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

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.