A pinboard by
Linda Zhang

Postdoctoral Researcher, Vanderbilt University


Learn about the role of gut microbes in cardiovascular disease and current therapeutic ventures.

Cardiovascular diseases account for one of three deaths in westernized societies and ranked as the leading cause of mortality worldwide. Atherosclerosis is a slow progressive disease that is characterized by a buildup of plaques in arteries which leads to coronary heart and artery diseases, angina, peripheral artery disease, and chronic kidney disease. While significant effort has been made in determining how atherosclerosis begins or progresses, much remains unclear.

The human gut microbiome is composed of over 100 trillion microbes and contributes to a number of functions for the host, operating like another organ. Such functions include: immune system modulation, protection against pathogens, chemical reactions with drugs, metabolism of foodstuffs, aiding calcium absorption, and more.

Recent evidence suggest a role of the gut microbiome in promoting atherogenesis through the generation of disease-promoting metabolites, such as trimethylamine N-oxide (TMAO), which forms from the metabolism of phosphatidylcholine or carnitine (high levels in red meat!) by gut microbes. Thus, targeting or “drugging” the gut microbiome to reduce levels of detrimental metabolites is currently of great scientific interest. You may find several research papers on this subject on my pinboard.

Another strategy to drug the gut microbiome is to increase levels of metabolites with known therapeutic benefits by use of engineered gut microbes. Currently researchers at Vanderbilt (including myself) are investigating the potential of incorporating engineered gut microbes that produce N-acylethanolamines (NAPEs) into the gut microbiota to ameliorate diseases such as obesity or atherosclerosis. We have recently demonstrated the efficacy of these engineered microbes in reducing obesity, described in a publication pinned below.

This pinboard is designed to inform you on the role of gut microbial metabolites in cardiovascular disease and to keep current on exciting recent studies from our laboratory as well as from scientists at other universities in developing therapies targeting the gut in order to ameliorate disease.


9/29/17 *Update - I am thinking about broadening the scope of my board to include how we are hacking our gut microbes to help with health conditions outside of cardiovascular disease. Stay tuned....


The human gut microbiome as source of innovation for health: Which physiological and therapeutic outcomes could we expect?

Abstract: From the moment of birth, each human being builds a microbe-host symbiosis which is key for the preservation of its health and well-being. This personal symbiotic coexistence is the result of progressive enrichments in microorganism diversity through external supplies. This diversity is nowadays massively overthrown by drastic changes related to clinical practice in birth management, environmental exposure, nutrition and healthcare behaviors. The last two generations have been the frame of massive modifications in life and food habits, with people being more and more sedentary, overfed and permeated with drugs and pollutants. We are now able to measure the impact of these changes on the gut microbiota diversity. Concomitantly, these modifications of lifestyle were associated with a dramatic increase in incidence of immune-mediated diseases including metabolic, allergic and inflammatory diseases and most likely neurodegenerative and psychiatric disorders. Microbiota is becoming a hot topic in the scientific community and in the mainstream media. The number of scientific publications increased by up to a factor three over the last five years, with gastrointestinal and metabolic diseases being the most productive areas. In the intellectual property landscape, the patent families on microbiota have more than doubled in the meantime. In parallel, funding either from National Institutes (e.g. from NIH which funds research mainly in the field of allergies, infections, cancer and cardiovascular diseases, from the White House which launched the national microbiome initiative) or by pharmaceutical companies follow the same trend, showing a boost and a strong support in the research field on microbiota. All major health players are investing in microbiome research as shown by the number of deals signed and by funding during 2015. The Giens round table addressed how the medicine of tomorrow, considering human beings as a human-microbe symbiotic supraorganism, could leverage microbiome knowledge and tools. The rationale for our working group has been structured around four domains of innovation that could derive from ongoing efforts in deciphering the interactions between human cells and intestinal microbiome as a central component of human health, namely: (1) development of stratification and monitoring tools; (2) identification of new target and drug discovery, as a part of our supra-genome; (4) exploitation of microbiota as a therapeutic target that can be modulated; (4) and finally as a source of live biotherapeutics and adjuvants. These four streams will exemplify how microbiota has changed the way we consider a wide range of chronic and incurable diseases and the consequences of long-lasting dysbiosis. In-depth microbiota analysis is opening one of the broadest fields of investigation for improving human and animal health and will be a source of major therapeutic innovations for tackling today's medical unmet needs. We thus propose a range of recommendations for basic researchers, care givers as well as for health authorities to gain reliability in microbiome analysis and accelerate discovery processes and their translation into applications for the benefits of the people. Finally, les Ateliers de Giens round table on microbiota benefited from the richness of the French ecosystem. France represents a center of excellence in the microbiota research field, with French institutions as Institut national de la recherche agronomique (INRA [Metagenopolis, Micalis]), Centre national de la recherché scientifique (CNRS), Unité de recherche sur les maladies infectieuses et tropicales émergentes (URMITE), Institut of Cardiometabolism and Nutrition (ICAN), Institut des maladies métaboliques et cardiovasculaires (I2MC), Institut national de la santé et de la recherche médicale (Inserm), Pasteur Institute and Gustave-Roussy being top-players for the number of publications.

Pub.: 31 Jan '17, Pinned: 09 Aug '17

Role of intestinal microbiota and metabolites on gut homeostasis and human diseases.

