Gut Microbiome Dysbiosis and Immunometabolism: New Frontiers for Treatment of Metabolic Diseases

Abstract

Maintenance of healthy human metabolism depends on a symbiotic consortium among bacteria, archaea, viruses, fungi, and host eukaryotic cells throughout the human gastrointestinal tract. Microbial communities provide the enzymatic machinery and the metabolic pathways that contribute to food digestion, xenobiotic metabolism, and production of a variety of bioactive molecules. These include vitamins, amino acids, short-chain fatty acids (SCFAs), and metabolites, which are essential for the interconnected pathways of glycolysis, the tricarboxylic acid/Krebs cycle, oxidative phosphorylation (OXPHOS), and amino acid and fatty acid metabolism. Recent studies have been elucidating how nutrients that fuel the metabolic processes impact on the ways immune cells, in particular, macrophages, respond to different stimuli under physiological and pathological conditions and become activated and acquire a specialized function. The two major inflammatory phenotypes of macrophages are controlled through differential consumption of glucose, glutamine, and oxygen. M1 phenotype is triggered by polarization signal from bacterial lipopolysaccharide (LPS) and Th1 proinflammatory cytokines such as interferon-γ, TNF-α, and IL-1β, or both, whereas M2 phenotype is triggered by Th2 cytokines such as interleukin-4 and interleukin-13 as well as anti-inflammatory cytokines, IL-10 and TGFβ, or glucocorticoids. Glucose utilization and production of chemical mediators including ATP, reactive oxygen species (ROS), nitric oxide (NO), and NADPH support effector activities of M1 macrophages. Dysbiosis is an imbalance of commensal and pathogenic bacteria and the production of microbial antigens and metabolites. It is now known that the gut microbiota-derived products induce low-grade inflammatory activation of tissue-resident macrophages and contribute to metabolic and degenerative diseases, including diabetes, obesity, metabolic syndrome, and cancer. Here, we update the potential interplay of host gut microbiome dysbiosis and metabolic diseases. We also summarize on advances on fecal therapy, probiotics, prebiotics, symbiotics, and nutrients and small molecule inhibitors of metabolic pathway enzymes as prophylactic and therapeutic agents for metabolic diseases.

Figure 1

Interplay of gut microbiome-intestinal epithelial cells (enterocytes, goblet cells and paneth cells) and host metabolism and immunity. The commensal, symbiotic, and pathogenic microorganisms provide a great variety of nutrients and metabolites for host metabolism, for energy homeostasis of organs and tissues, and for the innate and adaptive immune cell activation and function. A shift toward dysbiosis results from a decrease in symbiont and/or an increase in pathobiont bacteria in intestinal lumen. Increases in nitrate and oxygen (O₂) allow the growth of facultative anaerobic bacteria. Increase in the gut permeability and release of PAMPs, such as peptidoglycan and LPS, and DAMPs, such as double-stranded RNA, mtDNA, and ATP. Increase in the production of cytokines, chemokines, nitric oxide (NO), and reactive oxygen species (ROS) by dendritic cells and macrophages causes local and systemic inflammation. Chronic, low-grade systemic inflammation leads to impaired insulin action, insulin resistance, obesity, hypertension, and metabolic syndrome. Probiotics, prebiotics, fecal therapy, and small molecules targeting host genes and specific bacterial species or phylum/class may help to reestablish tissue homeostasis and microbiome healthy. SCFAs: short-chain fatty acids; PAMPs: pathogen-associated molecular patterns; DAMPs: damage-associated molecular patterns; LPS: lipopolysaccharide; AMPs: antimicrobial peptides; IgA: immunoglobulin A.

Figure 2

Metabolic pathways supporting macrophage reprogramming in either M2 or M1 phenotype. IL-4-stimulated M2 macrophage utilizes glycolysis, TCA, and mitochondrial oxidative phosphorylation (OXPHOS) to generate NADPH and ATP for energy. G-6-P and glutamine are used for generation of UDP-Glc-Nac required for receptors and protein glycosylation. LPS-stimulated M1 macrophage produces G-6-P that is reduced to pyruvate, in parallel, NAD⁺ is reduced to NADPH, and 2 ATP molecules are produced. In hypoxia, pyruvate is reduced to lactate, restoring NAD⁺ to glycolysis recycle, and thus, OXPHOX is uncoupled to glycolysis. TCA cycle in LPS-stimulated M1 macrophageis deviated after citrate and after succinate. Citrate is used for the syntheses of NO, ROS, and prostaglandins. Citrate is used by the enzyme immune-responsive gene 1 (IRG1) to generate itaconate that acts as an endogenous SDH inhibitor and also as antimicrobial. Succinate is oxidized by SDH and subsequently used for production of ROS from a complex 1 via reverse electron transport (RET). Succinate activates HIF-1α which in turn increases the transcription of IL-1β. Glutaminolysis provides NADPH for generation of ROS. SDH: succinate dehydrogenase; UDP-Glc-Nac: uridine diphosphate N-acetylglucosamine; NO: nitric oxide; ROS: reactive oxygen species. Arrows indicated the direction of reaction and products.