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eBriefing 
Microbial Influences in Cardio-Metabolic Diseases
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Posted March 15, 2017
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Obesity is a growing epidemic. In the United States alone, 35% of adults and 17% of children are clinically obese, a condition contributing to somewhere between 100,000–400,000 deaths each year. As such, research into the factors that modulate energy intake and weight gain has become a priority, and recent findings have implicated the microbiome as a crucial player in human metabolic processes. Millions of years of coevolution has shaped the human microbiome to act as an endocrine organ, producing compounds that directly influence our health, and perturbations of the microbiome—through antibiotics or westernized diets, for example—can provoke lasting physiological effects.
On November 3, the Microbiome Science Discussion Group at the New York Academy of Sciences presented Microbial Influences in Cardio-Metabolic Diseases. This symposium explored cutting edge research regarding the interplay between the human microbiome and metabolic health, highlighting potential medical and behavioral interventions for obesity-related disease.
Martin J. Blaser, from the departments of medicine, microbiology, and biology at New York University and VA Medical Center, started off the day by examining the effects of early life antibiotic use on the gut microbiome, and its implications for the obesity epidemic. In modern societies, decreased vertical transmission, increased sanitary conditions, and antibiotic administration has drastically decreased the diversity of the human microbiome. Early childhood is implicated as a critical time for microbiome development, and antibiotic administration during this time may cause substantial health consequences. Experimental evidence in mice directly implicates antibiotic use as a driver of obesity, mediated through the lasting effects on the gut microbiome community structure.
Humans have evolved enzymes, receptors, and transporters for the compounds produced by our microbial communities so that the microbiome functions essentially as an endocrine organ.
H. Bjørn Nielsen from Clinical-Microbiomics in Copenhagen, Patrice D. Cani of the Universite Catholique de Louvain, LDRI, and Gerald I. Shulman from Yale University School of Medicine all discussed different circulating metabolites produced by the microbiome, and their relation to insulin insensitivity and obesity. A large-scale analysis by Clinical-Microbiomics integrated serum metabolite and gut microbiome data, producing a immense amount of raw data, including 360 fully assembled microbial genomes comprised of 7 million microbial genes, as well as 325 serum metabolites, and 876 serum lipids. Following several rounds of data filtering and complexity reduction, researchers observed a significant association between the abundance of microbial species related to branched chain amino acid (BCAA) management and insulin insensitivity. As insulin resistance increases, the potential for the gut microbiome to synthesize BCAAs goes up and the potential for BCAA transport goes down. Experimental data from mice support this correlational result, suggesting that the gut microbiome may be responsible for the accumulation of BCAA metabolites in the serum of obese individuals, leading to insulin resistance.
Gut microbes fed a high-fat diet also influence metabolic endotoxemia through the increase of circulating lipopolysachharides (LPS) in the blood. In lean patients, the mucus layer of the intestinal wall acts as an effective barrier preventing large influxes of LPSs into the blood stream. High levels of circulating LPSs contribute to low-grade inflammation and insulin resistance, associated with obesity and type 2 diabetes. Akkermansia muciniphila, a gram-negative bacteria may be the microbial link explaining the beneficial effects of prebiotics or healthy diet on decreased circulating LPS and inflammation. Administration of A. muciniphila in mice increased the thickness of the intestinal mucosa and decreased metabolic endotoxemia (plasma LPS). Correlational studies in humans have also shown that obese individuals exhibit a lower abundance of A. muciniphilia, which then increases after gastric bypass in parallel with decreases in cholesterol, inflammation, and insulin resistance. Human trials for the use of A. muciniphilia in 100 obese patients is ongoing, with results hoped to be obtained by the end of 2017.
