Review article: Current opinion | Published 5 April 2016, doi:10.4414/smw.2016.14293 Cite this as: Swiss Med Wkly. 2016;146:w14293 Gastrointestinal tract: the leading role of mucosal immunity Anna Steinerta, Katarina Radulovicc, Jan Hendrik Niessa,b a Department of Gastroenterology, University Clinic of Visceral Surgery and Medicine, Inselspital, Bern, Switzerland b Division of Gastroenterology and Hepatology, University Hospital Basel, Switzerland c U1019, Team 7, Institut National de la Santé et de la Recherche Médicale (INSERM), Lille, France; Centre for Infection and Immunity of Lille, Institut Pasteur de Lille, France Summary by a complex interplay between host factors, environment- al influences and the intestinal microbiota. Not only im- An understanding of mucosal immunity is essential for the provements in endoscopic techniques, but also advances in comprehension of intestinal diseases that are often caused high throughput sequencing technologies, have expanded knowledge of how intestinal diseases develop. This review Abbreviations discusses how the host interacts with intestinal microbi- AhR aryl hydrocarbon receptor ota by the direct contact of host receptors with highly con- APRIL a proliferation-inducing ligand served structural motifs or molecules of microbes and also cAMP cyclic adenosine monophosphate by microbe-derived metabolites (produced by the microbe CD cluster of differentiation during adaptation to the gut environment), such as short- CYP7A1 cholesterol 7α-hydroxylase FACS fluorescence-activated cell sorting chain fatty acids, vitamins, bile acids and amino acids. FFAR free fatty acid receptor These metabolites are recognised by metabolite-sensing re- FGF15 fibroblast growth factor 15 ceptors expressed by immune cells to influence functions FMT faecal microbiota transplantation of macrophages, dendritic cells and T cells, such as migra- FODMAP low fermentable oligosaccharides, disaccharides, tion, conversion and maintenance of regulatory T cells and monosaccharides, and polyols regulation of proinflammatory cytokine production, which FXR farnesoid X receptor GCN general control nonderepressible is essential for the maintenance of intestinal homeostasis GPR G-protein coupled receptor and the development of intestinal diseases, such as inflam- IBD inflammatory bowel disease matory bowel diseases. First interventions in these com- IBS irritable bowel syndrome plex interactions between microbe-derived metabolites and IDO indoleamine-2,3-dioxygenase the host immune system for the treatment of gastrointest- Ig immunoglobulin inal diseases, such as modification of the diet, treatment IL interleukin with antibiotics, application of probiotics and faecal micro- LPS lipopolysaccharide MACS magnetic-activated cell sorting biota transplantation, have been introduced into the clin- MAIT cell, mucosal-associated invariant T cell ic. Specific targeting of metabolite sensing receptors for mTOR mammalian target of rapamycin the treatment of gastrointestinal diseases is in development. NcoR1 nuclear receptor co-repressor In future, precision medicine approaches that consider in- NF-κB nuclear factor kappa-light-chain-enhancer of activated B- dividual variability in genes, the microbiota, the environ- cells ment and lifestyle will become increasingly important for NO nitric oxide the care of patients with gastrointestinal diseases. PPAR peroxisome proliferator-activated receptor REG regenerating islet-derived protein Key words: ulcerative colitis, Crohn’s disease, RALDH retinal dehydrogenases rRNA ribosomal ribonucleic acid macrophages, dendritic cells, immune system, metabolites, SCFA short-chain fatty acids microbiome, metabolite recognition receptors TAT T-type amino acid transporter TGF transforming growth factor Introduction TGR transmembrane G protein coupled receptor Th T helper cell Every individual has to eat and drink and most people have Th17 IL-17 producing T helper cells experienced symptoms (such as nausea, abdominal pain, TLR Toll-like receptor TNF tumour necrosis factor vomiting or diarrhoea) that originate from the digestive Treg regulatory T cell tract at least at one point during their life. To study, dia- Swiss Medical Weekly · PDF of the online version · www.smw.ch Page 1 of 13 Review article: Current opinion Swiss Med Wkly. 2016;146:w14293 gnose and treat disorders of the digestive tract, gastroenter- microbial