Elucidating the role of fasting in intestinal stemness and tissue regeneration

阐明禁食在肠道干性和组织再生中的作用

• 批准号: 10333023
• 负责人: Chia-Wei Cheng
• 金额: $ 24.9万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-02 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10333023
• 关键词: 3-hydroxy-3-methylglutaryl-coenzyme A; Affect; Agonist; Biological Assay; Cell Lineage; Data; Defect; Enzymes; Fasting; Foundations; Genetic Transcription; Germ-Free; Health; Homeostasis; Human; Human body; Injury; Intervention; Intestines; Ketone Bodies; Ketones; LGR5 gene; Ligase; Mediating; Mediator of activation protein; Metabolic; Metabolism; Mus; Organ; Organoids; PPAR alpha; PPAR delta; Pathway interactions; Pharmacology; Play; Process; Production; Radiation; Regimen; Reporter; Role; Signal Transduction; Technology; Testing; Therapeutic; Tissues; Whole Organism; adult stem cell; beta-Hydroxybutyrate; epithelium regeneration; fatty acid oxidation; gut microbiome; gut microbiota; improved; in vivo; insight; intestinal epithelium; intestinal injury; ketogenesis; ketogentic; microbiome composition; mouse model; notch protein; novel; programs; regeneration function; response; single-cell RNA sequencing; stem cell aging; stem cell function; stem cells; stemness; tissue regeneration; tissue repair

7. Project Summary/Abstract Fasting interventions improve health in mice and in humans. Given that adult stem cells coordinate tissue adaptation, understanding the mechanism(s) that mediate the fasting response has important implications for enhancing tissue repair after injury and in aging where stem cell function declines. In the mammalian intestine, LGR5+ intestinal stem cells (ISCs) drive the rapid renewal of the intestinal lining. We previously showed that fasting augments ISC function by inducing a peroxisome proliferator-activated receptor delta (PPARδ) driven fatty acid oxidation (FAO) program. However, the in vivo role of PPARδ or downstream effector(s) of FAO metabolism that mediate the ISC fasting response remains unknown. In this proposal, we will test the hypotheses that 1) PPARδ signaling is necessary for the in vivo ISC fasting response, 2) PPARδ- activated FAO stimulates intestinal stemness through the production of the ketone body β-hydroxybutyrate (βOHB) in fasting, and 3) changes in the gut microbiome are necessary, sufficient or both in mediating the ISC fasting response. In support of these notions, we find that PPARδ agonist treatment emulates the effects of fasting on ISCs. Furthermore, we find that enzymes of the ketogenic pathway that produce the ketone metabolite βOHB, including its rate-limiting step HMGCS2 (3-hydroxy-3-methylglutaryl-CoA synthetase 2), highly enrich for LGR5+ ISCs. Also, elevation of HMGCS2 expression and βOHB levels upon fasting correlates with enhanced ISC function while loss of HMGCS2 dampens ISC capacity to propagate organoids and biases their differentiation towards the secretory lineage. Importantly, these deficits can be rectified by βOHB treatment in cultures. Thus, these observations provide a possible pathway for fasting through the modulation of HMGCS2-mediated ketogenesis to augment the regenerative function of ISCs. Lastly, fasting regimens are known to alter the gut microbiome composition but the extent to which these changes underlie the ISC fasting response requires elucidation. Remaining questions regarding the specific in vivo role of PPARδ as an upstream regulator of HMGCS2 expression and ISC fasting response, the in vivo role of HMGCS2 and βOHB as mediators of intestinal stemness and the contribution of the fasting gut microbiota in these processes.

7. 项目总结/文摘