Abstract: A vast diversity of microbes colonizes in the human gastrointestinal tract, referred to intestinal microbiota. Microbiota and products thereof are indispensable for shaping the development and function of host innate immune system, thereby exerting multifaceted impacts in gut health.This paper reviews the effects on immunity of gut microbe-derived nucleic acids, and gut microbial metabolites, as well as the involvement of commensals in the gut homeostasis. We focus on the recent findings with an intention to illuminate the mechanisms by which the microbiota and products thereof are interacting with host immunity, as well as to scrutinize imbalanced gut microbiota (dysbiosis) which lead to autoimmune disorders including inflammatory bowel disease (IBD), Type 1 diabetes (T1D) and systemic immune syndromes such as rheumatoid arthritis (RA).In addition to their well-recognized benefits in the gut such as occupation of ecological niches and competition with pathogens, commensal bacteria have been shown to strengthen the gut barrier and to exert immunomodulatory actions within the gut and beyond. It has been realized that impaired intestinal microbiota not only contribute to gut diseases but also are inextricably linked to metabolic disorders and even brain dysfunction.A better understanding of the mutual interactions of the microbiota and host immune system, would shed light on our endeavors of disease prevention and broaden the path to our discovery of immune intervention targets for disease treatment.

Pub.: 08 Jan '17, Pinned: 09 Aug '17

Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta-Analysis of Prospective Studies.

Abstract: Gut microbial metabolites have been implicated as novel risk factors for cardiovascular events and premature death. The strength and consistency of associations between blood concentrations of the gut microbial metabolites, trimethylamine-N-oxide (TMAO) and its precursors, with major adverse cardiovascular events (MACE) or death have not been comprehensively assessed. We quantified associations of blood concentrations of TMAO and its precursors with risks of MACE and mortality.PubMed and Embase databases were searched up, and a total of 19 prospective studies from 16 publications (n=19 256, including 3315 incident cases) with quantitative estimates of the associations of TMAO with the development of MACE or death were included in our main analysis. Multivariate-adjusted relative risks (RRs) were used when these were available. Elevated concentrations of TMAO were associated with a pooled RR of 1.62 (95% CI, 1.45, 1.80; Pheterogeneity=0.2; I(2)=23.5%) for MACE compared with low TMAO levels, and 1 study of black participants influenced the heterogeneity of the association. After excluding the data of blacks, the RRs were not different according to body mass index, prevalence of diabetes mellitus, history of cardiovascular diseases, and kidney dysfunction. Furthermore, elevated TMAO concentrations were associated with a pooled RR of 1.63 (1.36, 1.95) for all-cause mortality. Individuals with elevated concentrations of TMAO precursors (l-carnitine, choline, or betaine) had an approximately 1.3 to 1.4 times higher risk for MACE compared to those with low concentrations.Elevated concentrations of TMAO and its precursors were associated with increased risks of MACE and all-cause mortality independently of traditional risk factors.

Pub.: 01 Jul '17, Pinned: 04 Jul '17

Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions.

Abstract: Mass spectrometry- and nuclear magnetic resonance-based metabolomic studies comparing diseased versus healthy individuals have shown that microbial metabolites are often the compounds most markedly altered in the disease state. Recent studies suggest that several of these metabolites that derive from microbial transformation of dietary components have significant effects on physiological processes such as gut and immune homeostasis, energy metabolism, vascular function, and neurological behavior. Here, we review several of the most intriguing diet-dependent metabolites that may impact host physiology and may therefore be appropriate targets for therapeutic interventions, such as short-chain fatty acids, trimethylamine N-oxide, tryptophan and tyrosine derivatives, and oxidized fatty acids. Such interventions will require modulating either bacterial species or the bacterial biosynthetic enzymes required to produce these metabolites, so we briefly describe the current understanding of the bacterial and enzymatic pathways involved in their biosynthesis and summarize their molecular mechanisms of action. We then discuss in more detail the impact of these metabolites on health and disease, and review current strategies to modulate levels of these metabolites to promote human health. We also suggest future studies that are needed to realize the full therapeutic potential of targeting the gut microbiota.

Pub.: 23 Apr '16, Pinned: 14 Jun '17

Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity.

Abstract: Metabolic disorders, including obesity, diabetes, and cardiovascular disease, are widespread in Westernized nations. Gut microbiota composition is a contributing factor to the susceptibility of an individual to the development of these disorders; therefore, altering a person's microbiota may ameliorate disease. One potential microbiome-altering strategy is the incorporation of modified bacteria that express therapeutic factors into the gut microbiota. For example, N-acylphosphatidylethanolamines (NAPEs) are precursors to the N-acylethanolamide (NAE) family of lipids, which are synthesized in the small intestine in response to feeding and reduce food intake and obesity. Here, we demonstrated that administration of engineered NAPE-expressing E. coli Nissle 1917 bacteria in drinking water for 8 weeks reduced the levels of obesity in mice fed a high-fat diet. Mice that received modified bacteria had dramatically lower food intake, adiposity, insulin resistance, and hepatosteatosis compared with mice receiving standard water or control bacteria. The protective effects conferred by NAPE-expressing bacteria persisted for at least 4 weeks after their removal from the drinking water. Moreover, administration of NAPE-expressing bacteria to TallyHo mice, a polygenic mouse model of obesity, inhibited weight gain. Our results demonstrate that incorporation of appropriately modified bacteria into the gut microbiota has potential as an effective strategy to inhibit the development of metabolic disorders.

Pub.: 25 Jun '14, Pinned: 14 Jun '17