Gut microbiome and aging: Physiological and mechanistic insights

Ravinder Nagpal, Rabina Mainali, Shokouh Ahmadi, Shaohua Wang, Ria Singh, Kylie Kavanagh, Dalane W Kitzman, Almagul Kushugulova, Francesco Marotta, Hariom Yadav, Ravinder Nagpal, Rabina Mainali, Shokouh Ahmadi, Shaohua Wang, Ria Singh, Kylie Kavanagh, Dalane W Kitzman, Almagul Kushugulova, Francesco Marotta, Hariom Yadav

Abstract

The development of human gut microbiota begins as soon as the neonate leaves the protective environment of the uterus (or maybe in-utero) and is exposed to innumerable microorganisms from the mother as well as the surrounding environment. Concurrently, the host responses to these microbes during early life manifest during the development of an otherwise hitherto immature immune system. The human gut microbiome, which comprises an extremely diverse and complex community of microorganisms inhabiting the intestinal tract, keeps on fluctuating during different stages of life. While these deviations are largely natural, inevitable and benign, recent studies show that unsolicited perturbations in gut microbiota configuration could have strong impact on several features of host health and disease. Our microbiota undergoes the most prominent deviations during infancy and old age and, interestingly, our immune health is also in its weakest and most unstable state during these two critical stages of life, indicating that our microbiota and health develop and age hand-in-hand. However, the mechanisms underlying these interactions are only now beginning to be revealed. The present review summarizes the evidences related to the age-associated changes in intestinal microbiota and vice-versa, mechanisms involved in this bi-directional relationship, and the prospective for development of microbiota-based interventions such as probiotics for healthy aging.

Keywords: Aging; enteric nervous system; gut dysbiosis; gut permeability; intestinal microbiota; metabolic inflammation; prebiotics; probiotics.

Figures

Fig.1
Fig.1
The two-way connection between human gut microbiome and host aging, and the potential underlying and/or associated elements.
Fig.2
Fig.2
Age-related changes in the human gut microbial ecosystem, and potential factors that could affect microbiota composition at different stages of life. α-diversity: species (taxa) richness within a single host/microbial environment; β-diversity: diversity in microbial community (taxonomic abundance profiles) between different environments/samples) [4, 23, 31, 34, 73].
Fig.3
Fig.3
Features of the homeostatic intestinal environment (eubiosis) (A), and how a perturbed microbiota (dysbiosis) and gut barrier may instigate aging-related maladies (B). Under homeostatic conditions (eubiosis), the epithelial cells produce antimicrobial peptides (AMPs) in response to interleukins (e.g. IL-22) and also express pattern recognition receptors (e.g. Toll-like receptors; TLR). The gut microbes regulate mucous secretion and AMPs production and also regulate/enhance the gut barrier integrity via producing short-chain fatty acids (SCFAs). Goblet cells produce mucus to constrain pathobiont invasion. Lymphoid cells (e.g. TH17 cells) play a role in host defense by producing controlled arrays of IL-22. Dendritic cells (DCs) induce the activation and differentiation of naive B cells to produce plasma cells that produce commensal-specific IgA in the lamina propria. IgA is transported into the gut lumen as secreted IgA (sIgA) via (polymeric immunoglobulin receptor pIgR) receptors, where after sIgA binds to commensal microbes and soluble antigens, thereby restraining their adherence to the host epithelium and leakage through the gut barrier. However, under dysbiosis and/or senescent milieus, the altered microbiota composition and weakened/perturbed gut permeability may lead to increased adherence and leakage of various microbes and microbial by-products through the gut barrier thereby instigating hyper-inflammatory responses eventually increasing the host susceptibility to various gut-related as well as systemic ailments via perturbations in the magnitude of gut-brain axis, gut-liver axis etc. [7, 36, 63, 84, 124, 127, 128, 132, 133, 147].
Fig.4
Fig.4
Schematic illustration of putative pathway(s) by which aging-related alterations in gut microbiome and entero-neuro-endocrine system may affect brain health via deteriorated gut-brain communication signaling. In healthy adult host, the balanced gut microbiome configuration and intestinal barrier integrity help in maintaining balanced arrays of microbes, microbial by-products (e.g. short-chain fatty acids; SCFAs) and other entities such as neurotransmitters across the gut wall thereby maintaining a balanced enteric-immune and -inflammatory system through controlled proliferation of dendritic cells and macrophages which eventually helps in keeping the gut-brain communication and the functioning of central nervous system (CNS) under control. In old age, the altered gut microbiota diversity and weakened gut barrier integrity may perturb the microbial and biochemical environment across the intestinal epithelial cell lining via abnormal levels of SCFAs, lipopolysaccharide (LPS), secretory Immunoglobulin A (sIgA), histamins, serotonin (5-hydroxytryptamine; 5-HT), etc. thereby instigating an abnormal (hyper) inflammatory responses eventually affecting (disturbing) the gut-brain communication [84, 90, 93, 103, 104, 109, 112, 124, 158].

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