Study on the Microbiome and its Role in Obesity and Metabolic Syndrome

Prof. George Weinstock
Professor, Evnin Family Chair and Director of Microbial Genomics, Jackson Laboratory

Dr. Eran Elinav
The Rina Gudinski Career Development Chair, Weizmann Institute of Science

Kevan Herold, MD
Professor of Immunobiology and Internal Medicine, Yale School of Medicine

Project: Prof. George Weinstock of JAX and Dr. Eran Elinav will collaborate on a study of immunological and microbial contributions to obesity and the metabolic syndrome. Dr. Elinav, who completed his postdoctoral fellowship at Yale, is a physician-scientist (MD Ph.D.) and a member of the Weizmann Institute's Department of Immunology; his group studies the roles of microbiome-host immune interactions in health and disease. He is the incumbent of the Rina Gudinski Career Development Chair. Dr. Weinstock is Professor, Evnin Family Chair and Director of Microbial Genomics at JAX and former leader in the Human Genome Project, the Human Microbiome Project, and other large-scale applications of genomic technology. He received his Ph.D. from MIT and completed his postdoctoral fellowship at Stanford University Medical School.

Effects of the Microbiome on Immune Responses in Humanized Mice

Prof. George M. Weinstock
Professor, Evnin Family Chair and Director of Microbial Genomics, Jackson Laboratory

Anthony T. Vella, Ph.D.
Department of Immunology, School of Medicine, UConn Health

Atan Gross, Ph.D.
Department of Biological Regulation, Weizmann Institute for Science, Rehovot

Kevan C. Herold, M.D.
Professor of Immunobiology and Internal Medicine, Yale School of Medicine

Project: The human immune system is modulated by the microbiome. Several lines of investigation have described relationships between increases in common diseases such as allergies, autoimmune illnesses, and even obesity and type 2 diabetes to changes in the microbiome. These have increased in frequency in Western countries. Moreover, microbiome-related infections have become increasingly common, such as colitis from Clostridium difficile. In addition to serving as accelerators in the pathogenesis of these afflictions, the microbiome also can modify responses to biologics that are commonly used to treat patients. For example, recent studies have shown that in patients with cancer, responses to two commonly used immune therapeutics, anti-CTLA-4 monoclonal antibody (mAb) and anti-PD-L1 mAb are associated with the presence or absence of certain Bacteroides and Bifidobacterium species (Vetizou et al Science 2015, Sivan et al, Science 2015), and possibly mediated via surface polysaccharides of the bacteria.

Download Brief

Effects of the Microflora on Human Immune Responses

Kevan Herold, MD
Professor of Immunobiology and Internal Medicine, Yale School of Medicine

Project: Yale researchers have been interested in the role of the microbiome in modifying autoimmunity and the effects of immune agents on autoimmune therapies such as anti-CD3 antibody and others. In preliminary studies we have found that change in the microbiome, induced by antibiotics, can alter the effects of immune agents in humanized mice. In this model system, treatment of mice with human immune systems can block the effects of anti-CD3 antibody on preventing transplant rejection. Other studies, of agents such as anti-PD-L1 and anti-CTLA-4 antibodies have also shown that the effects of the drugs on cancer are modified by the micriobome of the host.

Yale researchers propose to evaluate the effects of the microflora on human immune responses following treatment with biologic agents in humanized mice. Specifically researchers propose to identify which organisms are important, how they modify immune cells, and determine whether the composition of the microbiome can determine responses to biologics among patients with autoimmunity and cancer. Yale researchers propose to collaborate with colleagues at the Weizmann Institute and Jackson laboratory who have expertise in the biology of the human microbiome and the effects of the microbiome on immune responses.

The collaboration will involve using model systems, bioinformatics, and analytics that have been developed at the three institutions. In some cases, investigators will travel to the other site to help establish models that may be used by collaborating research groups. Data can be shared electronically and web conferences can be used to enable teams to collaborate. Clinical material, from patients with autoimmunity and cancer can be obtained at Yale.

We anticipate that this collaboration will synergize efforts of research teams that are already working in this rapidly expanding area of investigation.</p.

Download Brief

High Fructose Corn Syrup and Brain Response Patterns

Robert Sherwin, MD
N. H. Long Professor of Medicine (Endocrinology); Section Chief, Endocrinology; Associate Dean for Clinical and Translational Sciences, Yale School of Medicine
Director, Yale Center for Clinical Investigation; Director, Yale Diabetes Research Center

