Microbial-Derived Metabolites Regulate the Colonic Crypt Niche

In the mammalian intestine, crypts of Leiberkühn house intestinal epithelial stem /progenitor cells at their base. We found that the presence of this structure was supported by the physiologic role of a prominent bacterial metabolite, butyrate. This bacterially-produced short chain fatty acid inhibited intestinal epithelial proliferation at physiologic concentrations. During homeostasis, butyrate did not suppress epithelial stem proliferation because it was metabolized by differentiated colonocytes. Provision of butyrate access to stem/progenitor cells either through mucosal injury or application to a crypt-less host led to inhibition of proliferation. The mechanism was dependent on HDAC inhibition in stem cells and the transcription factor Foxo3. Thus, the mammalian crypt unit structure provides energy for differentiated cells at a distance from the crypt base and this action prevents suppression of stem/progenitor proliferation. Overall design: In total 4 samples were analyzed from 2 independent experiments. Two samples of colonic stem cells treated with 1mM Butyrate and two samples of colonic stem cells treated with 1mM NaCl (mock) as a control

在哺乳动物肠道中，李贝库恩隐窝（crypts of Lieberkühn）的基底区域寄居着肠上皮干细胞/祖细胞。本研究发现，该隐窝结构的生理稳态维持，依赖于一类关键细菌代谢产物丁酸（butyrate）的生理学作用。这种细菌来源的短链脂肪酸在生理浓度下可抑制肠上皮细胞增殖。在生理稳态条件下，丁酸并不会抑制上皮干细胞增殖，因为它会被分化成熟的结肠上皮细胞代谢利用。当通过黏膜损伤或向无隐窝宿主施加丁酸的方式，使干细胞/祖细胞直接接触丁酸时，细胞增殖会受到显著抑制。该调控机制依赖于干细胞内的组蛋白去乙酰化酶（HDAC）抑制效应以及转录因子Foxo3。综上，哺乳动物肠隐窝结构可向远离隐窝基底的分化成熟细胞提供能量，这一机制避免了干细胞/祖细胞的增殖受到抑制。
实验设计：本研究共纳入2次独立实验的4份样本，其中2份为经1mM丁酸处理的结肠干细胞样本，剩余2份为经1mM氯化钠（NaCl）处理的结肠干细胞空白对照（mock）样本。