Gut Microbial Changes, Interactions, and Their Implications on Human Lifecycle: An Ageing Perspective

Abstract

Gut microbiota is established during birth and evolves with age, mostly maintaining the commensal relationship with the host. A growing body of clinical evidence suggests an intricate relationship between the gut microbiota and the immune system. With ageing, the gut microbiota develops significant imbalances in the major phyla such as the anaerobic Firmicutes and Bacteroidetes as well as a diverse range of facultative organisms, resulting in impaired immune responses. Antimicrobial therapy is commonly used for the treatment of infections; however, this may also result in the loss of normal gut flora. Advanced age, antibiotic use, underlying diseases, infections, hormonal differences, circadian rhythm, and malnutrition, either alone or in combination, contribute to the problem. This nonbeneficial gastrointestinal modulation may be reversed by judicious and controlled use of antibiotics and the appropriate use of prebiotics and probiotics. In certain persistent, recurrent settings, the option of faecal microbiota transplantation can be explored. The aim of the current review is to focus on the establishment and alteration of gut microbiota, with ageing. The review also discusses the potential role of gut microbiota in regulating the immune system, together with its function in healthy and diseased state.

Figures

Figure 1

Overview of development of microbiota. The gastrointestinal tract (GI) is most sterile during the in utero stage. The first colonization happens based on mode of delivery either C-section or natural (vaginal delivery). Corynebacterium sp. is thought to be early colonizers in C-section and Lactobacillus sp. in the vaginal delivery. As the time progress the commensal bacterial community grows and is influenced by the solid food intake. During the initial stages of microbiota establishment the TLR receptor actions are minimal allowing growth of commensals. Eventually the immune system also grows by demarking the commensals and pathogens. Bacteroidetes domination begins after two years of birth. The relative stability is attained at the adulthood with Bacteroidetes and Firmicutes dominating. The alteration happens with use of antibiotics, obesity, GI orders, and diet. During elderly the relative stability declines, commensal community reduces, and pathogenic species like Clostridium increases. Malnutrition, alcohol abuse, decline in metabolism, frequent hospitalization, nosocomial infections (Clostridium difficile), and other pathogenic infections leading to Polypharmacy and ultimately to various inflammatory diseases.

Figure 2

Interplay between immune system and gut microbiota in homeostasis, tolerance, and inflammation. (a) Both commensals and opportunists compete for the metabolites (SCFA) and various nutrients. The intestinal epithelial cells (IEC) play a role in steady state environment by releasing interleukins IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) factors in the presence of SCFA, PSA (Bact., fragilis), lipopolysaccharide (LPS), and AMPs (defensins, cathelicidins, and C-type lectins). IL-25, IL-33, and various growth related factors help in the transformation of progenitor basophils to basophils, activation of monocytes, macrophages, and mast cells functioning. The bacteriocins released by segmented filamentous bacteria (SFB) also influence the release of TSLP. The microfolding (M) cells upon sensing the presence of the microbes act as antigen presenting cell (APC) phagocytic activity by engulfing and presenting it to mucosal dendritic cells (DCs). In turn DCs are endowed with the ability to produce cytokines and other products such as IL-6 and IL-1β, tumor growth factor (TGF-β), retinoic acid (RA), and vitamin A. DCs form a major histocompatible complex (MHC) with the T cell receptors (TCR). In the presence of TGF-β and RA, the naïve T cells (CD4+ cells) transform into regulatory T cells (Treg). Simultaneously during interaction and competition of commensals and pathogens for nutrients, macrophages after recognition microbes released proinflammatory cytokine such as IL-10, which in turn helps with expansion of Treg cells which are already released during homeostasis and inflammation. Also with the help of DCs, macrophages release certain B cell activating factors which increase the production of secretory immunoglobulin A (SIgA) to maintain tolerance and steady state. (b) ((1) & (2)): in the elderly, there are declined physiological functioning and dysbiosis (reduction in commensal bacteria), resulting in an increase in pathogens. (3) The production of IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) by IEC reduces. (4) There is decline in M cell/APC activity to present PSA or microbe to DCs (activation of inflammatory pathway). Moreover lack of PSA stimulation reduces the IL-12 levels and releases T helper 2 cells. Decline in DCs not forming MHC with TCR reduces the population of active T cells such as Treg cells. Activation of B cells to plasma secretory cells and release of SIgA decreases. (5) The activation and function of macrophages (low levels of IL-10) are reduced. (6) The steady state or the tolerance is reduced. (7) Macrophages (inflammatory) are activated in the presence of pathogens and release proinflammatory cytokines (IL-1β, IL-6, and TNF-α) which leads to production of reactive oxygen species (ROS) and causes oxidative stress. Altogether with reduced levels of Treg and T helper cells and SIgA increase the pathogen invasion leading to release of proinflammatory cytokines and reduced anti-inflammatory cytokines increases inflammation, causing various GI disorders.