TKT maintains intestinal ATP production and inhibits apoptosis-induced colitis

Na Tian,Xuemei Tong,Ming Feng,Qi Liu,Yakui Li,Yemin Zhu,Yingning Ji,Ying Lu,Lifang Wu,Lei Hu,Lingfeng Tong,Tianle Xu,Ping Zhang

doi:10.1038/s41419-021-04142-4

Abstract

Inflammatory bowel disease (IBD) has a close association with transketolase (TKT) that links glycolysis and the pentose phosphate pathway (PPP). However, how TKT functions in the intestinal epithelium remains to be elucidated. To address this question, we specifically delete TKT in intestinal epithelial cells (IECs). IEC TKT-deficient mice are growth retarded and suffer from spontaneous colitis. TKT ablation brings about striking alterations of the intestine, including extensive mucosal erosion, aberrant tight junctions, impaired barrier function, and increased inflammatory cell infiltration. Mechanistically, TKT deficiency significantly accumulates PPP metabolites and decreases glycolytic metabolites, thereby reducing ATP production, which results in excessive apoptosis and defective intestinal barrier. Therefore, our data demonstrate that TKT serves as an essential guardian of intestinal integrity and barrier function as well as a potential therapeutic target for intestinal disorders.

Highlights

The mammalian intestinal epithelium is composed of a monolayer of columnar epithelial cells organized into crypts and villi that renews every 4–5 days [1]
Once the intestinal barrier function is disturbed by various risk factors such as deregulated apoptosis, the intestinal mucosa directly contacts with the luminal invading pathogens and ingested toxins to promote inflammatory responses, leading to intestinal disorders including inflammatory bowel disease (IBD) [4]
TKTΔIEC mice spontaneously develop colitis When exploring how loss of TKT in intestinal epithelial cells (IECs) resulted in growth retardation, we observed that TKTΔIEC mice displayed symptoms of colitis, including frequent loose stools, diarrhea and even rectal prolapses (Fig. 2A)

Summary

Introduction

The mammalian intestinal epithelium is composed of a monolayer of columnar epithelial cells organized into crypts and villi that renews every 4–5 days [1]. It is an important metabolic tissue, serving a variety of physiological functions including digestion and absorption of nutrients as well as forming a physical and biochemical barrier against enteric pathogens to maintain tissue homeostasis [1,2,3]. Metabolic genes including pyruvate kinase (PKM2), NADPH oxidase (NOX) and TIGAR have been shown to involve in the progression of IBD [11,12,13]. Focus on the regulation of metabolism in IBD may provide new insights into clinical therapies

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Conclusion