Acetate is also implicated in the molecular pathway by which the gut microbiome influences insulin insensitivity. Mice on a high fat diet display increased levels of acetate in the blood, and organ isolation experiments confirm that this increase is coming from the colon and cecum luminal contents. Mice on a regular chow diet that has been infused with acetate in concentrations typical of a mouse on a high fat diet display insulin resistance profiles similar to mice on high fat diets, isolating acetate as a mediator between diet and insulin insensitivity. Further experiments involving antibiotic administration and fecal transplants identified the microbes within the colon as the acetate producers. Unfortunately, high amounts of circulating acetate activates the parasympathetic nervous system, inducing a positive feedback loop reinforcing the consumption of a diet overabundant in energy.
Overconsumption of an energy-rich diet induces a positive feedback loop, whereby the gut microbiota produce increased amounts of acetate, activating the parasympathetic nervous system and ghrelin production, and stimulating further overeating. This is likely an evolutionary mechanism to overconsume during times of plenty.
Turning to a different area of the body, Joseph Finkelstein from the Center for Bioinformatics and Data Analytics and Columbia University College of Dental Medicine illustrated evidence supporting a causal relationship between oral microbiome health and cardio-metabolic disease through the Bradford Hill criteria for causation. Notable points include evidence of a dose dependent relationship between periodontal disease and risk of myocardial infarction, and experimental evidence of periodontitis treatment regimens and endothelial function.
Danielle Fowler from Boehringer Ingelheim Pharmaceuticals, Inc. and Stanley L. Hazen from the Cleveland Clinic examined the role of dietary choline in the development of cardio-renal disease in patients with diabetes. Dietary choline, heavily consumed in western societies through meat and dairy products, is microbially converted into a metabolite (TMAO) that plays a role in renal function and blood coagulation. Increased choline intake leads to increased circulating TMAO, associated with both kidney failure and increased blood clotting. Boehringer Ingelheim is in the process of identifying the bacterial species in the gut responsible for choline conversion to better treat type 2 diabetes patients. The Hazen lab identified dimethylbutanol as a substance that inhibits the production of TMA (a precursor of TMAO) by gut microbes, and decreases the amount of atherosclerotic plaque buildup in mice. These two projects aim to treat the negative health consequences associated with obesity, renal dysfunction and atherosclerosis, through the manipulation of bacterial species metabolic processes.
Diet may be the most important factor contributing to the gut microbial community composition, with individuals consuming a high-fat diet exhibiting significantly different and less diverse communities than those in lean individuals. Increased gut permeability is a typical side-effect of obese-type gut microbiota, allowing the metabolites produced by obese-typical gut microbes to enter circulation.
Rachel Carmody of Harvard University and Marion Soto of the Joslin Diabetes Center at Harvard Medical School demonstrated how the microbiome both shapes and is shaped by behavior. Diet is known to play perhaps the largest role in determining the gut microbiome, and the process of cooking food has a significant impact on microbial community structure and function. In mice, there were significant microbial differences in subjects fed cooked or raw sweet potato diets, likely due to the increased digestibility and decreased xenobiotic load of cooked items. Cooking food is unique to human society and pervasive across all its permutations. By understanding how cooked foods alter our gut microbiome, we can better understand the coevolution of humans and their microbial communities, and our respective roles in nutrient metabolism.
The compounds produced by gut microbes also have the capability to influence our psychological state. In mice fed a high-fat diet, antibiotics improve peripheral insulin signaling as well as signaling within the central nervous system. A high-fat diet induces depression and anxiety in mice, and fecal transplant and antibiotic experiments have shown that this is mediated through the differences in the gut microbiome. These data show how diet and obesity can influence the central nervous system and can be associated with neurobehavioral abnormalities.
Dan Winer of the University Health Network and University of Toronto closed the symposium with a discussion on the local intestinal immune system, and its relationship to obesity. Obese individuals exhibit a low-grade systemic inflammatory response due to compromised integrity of the gut lining. The innate immune system is implicated in regulating the integrity of the intestinal barrier, and intestinal T-cell production is increased in mice fed a high-fat diet. B cells and IgA also show changes within the intestines of mice. Inflammatory bowel disease medications function by decreasing intestinal inflammation, and have been shown to reduce inflammation in fat cells, increase gut microbial diversity, and increase intestinal barrier function in mice. Winer concludes that local targeting of the immune system through reduction in intestinal inflammation may be a novel treatment approach to improve glucose regulatory functions in insulin-resistant people.
