R01DK129840

The Role of Gut Microbes and Microbial-Derived Metabolites in the Development of Type 2 Diabetes in Humans - Project Summary

Mounting evidence links the gut microbiome - the modifiable "second genome" consisting of trillions of diverse microbes that inhabit the human gut - with Type 2 Diabetes Mellitus (T2DM) in humans. Studies using fecal transplant in mice have raised the central hypothesis that changes in the gut microbiome and the biochemical by-products originated from these microbes may be key modulators of the development of T2DM.

To date, however, knowledge of the specific microbial species that drive the development of T2DM in humans remains very limited. Human studies of the gut microbiome in T2DM have largely been cross-sectional and confounded by reverse causality. Indeed, many of the gut microbiome changes observed in human T2DM have been found to be a consequence of the disease or treatments, including the medication metformin, rather than a cause of T2DM.

In addition, the circulating metabolites derived from the gut microbes that contribute to the development of T2DM remain to be discovered. In this early-stage investigator NIH R01 application, we propose the largest prospective study of the role of the gut microbiome in T2DM using a Finnish cohort of 6,921 individuals with fecal and plasma samples collected in 2002 and over 15 years of subsequent clinical follow-up.

This proposed study brings together a diverse team with deep expertise in the human microbiome, mass-spectrometry-based metabolomics, computational biology, statistical epidemiology, and diabetes pathobiology, to specifically address the key biological and clinical questions regarding the role of gut microbes and microbial-derived metabolites in the development of incident T2DM in humans.

