center, National Cheng Kung University Hospital, Tainan, Taiwan.
⁸ Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan.
⁹ Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Abstract

Clostridioides difficile is a major causative pathogen of nosocomial antibiotic-associated diarrhea and severe colitis. Despite the use of vancomycin and fidaxomicin as standard drugs for the treatment of C. difficile infection (CDI), clinical relapse rates remain high. Therefore, new alternative therapeutics to treat CDI are urgently required. The nuclear receptor, peroxisome proliferator-activated receptor-γ (PPAR-γ), is mainly expressed in the adipose tissue and modulates lipid metabolism and insulin sensitization. Previous studies have shown that PPAR-γ is highly expressed in colonic tissues and regulates tight junction function in epithelial cells. However, the role of PPAR-γ in CDI pathogenesis remains unclear. In this study, we used a mouse model of CDI and found that both expression levels of PPAR-γ and the tight junction protein, occludin, were decreased in colonic tissues. Furthermore, to investigate the role of PPAR-γ in CDI, we used PPAR-γ defective mice and found that intestinal permeability and bacterial dissemination in these mice were significantly higher than those in wild-type mice during CDI. Administration of the PPAR-γ agonist, pioglitazone, to activate PPAR-γ activity improved the phenotypes of CDI, including bodyweight loss, inflammation, and intestinal integrity. Taken together, these results demonstrate that PPAR-γ is a potential therapeutic target in CDI, as it modulates colonic inflammation and integrity.

Keywords: Clostridioides difficile; occludin; peroxisome proliferator-activated receptor-γ; pioglitazone; tight junction.