Use the tabs above to find multimedia from this event.
Presentations available from:
Patrice D. Cani, PhD (Universite Catholique de Louvain, LDRI)
Martin Blaser, MD (New York University Langone Medical Center)
Marion Soto, PhD (Joslin Diabetes Center, Harvard Medical School)
Dan Winer, MD, FRCPC (University of Toronto)
Henrik Bjørn Nielsen, PhD (Clinical-Microbiomics A/S)
How to cite this eBriefing
The New York Academy of Sciences. Microbial Influences in Cardio–Metabolic Diseases. Academy eBriefings. 2016. Available at: www.nyas.org/Metabolic2016-eB
Resources
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Luck, H., Tsai, S., Chung, J., Clemente-Casares, X., Ghazarian, M., Revelo, X. S., ... & Copeland, J. K. (2015). Regulation of obesity-related insulin resistance with gut anti-inflammatory agents. Cell Metabolism, 21(4), 527-542.
Bruce-Keller, A. J., Salbaum, J. M., Luo, M., Blanchard, E., Taylor, C. M., Welsh, D. A., & Berthoud, H. R. (2015). Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity. Biological Psychiatry, 77(7), 607-615.
Tonetti, M. S., D'Aiuto, F., Nibali, L., Donald, A., Storry, C., Parkar, M., ... & Deanfield, J. (2007). Treatment of periodontitis and endothelial function. New England Journal of Medicine, 356(9), 911-920.
Perry, R. J., Peng, L., Barry, N. A., Cline, G. W., Zhang, D., Cardone, R. L., ... & Shulman, G. I. (2016). Acetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome. Nature, 534(7606), 213-217.
Everard, A., Belzer, C., Geurts, L., Ouwerkerk, J. P., Druart, C., Bindels, L. B., ... & De Vos, W. M. (2013). Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proceedings of the National Academy of Sciences, 110(22), 9066-9071.
Pedersen, H. K., Gudmundsdottir, V., Nielsen, H. B., Hyotylainen, T., Nielsen, T., Jensen, B. A., ... & Le Chatelier, E. (2016). Human gut microbes impact host serum metabolome and insulin sensitivity. Nature, 535(7612), 376-81.
Trasande, L., Blustein, J., Liu, M., Corwin, E., Cox, L. M., & Blaser, M. J. (2013). Infant antibiotic exposures and early-life body mass. International Journal of Obesity, 37(1), 16-23.
Organizers
John Hambor, PhD
Boehringer Ingelheim
website | publications
John Hambor is director of research beyond borders at Boehringer Ingelheim, where he coordinates a postdoctoral research program focused on developing new therapeutic concepts in collaboration with academic investigators. Previously, Hambor was a consultant with the Cell Therapy Group, specializing in stem cell-based drug discovery. Prior to serving as CEO of CellDesign, he spent 17 years researching at Pfizer, where he identified and validated new drug targets in the areas of inflammation and immunology and developed stem cell-based assays for drug efficacy and safety studies. Hambor received both a BA and MS in microbiology from Miami University of Ohio, and earned a PhD in pathology from Case Western Reserve University, followed by postdoctoral studies at Yale University. Since 200, he has been an adjunct assistant professor at Connecticut College. He also serves on the board of directors for the Connecticut Veterans Administration Research and Education Foundation and on the advisory committee for the Connecticut Regenerative Medicine Research Fund.
