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      Gut microbiome and aging: Physiological and mechanistic insights

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          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.

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          Most cited references131

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          Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.

          Toll-like receptors (TLRs) play a crucial role in host defense against microbial infection. The microbial ligands recognized by TLRs are not unique to pathogens, however, and are produced by both pathogenic and commensal microorganisms. It is thought that an inflammatory response to commensal bacteria is avoided due to sequestration of microflora by surface epithelia. Here, we show that commensal bacteria are recognized by TLRs under normal steady-state conditions, and this interaction plays a crucial role in the maintenance of intestinal epithelial homeostasis. Furthermore, we find that activation of TLRs by commensal microflora is critical for the protection against gut injury and associated mortality. These findings reveal a novel function of TLRs-control of intestinal epithelial homeostasis and protection from injury-and provide a new perspective on the evolution of host-microbial interactions.
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            An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system.

            The mammalian gastrointestinal tract harbors a complex ecosystem consisting of countless bacteria in homeostasis with the host immune system. Shaped by evolution, this partnership has potential for symbiotic benefit. However, the identities of bacterial molecules mediating symbiosis remain undefined. Here we show that, during colonization of animals with the ubiquitous gut microorganism Bacteroides fragilis, a bacterial polysaccharide (PSA) directs the cellular and physical maturation of the developing immune system. Comparison with germ-free animals reveals that the immunomodulatory activities of PSA during B. fragilis colonization include correcting systemic T cell deficiencies and T(H)1/T(H)2 imbalances and directing lymphoid organogenesis. A PSA mutant of B. fragilis does not restore these immunologic functions. PSA presented by intestinal dendritic cells activates CD4+ T cells and elicits appropriate cytokine production. These findings provide a molecular basis for host-bacterial symbiosis and reveal the archetypal molecule of commensal bacteria that mediates development of the host immune system.
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              Inflamm-aging. An evolutionary perspective on immunosenescence.

              In this paper we extend the "network theory of aging," and we argue that a global reduction in the capacity to cope with a variety of stressors and a concomitant progressive increase in proinflammatory status are major characteristics of the aging process. This phenomenon, which we will refer to as "inflamm-aging," is provoked by a continuous antigenic load and stress. On the basis of evolutionary studies, we also argue that the immune and the stress responses are equivalent and that antigens are nothing other than particular types of stressors. We also propose to return macrophage to its rightful place as central actor not only in the inflammatory response and immunity, but also in the stress response. The rate of reaching the threshold of proinflammatory status over which diseases/disabilities ensue and the individual capacity to cope with and adapt to stressors are assumed to be complex traits with a genetic component. Finally, we argue that the persistence of inflammatory stimuli over time represents the biologic background (first hit) favoring the susceptibility to age-related diseases/disabilities. A second hit (absence of robust gene variants and/or presence of frail gene variants) is likely necessary to develop overt organ-specific age-related diseases having an inflammatory pathogenesis, such as atherosclerosis, Alzheimer's disease, osteoporosis, and diabetes. Following this perspective, several paradoxes of healthy centenarians (increase of plasma levels of inflammatory cytokines, acute phase proteins, and coagulation factors) are illustrated and explained. In conclusion, the beneficial effects of inflammation devoted to the neutralization of dangerous/harmful agents early in life and in adulthood become detrimental late in life in a period largely not foreseen by evolution, according to the antagonistic pleiotropy theory of aging.
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                Author and article information

                Journal
                Nutr Healthy Aging
                Nutr Healthy Aging
                NHA
                Nutrition and Healthy Aging
                IOS Press (Nieuwe Hemweg 6B, 1013 BG Amsterdam, The Netherlands )
                2451-9480
                2451-9502
                6 November 2017
                15 June 2018
                2018
                : 4
                : 4
                : 267-285
                Affiliations
                [a ]Center for Obesity, Diabetes and Metabolism (Internal Medicine-Molecular Medicine), Wake Forest School of Medicine , Winston-Salem, NC, USA
                [b ]Department of Food Science and Technology, College of Agriculture, Isfahan University of Technology , Isfahan, Iran
                [c ]Department of Pathology (Comparative Medicine), Wake Forest School of Medicine , Winston-Salem, NC, USA
                [d ]Gerontology and Geriatric Medicine, Wake Forest School of Medicine , Winston-Salem, NC, USA
                [e ]Center for Life Sciences, NLA, Nazarbayev University , Astana, Republic of Kazakhstan
                [f ]ReGenera Research and Development for Aging Interventions, and San Babila Clinic, Corso Matteotti 1/A, Milano, Italy
                Author notes
                [* ]Corresponding author: Hariom Yadav, PhD., Center for Diabetes, Obesity and Metabolism (Internal Medicine-Molecular Medicine), Wake Forest School of Medicine, Department of Microbiology and Immunology, Biotech Place, Suite 2E-034, 575 Patterson Ave., Winston-Salem, NC 27101, USA. Tel.: +1 336 713 5049; Fax: +1 336 716 9928; E-mail: hyadav@ 123456wakehealth.edu .
                Article
                NHA170030
                10.3233/NHA-170030
                6004897
                29951588
                14b85f80-0df9-4fab-afd4-52351bc1347a
                © 2018 – IOS Press and the authors. All rights reserved

                This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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                Categories
                Review

                aging,enteric nervous system,gut dysbiosis,gut permeability,intestinal microbiota,metabolic inflammation,probiotics,prebiotics

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