The gut microbial endocrine organ: bacterially derived signals driving cardiometabolic diseases

Abstract

The human gastrointestinal tract is home to trillions of bacteria, which vastly outnumber host cells in the body. Although generally overlooked in the field of endocrinology, gut microbial symbionts organize to form a key endocrine organ that converts nutritional cues from the environment into hormone-like signals that impact both normal physiology and chronic disease in the human host. Recent evidence suggests that several gut microbial-derived products are sensed by dedicated host receptor systems to alter cardiovascular disease (CVD) progression. In fact, gut microbial metabolism of dietary components results in the production of proatherogenic circulating factors that act through a meta-organismal endocrine axis to impact CVD risk. Whether pharmacological interventions at the level of the gut microbial endocrine organ will reduce CVD risk is a key new question in the field of cardiovascular medicine. Here we discuss the opportunities and challenges that lie ahead in targeting meta-organismal endocrinology for CVD prevention.

Keywords: atherosclerosis; cardiovascular disease; microbiota; trimethylamine-N-oxide.

Figures

Figure 1. Model of Gut Microbial Participation in the Progression of Atherosclerotic CVD

Following dietary exposures of certain nutrients, gut microbiota can elicit both metabolism-dependent and metabolism-independent effects on the host. Metabolism-dependent effects include: 1) Microbial fermentation of dietary carbohydrates to generate short chain fatty acids (SCFA), which signal to the host to increase energy expenditure, inhibit histone deacetylase activity (HDAC), and enhance G-protein coupled receptor (GPCR) signaling; 2) Microbial conversion of primary bile acids to secondary bile acids, which signal to increase host brown adipose tissue (BAT) activation, energy expenditure, and insulin sensitivity, while dampening inflammation; and 3) Microbial conversion of choline and L-carnitine to trimethylamine (TMA), which is subsequently converted by the host flavin monooxygenase (FMO) enzyme family to trimethylamine-N-oxide (TMAO) in the liver. TMAO then increases atherosclerotic cardiovascular disease (CVD), including myocardial infarction (MI), stroke, and death, by altering cholesterol transport, increasing macrophage activation, and likely other mechanisms. Metabolism-independent effects are the result of gut hyperpermeability (leaky gut), allowing bacterial cell wall products such as lipopolysaccharide (LPS) and peptidoglycans to enter into the blood stream. Low circulating levels of these bacterial components collectively activate macrophages, which can reduce reverse cholesterol transport and increase insulin resistance, hyperlipidemia, and vascular inflammation. Collectively, metabolism-dependent and independent effects of the gut microbial endocrine organ converge to modulate risk of developing atherosclerotic CVD, MI, stroke, and death. Abbreviations: BA, bile acids; BAT, brown adipose tissue; CVD, cardiovascular disease; GPCR, G protein-coupled receptor; FMO, flavin monooxygenase; HDAC, histone deacetylase; LPS, lipopolysaccharide; MI, myocardial infarction; NOD1, nucleotide oligomerization domain-containing 1; SCFA, short chain fatty acids; TLR4, toll-like receptor 4; TMA, trimethylamine, TMAO, trimethylamine-N-oxide.

Figure 2. Host Receptor Systems for Sensing Bacterial Products Relevant to Cardiovascular Disease

Microbial products or metabolites are sensed by the host through dedicated receptor systems to elicit a biological response. Host receptors have been identified for both microbial metabolite-driven pathways and metabolism-independent pathways that signal to reorganize host metabolism and inflammation to alter CVD risk. Abbreviations: CD14, cluster of differentiation 14; FMO3, flavin monooxygenase 3; FXR, farnesoid X receptor; GPR41, G protein-coupled receptor 41; GPR43, G protein-coupled receptor 43; TGR5, G protein-coupled bile acid receptor 1; LPS, lipopolysaccharide; TLR4, toll-like receptor 4; NOD1, nucleotide-binding oligomerization domain-containing 1; SCFA, short chain fatty acids; TMA, trimethylamine; TMAO, trimethylamine-N-oxide.

Figure 3. Strategies to Target the Gut Microbial Endocrine Organ for Improving Cardiovascular Disease

Current strategies for manipulating gut microbiota and potentially impacting CVD include: 1) Dietary manipulation, 2) Prebiotics or Probiotics, 3) Fecal Microbiota Transplantation, 4) Antimicrobials/antibiotics, 5) Bacterial Enzyme Inhibitors, or 6) Host Enzyme Inhibitors. Abbreviations: FMO3, flavin monooxygenase 3; TMA, trimethylamine, TMAO, trimethylamine-N-oxide.