Enhancement of gut barrier integrity by a Bacillus subtilis secreted metabolite through the GADD45A-Wnt/β-catenin pathway

IF 23.7 Q1 MICROBIOLOGY
iMeta Pub Date : 2025-02-23 DOI:10.1002/imt2.70005
Shiqi Liu, Peiran Cai, Wenjing You, Mingshun Yang, Yuang Tu, Yanbing Zhou, Teresa G. Valencak, Yingping Xiao, Yizhen Wang, Tizhong Shan
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Abstract

Inflammatory bowel disease (IBD) represents a significant challenge to global health, characterized by intestinal inflammation, impaired barrier function, and dysbiosis, with limited therapeutic options. In this study, we isolated a novel strain of Bacillus subtilis (B. subtilis) and observed promising effects in protecting against disruption of the gut barrier. Our findings indicate that the enhancement of intestinal barrier function is primarily attributed to its metabolites. We identified a novel metabolite, 2-hydroxy-4-methylpentanoic acid (HMP), derived from B. subtilis, that significantly improved intestinal barrier function. We also show that growth arrest and DNA damage 45A (GADD45A) is a key regulator of mucosal barrier integrity, which is activated by HMP and subsequently activates the downstream Wnt/β-catenin pathway. Our findings potentially contribute to the development of probiotics-derived metabolites or targeted “postbiotics” as novel therapeutics for the treatment or prevention of IBD and other diseases associated with intestinal barrier dysfunction.

Abstract Image

枯草芽孢杆菌分泌代谢物通过GADD45A-Wnt/β-catenin途径增强肠道屏障完整性
炎症性肠病(IBD)是对全球健康的重大挑战,其特征是肠道炎症、屏障功能受损和生态失调,治疗选择有限。在这项研究中,我们分离了一株新的枯草芽孢杆菌(B. subtilis),并观察到在保护肠道屏障免受破坏方面有希望的效果。我们的研究结果表明,肠道屏障功能的增强主要归因于其代谢产物。我们发现了一种新的代谢物,2-羟基-4-甲基戊酸(HMP),来源于枯草芽孢杆菌,可以显著改善肠道屏障功能。我们还发现生长阻滞和DNA损伤45A (GADD45A)是粘膜屏障完整性的关键调节因子,它被HMP激活,随后激活下游Wnt/β-catenin通路。我们的发现可能有助于开发益生菌衍生代谢物或靶向“后益生菌”作为治疗或预防IBD和其他与肠屏障功能障碍相关疾病的新疗法。
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CiteScore
10.80
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