European Review for Medical and Pharmacological Sciences 2013; 17: 323-333 The role of intestinal microbiota and the immune system F. PURCHIARONI, A. TORTORA, M. GABRIELLI, F. BERTUCCI, G. GIGANTE, G. IANIRO, V. OJETTI, E. SCARPELLINI, A. GASBARRINI Department of Internal Medicine, School of Medicine, Catholic University of the Sacred Heart, Gemelli Hospital, Rome, Italy Abstract. – BACKGROUND: The human gut Introduction is an ecosystem consisting of a great number of commensal bacteria living in symbiosis with the The intestinal microbiota is composed of 1013-14 host. Several data confirm that gut microbiota is engaged in a dynamic interaction with the in- microorganisms (Figure 1), with at least 100 testinal innate and adaptive immune system, af- times as many genes as our genome, the micro- fecting different aspects of its development and biome. Its composition is individual-specific, function. ranges among individuals and also within the AIM: To review the immunological functions same individual during life. Many factors can in- of gut microbiota and improve knowledge of its fluence the gut flora composition, as diet, age, therapeutic implications for several intestinal medications, illness, stress and lifestyle. The gas- and extra-intestinal diseases associated to dys- regulation of the immune system. trointestinal (GI) tract contains both “friendly” METHODS: Significant articles were identified bugs, such as Gram-positive Lactobacilli and Bi- by literature search and selected based on con- fidobacteria dominate (> 85% of total bacteria), tent, including atopic diseases, inflammatory and potential pathogenic bacteria, coexisting in a bowel diseases and treatment of these condi- complex symbiosis. Several evidences show that tions with probiotics. intestinal microbiota supports energy metabolism RESULTS: Accumulating evidence indicates and immune and trophic functions in the host. that intestinal microflora has protective, meta- bolic, trophic and immunological functions and Furthermore, the concept of a “super-organism” is able to establish a “cross-talk” with the im- has emerged to reflect the physiologic impor- mune component of mucosal immunity, compris- tance of mutually advantageous bidirectional ing cellular and soluble elements. When one or host-microbe interactions in the gut. When this more steps in this fine interaction fail, autoim- equilibrium is altered several gastrointestinal and mune or auto-inflammatory diseases may occur. extraintestinal diseases can occur. Furthermore, it results from the data that probi- otics, used for the treatment of the diseases Gut Microbiota and caused by the dysregulation of the immune sys- Intestinal Mucosa Development tem, can have a beneficial effect by different mechanisms. Intestinal microflora has protective, metabolic, CONCLUSIONS: Gut microbiota interacts with trophic and immunological functions. In fact, to- both innate and adaptive immune system, play- gether with digestive enzymes, mucins, peristal- ing a pivotal role in maintenance and disruption sis, epithelial barrier with tight junctions, micro- of gut immune quiescence. A cross talk between biota belongs to the so called non-immune com- the mucosal immune system and endogenous microflora favours a mutual growth, survival and ponent of mucosal immunity and is able to estab- inflammatory control of the intestinal ecosys- lish a “cross-talk” with the immune component tem. Based on these evidences, probiotics can of mucosal immunity, comprising cellular and be used as an ecological therapy in the treat- soluble elements1. Commensal microbiota can ment of immune diseases. profoundly influence the development of the gut mucosal immune system and be crucial in pre- Key Words: venting exogenous pathogen intrusion, both by Gut microbiota, Intestinal immune system, Atopic direct interaction with pathogenic bacteria and by diseases, Inflammatory bowel disease, Probiotics. stimulation of the immune system. Comparative Corresponding Author: Flaminia Purchiaroni, MD; e-mail: [email protected] 323 F. Purchiaroni, A. Tortora, M. Gabrielli, F. Bertucci, G. Gigante, G. Ianiro, et al. Figure 1. GUT microbiota composition and distribution. studies in germ-free and conventional animals favours a mutual growth, survival and inflamma- have established that the intestinal microflora is tory control of the intestinal ecosystem. A typi- essential for the development and function of the cal feature of innate immunity is the ability of mucosal immune system especially during early distinguishing between potentially pathogenic life, a process important to overall immunity in microbial components and harmless antigens by adults2. Different studies over the time have “pattern recognition receptors” (PRRs) and demonstrated