How the Intricate Interaction among Toll-Like Receptors, Microbiota, and Intestinal Immunity Can Influence Gastrointestinal Pathology

Abstract

The gut is able to maintain tolerance to microbial and food antigens. The intestine minimizes the number of harmful bacteria by shaping the microbiota through a symbiotic relationship. In healthy human intestine, a constant homeostasis is maintained by the perfect regulation of microbial load and the immune response generated against it. Failure of this balance may result in various pathological conditions. Innate immune sensors, such as Toll-like receptors (TLRs), may be considered an interface among intestinal epithelial barrier, microbiota, and immune system. TLRs pathway, activated by pathogens, is involved in the pathogenesis of several infectious and inflammatory diseases. The alteration of the homeostasis between physiologic and pathogenic bacteria of intestinal flora causes a condition called dysbiosis. The breakdown of homeostasis by dysbiosis may increase susceptibility to inflammatory bowel diseases. It is evident that environment, genetics, and host immunity form a highly interactive regulatory triad that controls TLR function. Imbalanced relationships within this triad may promote aberrant TLR signaling, critically contributing to acute and chronic intestinal inflammatory processes, such as in IBD, colitis, and colorectal cancer. The study of interactions between different components of the immune systems and intestinal microbiota will open new horizons in the knowledge of gut inflammation.

An overview of the bacterial contribution to Crohn disease pathogenesis

“…Various mechanisms have been described through which the intestinal microbiota may interact with mucosal immunity (Hooper et al, 2012;El Aidy et al, 2015). One key pathway is tolllike receptor (TLR) signalling, which can influence regulatory T-cell populations, the autophagy pathway (Sun et al, 2011;Frosali et al, 2015), cellular epithelial proliferation, cytoprotective effects, immune cell recruitment, IgA production and secretion of antimicrobial peptides (RakoffNahoum et al, 2004;Shang et al, 2008;El Aidy et al, 2015). It is also increasingly evident that enteric bacteria influence production of effector CD4+ T helper (Th) cells, which are imperative in protecting the gut from developing colitis (Kullberg et al, 2002;Kamada & Núñez, 2014).…”

“…Bacteria can activate both the innate (macrophage, neutrophil and dendritic cells) and acquired (T and B cell) immune systems (Sartor, 2006;Hooper et al, 2012;Alexander et al, 2014;Kayama & Takeda, 2016). Bacteria can act as adjuvants to activated innate immune cells or as antigens to stimulate clonal expansion of T cells (Sartor, 2007;Frosali et al, 2015;Tanoue et al, 2016 (Zareie et al, 2001;Mahida, 2000;de Zoeten & Fuss, 2013). High levels of these pro-inflammatory molecules promote trafficking and migration of the circulating immune effector cells to the intestinal mucosa (Reaves et al, 2005;Griffith et al, 2014;Peterson & Artis, 2014).…”

“…NOD2 is primarily involved in bacterial clearance though binding muramyl dipeptide (MDP) to produce a number of antimicrobial peptides including defensins and mediates immune responses through activation of NFkB (Hruz et al, 2009;Dickson, 2016). Mutant CARD15 was found to be associated with defective clearance of invasive bacteria, accumulation of luminal and mucosal enteric flora and an exaggerated immune response owing to over-activation of NFkB (Sartor, 2006;Frosali et al, 2015). CARD15 mutants including Arg702Trp, Gly908Arg and Leu1007 fsins C were found at higher rates in families affected with CD and are associated with a 2-4-fold relative risk increase of CD in heterozygous individuals and to 20-40-fold Hold et al (2014) relative risk increase in homozygous individuals (Li et al, 2004;Cuthbert et al, 2002).…”

Histamine Receptor 2 is Required to Suppress Innate Immune Responses to Bacterial Ligands in Patients with Inflammatory Bowel Disease

“…4 Several regulatory mechanisms that control TLR activation have been described, thus preventing excessive inflammatory responses to the resident microbiota. 5 In particular, many host-derived and environment metabolites can influence immune reactivity and TLR activation, with significant effects on mucosal immune homeostasis. 6 Coordination between Supplemental digital content is available for this article.…”

NOD2 Modulates Serotonin Transporter and Interacts with TLR2 and TLR4 in Intestinal Epithelial Cells

“…PRRs are expressed in intestinal epithelial cells [11,12] and are able to recognize microbial-associated molecular patterns (MAMPs) to develop either inflammatory or tolerance responses [13]. In this context, several studies have reported that numerous PRRs, as TLR2, TLR4 [14] and NOD2 [15], seem to be implicated in IBD due to the dysfunctional recognition of commensal microbiota [16]. TLR2 is expressed in the cell surface and can detect molecular patterns associated with Gram-positive bacteria [17] through their heterodimers (TLR2/1 and TLR2/6) [18] while TLR4, also located on the cell surface, detects lipopolysaccharide (LPS), the major cell wall component of Gramnegative bacteria [19].…”