Document text
Principal Investigator: JUSTIN L SONNENBURG
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $427,265
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
The human gastrointestinal tract houses a complex gut microbiota, or microbiome that is tightly linked with numerous inflammatory and metabolic diseases. The gut microbiota influences local and systemic immune responses, chronic low-grade inflammation, and plays an important role in the pathogenesis of obesity-related insulin resistance, type 2 diabetes, and inflammatory bowel diseases. Diet is a key modulator of gut microbiota metabolism, composition, and functional capacity as well as human health. Despite recent progress, still relatively little is known about the mechanisms that connect specific diets and molecules within diet to the microbiota and human health. Fermented foods have been recently shown to increase human gut microbiota diversity and decrease markers of inflammation, and preliminary data within this application show that fermented vegetable brine (FVB), filter sterilized FVB (sFVB) and lactate (a major metabolite within sFVB) can induce regulatory T cells (Tregs) in mice. This application is focused on investigating molecules within fermented vegetable brine, with a focus on lactate, that are capable of modulating aspects of host biology relevant allergy and inflammation and understanding how cues from gut microbes impact these interactions. The goals of this application include (i) defining the mechanisms by which fermented foods vegetable brine facilitate the engraftment of new strains to increase microbiota diversity, (ii) characterizing the requirement of gut microbes in lactate induced Treg expansion, (iii) determining the host perception pathways that are responsible for lactate-induced Treg expansion in a mouse model. Aim 1 will determine how microbiota diversity acquisition, a feature of gut microbiomes linked to health, is promoted by fermented foods. This aim will reveal to what extent diversity increase is intrinsic to a microbiota versus requires exogenous microbes. Aim 2 will investigate the dependence of lactate induced Treg expansion on components of the gut microbiota. Experiments will identify how specific gut resident microbes impact Treg expansion in the presence of oral lactate and what molecular cues are required for Treg expansion. Aim 3 will employ mice genetically lacking lactate-binding G-protein coupled receptors to establish the basis of lactate perception. This project will advance our understanding of how fermented foods and metabolites within these foods impact the microbiota and host biology for improved health.
Terms: <21+ years old><Activities of Daily Living><Activities of everyday life><Adult><Adult Human><Adult-Onset Diabetes Mellitus><Affect><Alimentary Canal><Allergic><Allergic to food><Allergy><Allergy to food><Anaphylactic Reaction><Anaphylactic Shock><Anaphylaxis><Animal Disease Models><Area><Binding><Biological><Biology><Cellular Immune Function><Chronic><Chronic Disease><Chronic Illness><Clinical Trials><Complex><Consumption><Cues><Data><Dependence><Diet><Dietary Intervention><Digestive Tract><Disease><Disorder><Distal><Engraftment><Fermentation><Food><Food Allergy><Food Hypersensitivity><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GI Tract><GI microbiome><GI microbiota><GPCR><Gastrointestinal Tract><Gastrointestinal microbiota><Gastrointestinal tract structure><Gnotobiotic><Gnotobiotics><Goals><Health><Health Promotion><Human><Hypersensitivity><Immune><Immune response><Immune system><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Incidence><Inflammation><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Inflammatory Response><Insulin Resistance><Intermediary Metabolism><Ketosis-Resistant Diabetes Mellitus><Link><Maturity-Onset Diabetes Mellitus><Medicine><Metabolic Diseases><Metabolic Disorder><Metabolic Processes><Metabolism><Mice><Mice Mammals><Microbe><Modeling><Modern Man><Molecular><Molecular Interaction><Murine><Mus><NIDDK><NIDDM><NIH><National Institute of Diabetes and Digestive and Kidney Diseases><National Institutes of Health><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nutrition Interventions><Nutritional Interventions><Obesity><Oral><Pathogenesis><Pathway interactions><Perception><Play><Population><Prediabetes><Prediabetes syndrome><Prediabetic State><Regulatory T-Lymphocyte><Research><Role><Salutogenesis><Severities><Slow-Onset Diabetes Mellitus><Small Intestines><Stable Diabetes Mellitus><Strategic Planning><T2 DM><T2D><T2DM><Therapeutic><Therapeutic Intervention><Thesaurismosis><Treg><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><United States National Institutes of Health><Vegetables><Work><Yogurt><adiposity><adult onset diabetes><adulthood><alimentary tract><biologic><chronic disorder><combat><community microbes><corpulence><daily living function><daily living functionality><diet intervention><dietary><dietary vegetable><diets><digestive canal><digestive tract microbiome><disease model><disorder model><enteric microbial community><enteric microbiome><enteric microbiota><experiment><experimental research><experimental study><experiments><fecal sample><functional ability><functional capacity><gastrointestinal microbial flora><gastrointestinal microbiome><gut commensal><gut community><gut flora><gut microbe community><gut microbes><gut microbial community><gut microbial composition><gut microbial consortia><gut microbial species><gut microbiome><gut microbiota><gut microbiotic><gut microflora><gut-associated microbiome><host microbiota><host microflora><host response><immune function><immune system response><immunoresponse><improved><inflammation marker><inflammatory disease of the intestine><inflammatory disorder of the intestine><inflammatory marker><inflammatory modulation><insulin resistant><insulin tolerance><intervention therapy><intestinal autoinflammation><intestinal biome><intestinal flora><intestinal microbes><intestinal microbiome><intestinal microbiota><intestinal microflora><intestinal tract microflora><ketosis resistant diabetes><maturity onset diabetes><member><metabolism disorder><metagenome sequencing><metagenomic sequencing><microbial colonization><microbial community><microbial consortia><microbial flora><microbiome><microbiota><microbiota composition><microflora><mouse model><multispecies consortia><murine model><new approaches><novel approaches><novel strategies><novel strategy><nutrition><pathway><polymicrobial community><pre-diabetes><pre-diabetic><prediabetic><prevent><preventing><promoting health><reconstitute><reconstitution><regulatory T-cells><resident microbes><resident microflora><small bowel><social role><stool sample><stool specimen><systemic inflammation><systemic inflammatory response><type 2 DM><type II DM><type two diabetes>