Featuring: Henrik Bjørn Nielsen (Clinical-Microbiomics A/S), Martin J. Blaser (New York University Langone Medical Center), Patrice D. Cani (Universite Catholique de Louvain, LDRI), Rachel Carmody (Harvard University), Stanley L. Hazen (Cleveland Clinic), Gerald I. Shulman (Yale University School of Medicine), Marion Soto (Joslin Diabetes Center, Harvard Medical School), and Dan Winer (University of Toronto)Presented by the Microbiome Science Discussion Group at the New York Academy of Sciences
Reported by Rachel Petersen | Posted March 15, 2017
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.
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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