Project: In America, 34% of adolescents and 67% of adults are overweight or obese, substantially increasing their long-term risk for developing type 2 diabetes and cardiovascular disease. Increased consumption of sugar-sweetened beverages is postulated to be a contributor to the obesity epidemic. It is not known, however, whether consumption of commonly-consumed sugars, such as high fructose corn syrup (HFCS), affects neural responses in reward-motivation, hunger-satiety, and decision-making areas of the human brain, thereby potentially altering eating behavior. In the proposed study, we will investigate how HFCS affects brain response patterns in obese and normal weight adolescents and adults, providing new insights into the factors influencing eating behavior and the development of obesity. The overall aim of this project is to identify brain response patterns in reward-motivation, hunger-satiety, and decision-making brain regions in response to drinking HFCS in normal weight and obese adolescents and adults. Our preliminary data using brain imaging have shown that obese adults as well as adolescents show much greater brain changes in motivation-reward and emotion processing regions during high-calorie food cue stimuli or following consumption of glucose, particularly in children. Thus, in an environment inundated with advertising promoting consumption of high-calorie foods, our data suggest that adolescents may be particularly vulnerable to such food cues, as their brains, particularly prefrontal cortices involved in inhibiting and regulating desires and emotions, are not fully developed. Whether the changes in brain function in obesity are reversible and the neurochemical mechanisms driving these changes are unknown, and will be a future direction of this work. These collaborative studies will take advantage of the brain imaging facilities at Yale and will involve patients recruited from Yale and the University of Connecticut. In addition, the work will take advantage of the scientific and metabolic analytic expertise of the Jackson Lab and the Weizmann Institute.

Altering Microbial Communities in the Gut

Martin Kriegel, MD, Ph.D.
Assistant Professor of Immunobiology and Rheumatology, Yale School of Medicine

Project: The Kriegel lab is interested in understanding how genetics shape the microbiome, the collection of all microbes living on us. These microbes are needed for immune and metabolic functions of healthy people. Preliminary data from the Kriegel lab suggests that an alteration in an autoimmune-predisposing gene, that is known to contribute to type 1 diabetes, changes the composition of a group of gut microbes. It is speculated that the change in the gut microbial community in subjects that carry this genetic risk factor, leads to immune dysregulation. Kriegel plans to collaborate with Herold at Yale and colleagues at Jackson Laboratory to test if type 1 diabetes patients with this autoimmune predisposition harbor similar microbiome changes. If so, they want to study if the altered microbial communities in the gut affect certain immune cells to facilitate autoimmune destruction of the insulin-producing cells in the pancreas.

Involvement of Stress-Signaling Molecules in Metabolic Functions

Prof. Alon Chen
Head, Department of Neurobiology, Weizmann Institute of Science

Dr. Yael Kuperman
The Sarah and Rolando Uziel Research Associate Chair, Assistant Staff Scientist Department of Veterinary Resources, Weizmann Institute of Science

Gerald I. Shulman
Professor of Medicine (Endocrinology) and Professor of Cellular and Molecular Physiology; Investigator, Howard Hughes Medical Institute; Co-Director, Yale Diabetes Research Center; Director, Yale Mouse Metabolic Phenotyping Center

Project: Chen, Kuperman and Shulman will exchange expertise and knowledge available at the Yale and Weizmann Institute Metabolic Phenotyping Centers and will resume past collaborations on the involvement of stress-signaling molecules, in both brain and muscle, in regulating metabolic functions and stress-induced metabolic diseases such as obesity, type-2 diabetes and eating disorders.

The Role of "Gatekeeper" MTCH2 in Controlling Obesity

Anthony Vella, Ph.D.
Department of Immunology, School of Medicine, UConn Health

Atan Gross, Ph.D.
Department of Biological Regulation, Weizmann Institute for Science, Rehovot

Project: Cells require energy to execute biological function and hematopoietic cells are no exception. This is especially true for immune cells combating cancer, infection or other environmental stimuli. An excellent example are tumor-specific T cells which must be fortified with different capabilities of generating energy to tolerate the depleting pool of glucose and hypoxic environment generated by tumors. In particular, tumor cell consumption of glucose reduces availability to activated T cells, but mechanisms to overcome these deficits are beginning to be uncovered. In this proposal the collaborative teams of Vella and Gross will investigate the role of a key outer mitochondrial membrane protein called mitochondrial carrier homolog 2 (MTCH2). MTCH2 is regarded as a gatekeeper for oxidative phosphorylation (OXPHOS) since its absence profoundly enhances OXPHOS resulting in increased energy consumption. Our overarching hypothesis is that MTCH2 controls the ability of anti-tumor specific T cells to attack tumors, but immune costimulation overcomes this process by uncoupling either expression of MTCH2 or its function. Although MTCH2 has been shown to control OXPHOS and its absence associated with increased metabolism or energy consumption, the interactome of MTCH2 remains unclear. Our 2^nd hypothesis is that the absence of MTCH2 rearranges the mitochondrial proteome and will promote novel interactions that facilitate OXPHOS. This data will be clinically useful in the development of new ways to control obesity and hopefully unveil novel protein interactions that might be open to pharmaceutical targeting.

Download Brief