Erick Young, PhD
Boehringer Ingelheim
website | publications
Erick R. R. Young obtained his PhD in synthetic bioorganic chemistry from Pennsylvania State University and completed post-doctoral studies in natural product synthesis at Ohio State University. Upon joining Boehringer Ingelheim Pharmaceuticals (BI) in 1998, he served as a small molecule research project leader for immunology and cardiometabolic diseases. Over time, he became increasingly involved in the generation of new target concepts and championing novel therapeutic modalities for the enablement of new target class space. He is currently director of external innovation for the newly formed Research Beyond Borders division of BI, where his primary focus is the conception, identification, and enablement of new therapeutic mechanisms and disease indications outside the organizations current scope or capabilities.
Nilufer Seth, PhD
Pfizer, Inc.
website | publications
Nilufer Seth works in the Emerging Science Group in the Inflammation and Immunology Research Unit at Pfizer. She received her PhD in molecular biology and biochemistry from the Medical College of Augusta before joining the Dana-Farber Cancer Institute for her post-doctoral training, where her research focused on design and development of novel approaches to ex vivo identify and analyze antigen-specific CD4 T cells subsets in human diseases and mouse models of autoimmunity. At Wyeth, she joined the inflammation and immunology department, where she worked on small and large molecule therapeutic programs targeting immune cells and inflammatory cytokines. Currently, she leading and developing Pfizer's microbiome strategy, efforts and projects. Her focus is on developing medicines that will reshape the treatment of inflammatory and autoimmune diseases by harnessing strategies and pathways used by the human gut microbiota to maintain barrier and immune homeostasis.
Sonya Dougal, PhD
The New York Academy of Sciences
Caitlin McOmish, PhD
The New York Academy of Sciences
Speakers
Henrik Bjørn Nielsen, PhD
Clinical-Microbiomics A/S
website | publications
H. Bjørn Nielsen, chief scientific officer at Clinical-Microbiomics A/S, has since 2008 been a frontrunner in the field of microbiome research. His participation in the MetaHit consortium led to a series of important scientific papers describing the human gut microbiome, including his pioneering work on co-abundance binning of metagenomics data into metagenomic species, bacteriophages, and other mobile genetic elements. This year Nielsen has authored 4 papers published in Nature journals, including a three-pronged association study that links microbiome, serum metabolome, and clinical data in pre-diabetic Danes, and a study that reports on the largest metatranscriptomics to date. At Clinical-Microbiomics, Nielsen heads innovation with clients and the continued adaptation and development of new analysis concepts and methods.
Martin J. Blaser, MD
New York University Langone Medical Center
website | publications
Martin J. Blaser is the Muriel and George Singer Professor of Medicine, professor of microbiology, and director of the Human Microbiome Program at the NYU School of Medicine. Over three decades, his work has focused on particular organisms that also are model systems for understanding the interactions of residential bacteria with their human hosts. Over the last 15 years, he has been studying the relationship of the human microbiome with health and such diseases as asthma, obesity, diabetes, and allergies. He has served as president of the Infectious Diseases Society of America, chair of the Board of Scientific Counselors of the National Cancer Institute, and on the Scientific Advisory Board of the Doris Duke Charitable Foundation. He was elected to the National Academy of Medicine and the American Academy for Arts and Sciences. He now is serving as the Chair of the Presidential Advisory Council for Combating Antibiotic-Resistant Bacteria.
Patrice D. Cani, PhD
Université Catholique de Louvain, LDRI
website
Rachel Carmody, PhD
Harvard University
website | publications
Rachel Carmody is an assistant professor in human evolutionary biology and co-director of the Nutritional & Microbial Ecology Laboratory at Harvard University. She received her PhD in human evolutionary biology from Harvard in 2012, and recently completed a postdoctoral fellowship in microbiology & immunology at the University of California, San Francisco. Carmody's research investigates the biological, behavioral, and environmental determinants of dietary energy gain, with special interests in the energetic consequences of food processing and the contributions of the gut microbiome to energy metabolism. Her past studies have shown that the adoption of cooking by human ancestors would have transformed the energy landscape, helping to support the emergence of costly traits like larger body and brain size despite reductions in tooth and gut size. Carmody is the recipient of an NSF Graduate Research Fellowship, NIDDK/NIA Keystone Scholarship, and NIH Ruth L. Kirschstein National Research Service Award.
