Budesonide, an anti-inflammatory drug, exacerbate clostridioides difficile colitis in mice

Qianyun Lin; Zitong Li; Lei Lu; Hua Xu; Eddie Lou; Alyssa Chen; Dustin Sun; Wuyi Zhang; Weishu Zhu; Eric U Yee; Pamela Suzanne Sears; Xinhua Chen; Ciaran P Kelly

doi:10.1016/j.biopha.2023.115489

Budesonide, an anti-inflammatory drug, exacerbate clostridioides difficile colitis in mice

Biomed Pharmacother. 2023 Nov:167:115489. doi: 10.1016/j.biopha.2023.115489. Epub 2023 Sep 15.

Authors

Qianyun Lin¹, Zitong Li², Lei Lu³, Hua Xu⁴, Eddie Lou⁴, Alyssa Chen⁴, Dustin Sun⁴, Wuyi Zhang⁴, Weishu Zhu⁴, Eric U Yee⁵, Pamela Suzanne Sears⁶, Xinhua Chen⁷, Ciaran P Kelly⁸

Affiliations

¹ Department of Gastroenterology, Beijing Friendship Hospital, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Capital Medical University, Beijing, China; Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA.
² Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
³ Section of Neonatology, Department of Paediatrics and Medicine, the University of Chicago, Chicago, IL, USA.
⁴ Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA.
⁵ Department of Pathology, Beth Israel Deaconess Medical Centre, Boston, MA, USA; Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
⁶ Merck & Co., Inc, Rahway, NJ, USA.
⁷ Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA. Electronic address: xchen1@bidmc.harvard.edu.
⁸ Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA. Electronic address: ckelly2@bidmc.harvard.edu.

PMID: 37713991
DOI: 10.1016/j.biopha.2023.115489

Abstract

Background and aims: Clostridioides difficile infection (CDI) induces intense acute inflammatory responses through toxin release. A combination of antibiotic and anti-inflammatory agents is sometimes recommended in severe, non-responsive cases, although clinical trials have been inconclusive, raising concerns about potential complications. This study aims to investigate the effect of budesonide and mesalamine in the treatment of CDI in a murine model, by evaluating the combination of fidaxomicin and these anti-inflammatory drugs.

Method: C57BL/6 J female mice pretreated with an antimicrobial mixture were challenged with C. difficile VPI 10463 or culture media by gavage. After the challenge, mice received placebo, fidaxomicin alone (20 mg/kg), or fidaxomicin combined with mesalamine (200, 400 mg/kg) or budesonide (0.2, 1, 10 mg/kg) for 5 days. The mice were monitored for 7 days with weight and survival. Colon and cecum tissues were harvested for histological assessment.

Results: CDI of mice caused 80% mortality. Fidaxomicin completely protected against CDI in all parameters (weight, survival and pathscores). Mortality rates were up to 90%, 70% in budesonide(10 mg/kg) and mesalamine (400 mg/kg) treatment group, respectively. Budesonide (0.02,0.1 and 1 mg/kg) adjunction to fidaxomicin worsened the disease outcome according to all tested parameters. While mesalamine in combination with fidaxomicin (200, 400 mg/kg) did not lead to any deaths during CDI treatment, it did not provide additional benefits.

Conclusions: Anti-inflammatory drugs including corticosteroid therapy may worsen the incidence and severity of CDI in this mouse model. These studies may have important clinical implications for understanding the role of anti-inflammatory/ corticosteroid therapy in CDI and inflammatory bowel disease management.

Keywords: Budesonide; C. difficile; Fidaxomicin; Mesalamine.