The role of gut microbiota in programming the immune phenotype

Abstract

The human fetus lives in a germ-free intrauterine environment and enters the outside world containing microorganisms from several sources, resulting in gut colonization. Full-term, vaginally born infants are completely colonized with a diverse array of bacterial families in clusters (Phyla) and species (>1000) by the first year of life. Colonizing bacteria communicating with the gut epithelium and underlying lymphoid tissues ('bacterial-epithelial crosstalk') result in a functional immune phenotype and no expression of disease (immune homeostasis). Appropriate colonization is influenced by the prebiotic effect of breast milk oligosaccharides. Adequate colonization results in an innate and adaptive mucosal immune phenotype via communication between molecular patterns on colonizing bacteria and pattern-recognition receptors (e.g., toll-like receptors) on epithelial and lymphoid cells. This ontogeny affects the immune system's capacity to develop oral tolerance to innocuous bacteria and benign antigens. Inadequate intestinal colonization with premature delivery, delivery by Cesarean section and excessive use of perinatal antibiotics results in the absence of adequate bacterial-epithelial crosstalk and an increased incidence of immune-mediated diseases [e.g., asthma, allergy in general and necrotizing enterocolitis (NEC)]. Fortunately, infants with inadequate intestinal colonization can be restored to a bacterial balance with the intake of probiotics. This has been shown to prevent debilitating diseases such as NEC. Thus, understanding the role of gut microbiota in programming of the immune phenotype may be important in preventing disease expression in later childhood and adulthood.

Fig. 1

A schematic representation of a cross section of small intestine of human fetus in utero v. the newborn human infant. Fetal intestine appears thin and exhibits a slow epithelial proliferation rate with a paucity of gut-associated lymphoid tissue (GALT), whereas infant intestine manifests a robust, diverse epithelium with a fast turnover rate and abundant GALT elements. Reprinted with permission from Walker.

Fig. 2

Diagram of ‘colonization resistance’ in extrauterine intestine. Upon shift from a liquid to a solid diet, a larger number of anaerobic symbiotic microbiota attach to the luminal surface of the intestinal epithelium that prevents potential penetration by pathogenic (mostly aerobic) flora (a), which does occur with abnormal colonization (b) lacking ‘colonization resistance’.

Fig. 3

This figure shows the importance of bacterial colonization, intestinal mucus and epithelial barriers that work in concert with components of submucosal gut-associated lymphoid tissue to maintain immune homeostasis in the intestine. Shown are key elements including (a) microvilli, (b) epithelial cell tight junctions, (c) apical glycocalyx, (d) antimicrobial peptides, (e) microfold cells (M cells), (f) dendritic cells (DCs) in Peyer's patch and (g) specialized DCs extending dendrites into the gut lumen for sampling lumina intact antigens and/or microbiota. Reprinted with permission from Chichlowski et al.

Fig. 4

A diagram of human neonatal intestine mucosal immunologic development. At birth, these components including (1) M cells, (2) Peyer's patches rich in lymphoid elements, (3) interstitial lymphocytes and (4) intraepithelial lymphocytes. The proper development of these defense components requires the stimulation from colonizing bacteria. Reprinted with permission from Walker.

Fig. 5

A diagram that shows two ways by which symbiotic bacteria can condition dentritic cells to promote immunoglobulin A (IgA) production. One is by way of M cells, which transfer commensal bacteria to dentritic cells in Peyer's patches; the other is that dendritic cells (DCs) directly sample commensal bacteria by extending dendrites into the gut lumen. Bacterial-laden DCs home to mesenteric lymph nodes, where an efficient anti-commensal microbiota IgA response is elicited from plasma cells. sIgA, secretory immunoglobulin A.

Fig. 6

Commensal bacteria evoke T-cell responses via dendritic cells (DCs) by binding to toll-like receptor 2 (TLR2) and/or TLR4 on the surface of penetrating dendrites. Commensal microbiota induce MHCII⁺ CD11c⁺ DCs to secreted interleukin-10 (IL-10) or IL-12 and IFNγ by which naïve Th0 cells are primed to differentiate into TH1, TH2 or Treg, respectively. Reprinted with permission from Walker.

Fig. 7

Schematic representation of oral tolerance induction by gut microbiota. In the intestinal lumen, gut microbiota activate dendritic cells (DCs) via the toll-like receptor 2 (TLR2)/TLR4 signaling pathways. Activated DCs cause maturation of TH0 to subsets (TH3, Tr1) of Treg cells via release of interleukin-10 (IL-10) to stimulate transforming growth factor beta (TGF-β) release and thereby suppress immunoglobulin E (IgE) production.

Fig. 8

Probiotic secretions attenuate LPS/interleukin (IL)-1β-induced excessive IL-8 secretion in the immature human intestinal xenografts. Organ cultures of immature human xenografts were challenged by LPS (50 μg/ml) or IL-1β (1 ng/ml) with and without 48 h pre-exposure to probiotic-conditioned media. (a) IL-8 mRNA expression was measured after 12 h and (b) IL-8 (pg/mg of protein) was measured after 16–18 h. A highly significant induction of IL-8 mRNA as well as IL-8 secretion was observed in immature xenografts. However, exposure to probiotic-conditioned media before stimulation resulted in a highly significant decrease in IL-8 mRNA levels (P < 0.001, **) and IL-8 secretion (P < 0.001, **), as well as in immature xenografts. Reprinted with permission from Ganguli et al.