Stanley L. Hazen, MD, PhD
Cleveland Clinic
website | publications
Stanley Hazen received both his PhD in biophysical chemistry and molecular biology and medical degree at Washington University School of Medicine in St. Louis. He then performed his residency in internal medicine and specialty fellowship in endocrinology, diabetes, and metabolism at Barnes Jewish Hospital. He has been at the Cleveland Clinic since 1997, where he currently serves as the chair of the Department of Cellular & Molecular Medicine at the Cleveland Clinic's Lerner Research Institute. He is also section head of preventive cardiology & rehabilitation at the Cleveland Clinic, and holds both the Jan Bleeksma Chair in Vascular Cell Biology and Atherosclerosis, and the Leonard Krieger Chair in Preventive Cardiology. Hazen has published over 350 peer reviewed publications. He has been elected as member to honorary clinical and basic science societies including election as a Fellow to the American Association for the Advancement of Science (AAAS) in 2008, and most recently, election to the National Academy of Medicine (2017).
Gerald I. Shulman, MD, PhD
Yale University School of Medicine
website | publications
Gerald Shulman is an investigator of the Howard Hughes Medical Institute and the George R. Cowgill Professor of Physiological Chemistry, Medicine and Cellular & Molecular Physiology at Yale University. He is also co-director of the Yale Diabetes Research Center. Shulman completed his undergraduate studies in biophysics at the University of Michigan, and he received his MD and PhD from Wayne State University. Following internship and residency at Duke University Medical Center, he did an endocrinology fellowship at the Massachusetts General Hospital / Harvard Medical School and additional postdoctoral work in molecular biophysics and biochemistry at Yale before joining the faculty at Harvard Medical School, before subsequently returning to Yale. Shulman is a fellow of the American Association for the Advancement of Science and has been elected to the American Society for Clinical Investigation, the Association of American Physicians, the Institute of Medicine and the National Academy of Sciences.
Marion Soto, PhD
Joslin Diabetes Center, Harvard Medical School
website | publications
Marion Soto is a senior research fellow in the C. Ronald Kahn Laboratory in the Department of Integrative Physiology and Metabolism at Joslin Diabetes Center. She earned her PhD in nutrition and neurobiology from AgroParisTech in France. Her research focuses on how type 2 diabetes and insulin resistance in the brain lead to defects in cognition and behavior. Soto's research interests combine both basic science investigations and translation into clinical research, using several MRI techniques in patients with type 2 diabetes to understand how this pathology affects brain function. In addition to her focus on insulin signaling in the brain, Soto is interested in the role of the microbiome in the pathogenesis of obesity and metabolic syndrome. Her studies on the interaction between the microbiome, brain, and behavior in mice led her to discover that the microbiota can regulate neurobehavioral abnormalities relevant to obesity and diabetes.
Dan Winer, MD, FRCPC
University Health Network and University of Toronto
website | publications
Dan Winer is a scientist at the Toronto General Research Institute at the University Health Network (UHN). He is an assistant professor in the departments of laboratory medicine and pathobiology, and immunology at the University of Toronto, and a pathologist at UHN. Recently, Winer has identified the immune system in the gut as a new regulator of whole body glucose homeostasis. Winer is the recipient of several awards including the Benjamin Castleman Award for human pathology research, a Canada Research Chair in immunometabolism, and an Amgen New Investigator award. The Winer laboratory is funded by grants from the Canadian Diabetes Association, the Canadian Institutes of Health Research, the J.P. Bickell Foundation, the Banting and Best Diabetes Center, the Ontario Ministry of Innovation, and the Canadian Foundation for Innovation.