2. Academic Validation
  3. Metabolic engineering of commensal bacteria for gut butyrate delivery and dissection of host-microbe interaction

Metabolic engineering of commensal bacteria for gut butyrate delivery and dissection of host-microbe interaction

  • Metab Eng. 2023 Sep 17:80:94-106. doi: 10.1016/j.ymben.2023.09.008.
Xu Gong 1,  Hongwei Geng 1,  Yun Yang 2,  Shuyi Zhang 3,  Zilong He 4,  Yubo Fan 4,  Fengyi Yin 4,  Zhifa Zhang 4,  Guo-Qiang Chen 5
Affiliations

Affiliations

  • 1 Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Engineering Medicine, Beihang University, Beijing, 100191, PR China; Key Laboratory of Big Data-Based Precision Medicine, Ministry of Industry and Information Technology, Beihang University, Beijing, 100191, PR China.
  • 2 Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Engineering Medicine, Beihang University, Beijing, 100191, PR China; Key Laboratory of Big Data-Based Precision Medicine, Ministry of Industry and Information Technology, Beihang University, Beijing, 100191, PR China. Electronic address: [email protected].
  • 3 School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, PR China; Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, PR China.
  • 4 Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Engineering Medicine, Beihang University, Beijing, 100191, PR China.
  • 5 Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, PR China; MOE Key Lab of Industrial Biocatalysis, Department of Chemical Engineering, Tsinghua University, Beijing, 100084, PR China; Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, PR China. Electronic address: [email protected].
PMID: 37717646 DOI: 10.1016/j.ymben.2023.09.008
Abstract

An overwhelming number of studies have reported the correlation of decreased abundance of butyrate-producing commensals with a wide range of diseases. However, the molecular-level mechanisms whereby gut butyrate causally affects the host mucosal immunity and pathogenesis were poorly understood, hindered by the lack of efficient tools to control intestinal butyrate. Here we engineered a facultative anaerobic commensal bacterium to delivery butyrate at the intestinal mucosal surface, and implemented it to dissect the causal role of gut butyrate in regulating host intestinal homeostasis in a model of murine chronic colitis. Mechanistically, we show that gut butyrate protected against colitis and preserved intestinal mucosal homeostasis through its inhibiting effect on the key Pyroptosis executioner gasdermin D (GSDMD) of colonic epithelium, via functioning as an HDAC3 Inhibitor. Overall, our work presents a new avenue to build synthetic living delivery bacteria to decode causal molecules at the host-microbe interface with molecular-level insights.

Keywords

Butyrate; Colitis; Engineered bacteria; In situ delivery; Pyroptosis.

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