Age-associated modifications of intestinal permeability and innate immunity in human small intestine

Abstract

The physical and immunological properties of the human intestinal epithelial barrier in ageing are largely unknown. Ileal biopsies from young (7-12 years), adult (20-40y) and ageing (67-77y) individuals not showing symptoms of gastrointestinal pathologies were used to assess levels of inflammatory cytokines, barrier integrity, and cytokine production in response to microbial challenges. Increased expression of IL-6, but not IFNγ, TNF-α and IL-1β was observed during ageing; further analysis showed that CD11c + dendritic cells (DCs) are one of the major sources of IL-6 in the ageing gut and expressed higher levels of CD40.

Gastrointestinal (GI) Tract Microbes and Microbial Neurotoxins in the Human Central Nervous System (CNS) in Alzheimer’s Disease (AD)

“…Of further related interest are the recent observations: (i) that the increased abundance of gram-negative GI tract bacteria such as B. fragilis in AD patients appears to result in increased generation and translocation of LPS and other Bacteroides-derived neurotoxins from the GI tract into the systemic circulation, which in turn may contribute to AD neuropathology through the release of pro-inflammatory cytokines, systemic inflammation, an increase in GI-tract or BBB permeability or other AD-relevant pathogenic mechanisms [9,[29][30][31][32], and (ii) that an increase in Bacteroidetes in the GI tract is also associated with Parkinson's disease (PD; [33]) and with sporadic AD hippocampus and neocortex, two anatomical regions targeted by the AD process [6,[34][35][36]. Importantly, while only the inflammatory potential of LPS towards primary human neuronal-glial (HNG) co-cultures have been studied and quantified by the induction of the pro-inflammatory NFkB p50/p65 complex, Bacteroidetes species are capable of secreting an unusually complex array of highly lethal neurotoxins including amyloids, sncRNAs and endotoxins which, when released from the confines of the healthy GI tract, are systemically pathogenic and can be highly detrimental to the homeostatic function of human CNS neurons [15].…”

“…This suggests that GI-tract microbiome-derived LPS may be an important initiator and/or significant contributor to failure in adequate gene expression the AD CNS including those genes involved in the modulation of inflammatory signaling (Figure 1; manuscript submitted). In humans, intestinal permeability increases with age and elderly individuals show an association between increased LPS-binding protein (a marker of microbial translocation) and inflammation [5,10,31] and gram-negative E. coli fragments co-localize with amyloid plaques [29]. Taken together these results suggest that the increased abundance of Bacteroides in patients with AD may result in an increased translocation of LPS from the gut to the systemic circulation, which in turn may exacerbate AD pathology through enhanced pro-inflammatory signaling or related pathogenetic mechanisms [5,10,54,55].…”

Influence of Commensal Microbiota on the Enteric Nervous System and Its Role in Neurodegenerative Diseases

“…Nevertheless, there are always single microbes translocating the mucosal barrier without generating severe trouble, due to their immediate contact with the intrinsic mucosal immune system. Since the mucosal barrier disintegrates with age [e.g., 21] or disease [e.g.,22], the amount of bacteria crossing the epithelium can increase. The quality of the mucosal barrier is maintained by the protective effect of the ENS, and especially the enteric glia, which are in close contact with the enterocytes.…”

Drug Prescribing to the Elderly Patients

“…Intestinal bacterial overgrowth and associated malabsorption can adversely affect nutritional status. Compromise of barrier function and decrease in myenteric neurons may induce painless ulcerations 6,7 . In the large intestine, more prevalence of mucosal atrophy, muscosal glands abnormalities, hypertrophy of muscularis mucosa, altered coordination of contractions with reduction of colonic propulsive motility that underly chronic constipation.…”