Interaction Between the Gut Microbiota and Colonic Enteroendocrine Cells Regulates Host Metabolism

Endocrinology Gastroenterology Medicine Bioengineering Biochemistry Life Sciences Microbiology
gut microbiota colonic enteroendocrine cells host metabolism obesity gut-brain axis glutamate

Title Page

Interaction Between Gut Microbiota and Colonic Enteroendocrine Cells Regulates Host Metabolism

Research Background

Obesity is a major health issue in the 21st century and a significant factor contributing to various adverse health consequences such as diabetes, fatty liver disease, and cardiovascular diseases. Therefore, exploring the biological mechanisms behind obesity is of great importance. Recent studies have shown that the gut microbiota plays a crucial role in host weight regulation. However, the role of colonic enteroendocrine cells (EECs) in host metabolic regulation has not been thoroughly investigated. The research team aims to uncover the specific functions of colonic EECs in host metabolic regulation and obesity development, attempting to solve this important scientific question.

Publication Source

The research findings were published in Nature Metabolism. The main authors include Shuai Tan, Jacobo L. Santolaya, Tiffany Freeney Wright, etc., from various research institutions such as Chongqing Medical University and UT Southwestern Medical Center. The paper was accepted and published online on April 9, 2024, furthering the understanding of the interaction between colonic EECs and the gut microbiota.

Research Design and Methods

Experimental Procedures

The research team utilized mouse models to investigate the role of colonic EECs in metabolic regulation. The specific methods included:

  1. Model Construction: By specifically deleting the neurog3 gene in the colon, a mouse model with colonic EEC deficiency (EECδcol) was created. RNA sequencing was used to verify the absence of colonic EECs.
  2. Obesity and Metabolic Studies: Using different diets (high-fat diet and normal diet), the research team monitored and compared the body weight changes, body fat percentages, pathological changes in the liver and adipose tissues, etc., between EECδcol mice and wild-type mice at different ages.
  3. Food Intake and Energy Balance Experiments: Through metabolic cage experiments, parameters such as food intake, energy expenditure, physical activity levels, and fecal heat output were measured in the mice.
  4. Glucose Tolerance Tests: By intraperitoneal injection of glucose and insulin, the glucose tolerance and insulin sensitivity of the mice were evaluated.

Furthermore, the study also explored the role of the gut microbiota in the obesity of EECδcol mice through techniques such as antibiotic treatment, co-housing experiments, and fecal transplantation.

Sample Processing and Technical Applications

The research utilized techniques such as RNA sequencing, mass spectrometry, and GC-MS to analyze tissue samples, fecal samples, and blood samples from the mice. Additionally, antibody labeling, microscopic imaging, and other methods were employed to observe changes in tissues. In terms of intestinal motility, ex vivo colonic motility recordings and spatio-temporal mapping techniques were used to evaluate the impact of colonic EEC deficiency on intestinal motility.

Research Results

  1. Colonic EEC Deficiency Leads to Obesity: EECδcol mice exhibited obesity characteristics under both normal and high-fat diets, primarily manifested as adipose tissue expansion and hepatic steatosis.
  2. Increased Food Intake: EECδcol mice displayed significantly higher food intake, while energy expenditure and physical activity levels remained unchanged.
  3. Impaired Glucose Tolerance: After intraperitoneal glucose injection, EECδcol mice showed a significant reduction in insulin and GLP-1 (glucagon-like peptide-1) responses, indicating impaired glucose tolerance.
  4. Role of the Gut Microbiota: Experiments involving antibiotic treatment, bacterial re-cultivation, and fecal transplantation demonstrated that the gut microbiota played a necessary and sufficient role in the obesity development of EECδcol mice. The fecal composition of EECδcol mice changed, with a specific increase in glutamate levels, which significantly increased food intake in mice.
  5. Intestinal Motility Dysregulation: EECδcol mice exhibited discoordinated colonic motility patterns, suggesting that colonic EECs also play an important role in the coordination of intestinal motility.

Conclusions and Significance

This study demonstrated the crucial role of colonic EECs in regulating host food intake, body weight, and metabolism. Notably, the research indicated that colonic EECs influence host metabolism by modulating the gut microbiota, with glutamate emerging as a key molecule. This discovery not only revealed the role of the colon in host metabolic regulation but also provided new insights for obesity treatment – by modulating the interaction between colonic EECs and the microbiota, weight control and metabolic health management could be achieved.

Research Highlights

  1. Discovery of an Overlooked Metabolic Regulatory Pathway: The study uncovered the mechanism by which colonic EECs influence host metabolism through the gut microbiota.
  2. Application of Diverse Experimental Techniques: The research comprehensively employed techniques such as gene editing, mouse models, mass spectrometry analysis, metabolic cage experiments, and more, ensuring comprehensiveness and rigor.
  3. Potential Clinical Value: The research results provided new molecular targets for regulating obesity and related metabolic disorders through the gut microbiota, possessing significant potential for applications.

Additional Information

The study supplemented some innovative methods, such as using colon-specific neurog3 gene deletion to study the functions of colonic EECs, and designed multiple parallel control experiments to ensure the reliability and reproducibility of the results. The research also pointed out issues that need further investigation, such as elucidating detailed mechanisms and developing potential therapeutic approaches. This type of research plays an important role in advancing the understanding of obesity pathological mechanisms and exploring corresponding clinical intervention strategies.