San Diego University Of California

(1) TO PROMOTE EXTRAMURAL BASIC AND CLINICAL BIOMEDICAL RESEARCH THAT IMPROVES THE UNDERSTANDING OF THE MECHANISMS UNDERLYING DISEASE AND LEADS TO IMPROVED PREVENTIONS, DIAGNOSIS, AND TREATMENT OF DIABETES, DIGESTIVE, AND KIDNEY DISEASES. PROGRAMMATIC AREAS WITHIN THE NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES INCLUDE DIABETES, DIGESTIVE, ENDOCRINE, HEMATOLOGIC, LIVER, METABOLIC, NEPHROLOGIC, NUTRITION, OBESITY, AND UROLOGIC DISEASES. SPECIFIC PROGRAMS AREAS OF INTEREST INCLUDE THE FOLLOWING: (A) FOR DIABETES, ENDOCRINE, AND METABOLIC DISEASES AREAS: FUNDAMENTAL AND CLINICAL STUDIES INCLUDING THE ETIOLOGY, PATHOGENESIS, PREVENTION, DIAGNOSIS, TREATMENT AND CURE OF DIABETES MELLITUS AND ITS COMPLICATIONS, NORMAL AND ABNORMAL FUNCTION OF THE PITUITARY, THYROID, PARATHYROID, ADRENAL, AND OTHER HORMONE SECRETING GLANDS, HORMONAL REGULATION OF BONE, ADIPOSE TISSUE, AND LIVER, ON FUNDAMENTAL ASPECTS OF SIGNAL TRANSDUCTION, INCLUDING THE ACTION OF HORMONES, COREGULATORS, AND CHROMATIN REMODELING PROTEINS, HORMONE BIOSYNTHESIS, SECRETION, METABOLISM, AND BINDING, AND ON HORMONAL REGULATION OF GENE EXPRESSION AND THE ROLE(S) OF SELECTIVE RECEPTOR MODULATORS AS PARTIAL AGONISTS OR ANTAGONISTS OF HORMONE ACTION, AND FUNDAMENTAL STUDIES RELEVANT TO METABOLIC DISORDERS INCLUDING MEMBRANE STRUCTURE, FUNCTION, AND TRANSPORT PHENOMENA AND ENZYME BIOSYNTHESIS, AND BASIC AND CLINICAL STUDIES ON THE ETIOLOGY, PATHOGENESIS, PREVENTION, AND TREATMENT OF INHERITED METABOLIC DISORDERS (SUCH AS CYSTIC FIBROSIS). (B) FOR DIGESTIVE DISEASE AND NUTRITION AREAS: GENETICS AND GENOMICS OF THE GI TRACT AND ITS DISEASES, GENETICS AND GENOMICS OF LIVER/PANCREAS AND DISEASES, GENETICS AND GENOMICS OF NUTRITION, GENETICS AND GENOMICS OF OBESITY, BARIATRIC SURGERY, CLINICAL NUTRITION RESEARCH, CLINICAL OBESITY RESEARCH, COMPLICATIONS OF CHRONIC LIVER DISEASE, FATTY LIVER DISEASE, GENETIC LIVER DISEASE, HIV AND LIVER, CELL INJURY, REPAIR, FIBROSIS AND INFLAMMATION IN THE LIVER, LIVER CANCER, LIVER TRANSPLANTATION, PEDIATRIC LIVER DISEASE, VIRAL HEPATITIS AND INFECTIOUS DISEASES, GASTROINTESTINAL AND NUTRITION EFFECTS OF AIDS, GASTROINTESTINAL MUCOSAL AND IMMUNOLOGY, GASTROINTESTINAL MOTILITY, BASIC NEUROGASTROENTEROLOGY, GASTROINTESTINAL DEVELOPMENT, GASTROINTESTINAL EPITHELIAL BIOLOGY, GASTROINTESTINAL INFLAMMATION, DIGESTIVE DISEASES EPIDEMIOLOGY AND DATA SYSTEMS, NUTRITIONAL EPIDEMIOLOGY AND DATA SYSTEMS, AUTOIMMUNE LIVER DISEASE, BILE, BILIRUBIN AND CHOLESTASIS, BIOENGINEERING AND BIOTECHNOLOGY RELATED TO DIGESTIVE DISEASES, LIVER, NUTRITION AND OBESITY, CELL AND MOLECULAR BIOLOGY OF THE LIVER, DEVELOPMENTAL BIOLOGY AND REGENERATION, DRUG-INDUCED LIVER DISEASE, GALLBLADDER DISEASE AND BILIARY DISEASES, EXOCRINE PANCREAS BIOLOGY AND DISEASES, GASTROINTESTINAL NEUROENDOCRINOLOGY, GASTROINTESTINAL TRANSPORT AND ABSORPTION, NUTRIENT METABOLISM, PEDIATRIC CLINICAL OBESITY, CLINICAL TRIALS IN DIGESTIVE DISEASES, LIVER CLINICAL TRIALS, OBESITY PREVENTION AND TREATMENT, AND OBESITY AND EATING DISORDERS. (C) FOR KIDNEY, UROLOGIC AND HEMATOLOGIC DISEASES AREAS: STUDIES OF THE DEVELOPMENT, PHYSIOLOGY, AND CELL BIOLOGY OF THE KIDNEY, PATHOPHYSIOLOGY OF THE KIDNEY, GENETICS OF KIDNEY DISORDERS, IMMUNE MECHANISMS OF KIDNEY DISEASE, KIDNEY DISEASE AS A COMPLICATION OF DIABETES, EFFECTS OF DRUGS, NEPHROTOXINS AND ENVIRONMENTAL TOXINS ON THE KIDNEY, MECHANISMS OF KIDNEY INJURY REPAIR, IMPROVED DIAGNOSIS, PREVENTION AND TREATMENT OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE, IMPROVED APPROACHES TO MAINTENANCE DIALYSIS THERAPIES, BASIC STUDIES OF LOWER URINARY TRACT CELL BIOLOGY, DEVELOPMENT, PHYSIOLOGY, AND PATHOPHYSIOLOGY, CLINICAL STUDIES OF BLADDER DYSFUNCTION, INCONTINENCE, PYELONEPHRITIS, INTERSTITIAL CYSTITIS, BENIGN PROSTATIC HYPERPLASIA, UROLITHIASIS, AND VESICOURETERAL REFLUX, DEVELOPMENT OF NOVEL DIAGNOSTIC TOOLS AND IMPROVED THERAPIES, INCLUDING TISSUE ENGINEERING STRATEGIES, FOR UROLOGIC DISORDERS,RESEARCH ON HEMATOPOIETIC CELL DIFFERENTIATION, METABOLISM OF IRON OVERLOAD AND DEFICIENCY, STRUCTURE, BIOSYNTHESIS AND GENETIC REGULATION OF HEMOGLOBIN, AS WELL AS RESEARCH ON THE ETIOLOGY, PATHOGENESIS, AND THERAPEUTIC MODALITIES FOR THE ANEMIA OF INFLAMMATION AND CHRONIC DISEASES. (2) TO ENCOURAGE BASIC AND CLINICAL RESEARCH TRAINING AND CAREER DEVELOPMENT OF SCIENTISTS DURING THE EARLY STAGES OF THEIR CAREERS. THE RUTH L. KIRSCHSTEIN NATIONAL RESEARCH SERVICE AWARD (NRSA) FUNDS BASIC AND CLINICAL RESEARCH TRAINING, SUPPORT FOR CAREER DEVELOPMENT, AND THE TRANSITION FROM POSTDOCTORAL BIOMEDICAL RESEARCH TRAINING TO INDEPENDENT RESEARCH RELATED TO DIABETES, DIGESTIVE, ENDOCRINE, HEMATOLOGIC, LIVER, METABOLIC, NEPHROLOGIC, NUTRITION, OBESITY, AND UROLOGIC DISEASES. (3) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM. THE SBIR PROGRAM AIMS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO ENHANCE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. (4) TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM. THE STTR PROGRAM INTENDS TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.847 - Diabetes, Digestive, and Kidney Diseases Extramural Research

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [HHS - NIH]

La Jolla, California 92093 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 396% from $642,344 to $3,184,687.