that the development of the ultra- among those toll-like receptors (TLRs) enable structure of the intestinal mucosa is dependent on mammalian cells to recognize conserved charac- luminal bacteria. For example, villus capillaries teristic molecules present on microorganisms in germ-free mice develop poorly during wean- and described as pathogen-associated molecular ing and remain poorly developed until adulthood, patterns (PAMPs)9-11. Since these molecules e.g. indicating a microbial contribution in angiogene- lipopolysaccharides, peptidoglycans, flagellin, sis of villus-core3-5. Germ-free animals show de- formylated peptides and others, are present also fects in the development of gut-associated lym- on commensal bacteria it seems more precise to phoid tissue (GALT) and antibody production, call them microbe-associated molecular patterns fewer cellular lymphoid follicles (Peyer’s patch- (MAMPs). In mammals TLRs are present on es), reduced cellular lamina propria, and fewer macrophages, neutrophils, dendritic cells (DCs), plasma cells in germinal center of the mesenteric intestinal epithelial cells (ECs) and other cells lymph node (MLNs) compared with animals un- belonging to innate immune system. Over the der conventional conditions6-8. The microbiota al- time, researches have led different studies so contributes to the development of intra-epithe- demonstrating that microbiota can regulate the lial lymphocytes (IEL). intestinal innate immune system by modulating TLRs expression on immunosensory cells sur- Gut Microbiota and Innate Immune System face through MAMPs; recognition of microbes A cross talk between the mucosal innate im- leads to activation of nuclear factor-kappa B mune system and endogenous microflora (NF-κB) signaling pathway and consequently 324 The role of intestinal microbiota and the immune system triggers cytokine production, up-regulation of tions by adhering to pathogens15,16 and protect co-stimulatory molecules on antigen presenting against acid gastric and duodenal secretions. The cells, leading to activation of T cells. Thus, in- mucus also provide a medium in which bacterial- nate immunity is tightly linked to adaptive im- derived metabolites with signaling functions are munity9-11. secreted and concentrated. Thus, the mucus layer In physiological conditions, complex and may promote mutualism by keeping bacteria at poorly understood cell interactions regulate in bay and restricting overt immune stimulation the gut responses to food antigens and to anti- while facilitating host-commensal or commensal- gens of the normal microflora in close proximity commensal cross-talk through the diffusion of to a large population of rapidly renewing ECs, bacterial products. specialized IELs and other immunologically ac- tive cells present in the mucosa. Cells of innate Gut Microbiota and immunity are able to produce cytokines essential Adaptative Immune System for inflammatory reactions as well as factors crit- An important immune compartment in the ical for the subsequent initiation of specific im- bowel is the lamina propria, where is present a munity. The contact with bacteria and their com- large number of macrophages, DCs, T cells, and ponents through the PRRs on their surface initi- IgA-secreting B cells. Acquired immune re- ates innate immunity responses11. So far, the ex- sponse is primarily imprinted in GALT (Peyer’s pression and modulation of TLRs on DCs (which patches (PPs) and MLNs)17-19. Indeed, regulatory represent the link between innate and adaptive cells are also present in the lamina propria where immunity) and on ECs play an active role during they maintain tolerance to foods and self-anti- interaction with external environment and in reg- gens. In the lamina propria are also present resi- ulating the mucosal immune responses. dent CD4, CD8 and B cells, while some CD8 ECs are perhaps the most important part of lymphocytes migrate to tip of the villous, where the innate defense mechanism of mucosal sur- they became IELs20,21. The B cells in the lamina faces. It has been recently shown that ECs are propria are activated and become IgA-producing directly involved in various immune processes, plasma cells. The IgA is transported across the in addition to their absorptive, digestive and se- epithelial layer and secreted in the gut lumen. cretory functions. For example, they show a pe- Antigens sampled in the lamina propria are taken culiar capacity of transporting secretory im- up by DCs and transported via draining lymphat- munoglobulins, produced by plasma cells in ic vessels to the MLNs and secondarily to the gut lamina propria, to the lumen, by binding these lymphoid tissue (PPs), to response to gut anti- to a receptor of polymeric immunoglobulins gens. The important feature