Intestinal Microbiota as a Host Defense Mechanism to Infectious Threats

Abstract

The intestinal microbiota is a complex microbial community, with diverse and stable populations hosted by the gastrointestinal tract since birth. This ecosystem holds multiple anti-infectious, anti-inflammatory, and immune modulating roles decisive for intestinal homeostasis. Among these, colonization resistance refers to the dynamic antagonistic interactions between commensals and pathogenic flora. Hence, gut bacteria compete for the same intestinal niches and substrates, while also releasing antimicrobial substances such as bacteriocines and changing the environmental conditions. Short chain fatty acids (SCFAs) generated in anaerobic conditions prompt epigenetic regulatory mechanisms that favor a tolerogenic immune response. In addition, the commensal flora is involved in the synthesis of bactericidal products, namely secondary biliary acids or antimicrobial peptides (AMPs) such as cathellicidin-LL37, an immunomodulatory, antimicrobial, and wound healing peptide. Gut microbiota is protected through symbiotic relations with the hosting organism and by quorum sensing, a specific cell-to-cell communication system. Any alterations of these relationships favor the uncontrollable multiplication of the resident pathobionts or external entero-pathogens, prompting systemic translocations, inflammatory reactions, or exacerbations of bacterial virulence mechanisms (T6SS, T3SS) and ultimately lead to gastrointestinal or systemic infections. The article describes the metabolic and immunological mechanisms through which the intestinal microbiota is both an ally of the organism against enteric pathogens and an enemy that favors the development of infections.

Keywords: bacterial enteropathogens; colonization resistance; commensal flora; infection; intestinal microbiota; mucosal immunity; short chain fatty acids.

FIGURE 1

Microbiota and the intestinal barrier against infectious threats. (A) Symbionts shape mucosal immunity and protect intestinal epithelia. The commensal flora, intestinal epithelia covered by mucus, and the mucosal immune response form a complex intestinal barrier against infectious threats. The first line of defense is represented by the mucus layer as well as by antimicrobial peptides (cathelicidin), bacteriocins, and intestinal IgA that ensure the integrity of intestinal epithelial cells (IECs). The commensal flora is interconnected through Quorum-sensing signals (e.g., AI-2 inducer) and is anchored to the protective mucus, at a distance from the intestinal epithelia. Thus commensal species reach high densities in mucosal niches and use available nutrient sources contributing to the colonization resistance. The mucosal immunity is best represented by a network of cells and cytokines within the lamina propria, submucosa and mesenteric ganglia that are ultimately modulated by the commensal flora. Commensals activate resident submucosal dendritic cells (DCs) and initiate an immunosuppressive response through NFkB/TGFβ pathway which in turn activates the lymphnode CD103⁺ DCs mesenteric population. These DCs subset have the ability to prime naïve CD4+ T cell lymphocytes from mesenteric ganglia and induce immunosuppressive CD4+ T cells lineages, namely Th3, FoxP3+ (TREG) and Th2-inducing IL10, and TGF-β cytokines. The immune-tolerant response protects IECs and allows symbiotic relationships between the organism and commensal flora. (B) Intestinal pathogens activate inflammatory mediators and promote invasion. Pathogenic species possess virulence factors (T6SS or T3SS system, flagella, mucus binding proteins, mucinases, etc.) that enable their mucus diffusion and translocation across IECs. Herein pathogens activate TLR4 and 5 receptors and subsequently induce the release of inflammatory cytokines, IL1, IL6, and IL8. These cytokines further activate the CD103+/-DCs population and either promote CD4 T helper cells polarization into inflammatory Th1, Th17, and CD8-cytotoxic subsets or stimulate B lymphocytes to express IgG, while also reducing the immunosuppressive response. The IgG activity and inflammatory response driven by Th1/Th17-related cytokines, IFN-γ, IL-17, limits the bacterial invasion. The AI-2 inducer produced by certain symbionts can also prevent intestinal colonization with pathogenic species through negative feedback signals. However a significant gut inflammatory response allows bacterial translocation.

FIGURE 2

The role of short chain fatty acids (SCFA) in the anti-infectious defense. (A) SCFA are fermentation products of the commensal flora and exert anti-inflammatory and trophic roles on the intestinal epithelial cells (IECs). SCFA elicit effects on IECs metabolism increasing colonic acidity and preventing the colonization with pathogenic germs. SCFA play a significant role in the preservation of tight epithelial junctions through the activation of HIF factor and by decreasing enterocyte apopotosis. As a result SCFA decrease epithelial permeability. At a cellular level SCFA activate specific G protein-coupled receptors (GPR), modulate the chromatin through histone deacetylase (HADC) inhibition, supress the nuclear factor (NF)-κB and reduce the release of pro-inflammatory cytokines (IL6, TNF-α). SCFA regulate the inflammatory response by promoting tolerogenic dendritic cells (DCs), IL-10-producing T-helper cells (TREG), and Th2 response including B-cell IgA production. The immune role of SCFA relies on their ability to induce an anti-inflamatory response and to stimulate antimicrobial molecules, namely cathelicidin (LL37) and intestinal IgA. Consequently SCFA offer protection to IEC and decrease the risk of bacterial invasion and toxin translocation. (B) The absence of SCFA leads to epithelial breaches and translocations of bacteria and lipopolysaccharides (LPS). The inflammatory response involves the following: the activation of toll-like receptor 4 (TLR4) by pathogenic flora, HDAC activity, the (NF)-B transcription, DCs stimulation which promotes mesenteric Th1/Th17 cell differentiation, the release of pro-inflammatory cytokines IL6, TNF-α, IFN–γ, IL17, and neutrophil migration.