interactions and discuss potential future lines of ology is a medical specialty with a constant need for new research in mucosal immunity. technological devices. Advances in imaging technologies, especially the development of high-resolution endoscopes, It all starts at or even before birth have revolutionised the way in which gastrointestinal dis- eases are examined [1]. Nowadays endoscopes are not only As embryos we develop in a sterile intrauterine environ- used as diagnostic tools, but also for treating patients: to ment that prevents rejection of the foreign foetus by the stop bleedings [2], remove polyps [3], dissect pre- or even mother [32]. The placenta forms a barrier that separates cancerous lesions and [4] to drain extraintestinal cysts into not only the mother’s immune system from the foetus, but the gastrointestinal tract [5]. The response to treatments also prevents the passage of microorganisms into the foetus in patients with inflammatory bowel diseases (IBD) is in [33]. However, bacterial products, such as lipopolysacchar- part evaluated by endoscopy (mucosal healing) [6]. Con- ides (LPS) or bacterial metabolites are able to cross the focal endomicroscopy can be used to predict relapses by placenta to programme the development of the foetus. For determining cell shedding and barrier loss [7] and predict example, neutralisation of LPS in stressed animals pre- the response to antitumour necrosis factor (TNF) therapies vents abortion of the foetus [34]. During birth the baby by detecting in vivo fluorescein-labelled anti-TNF antibod- is exposed to multiple prokaryotic organisms located in ies [8]. Even parts of the microflora (i.e., Helicobacter the vaginal tract, an overwhelming environmental stressor. pylori) can be visualised with confocal endomicroscopy Several mechanisms enable the baby to survive the first [9]. However, gastrointestinal diseases, such as IBD, are contacts with microbes [35]: the expression levels of Toll- very complex. IBD is caused by the interplay of various ge- like receptor 3 (TLR3) [36], the antimicrobial peptides re- netic, environmental and immunological factors [10]. IBD generating islet-derived proteins (REG) 3-β and -γ, the manifests in different phenotypes and requires complicated α-defensins, the cytokines interleukin (IL)-18 and IL-15 therapies that have to be tailored individually for every pa- and the proliferation-inducing ligand APRIL are reduced tient in an effort to achieve precision medicine [11, 12]. as compared with adults [35]. Conversely, the expression There have been 163 gene loci identified that are associ- of cathelicidin-related antimicrobial peptide, IL-27, trans- ated with IBD [13]. However, only three main loci pre- forming growth factor-β (TGF-β) and thymic stromal dict the clinical phenotype of IBD; for example, NOD2 is lymphopoietin is increased in the neonate [35]. Further- associated with ileal Crohn’s disease and HLA susceptib- more, monocyte-derived cells replace yolk sac derived ility is associated with colonic Crohn’s disease. No vari- macrophages at the time of birth [37]. CD44- and ant is able to predict disease progression, which can so CD69-expressing T and B cells that populate the lamina far only be predicted by epidemiological or environment- propria prevent overwhelming immune responses to col- al factors, such as age of disease onset or smoking [14]. onisation with the bacterial consortia [38]. Activation of Mucosal immunology together with genetics, microbiology CD69 leads to the production of the immuneregulatory and virology is essential to explain interindividual differ- cytokine TGF-β and downregulation of the production of ences between patients [15]. The importance of immuno- proinflammatory cytokines [39]. It needs to be pointed out logical factors in gastrointestinal diseases is highlighted by that the microbial consortia of newborns are not stable at the fact that most lymphocytes in the human body are loc- the beginning of the colonisation period. The final com- ated within the digestive tract [16, 17], where they have to position of the flora depends on the mode of delivery, en- deal with a high abundance of microbial consortia (up to vironmental hygiene status, diet and medication. At birth, 1014 organisms, exceeding our own cell number by a factor facultative anaerobic bacteria, including Escherichia coli, of 10) [18, 19], viruses and bacteriophages [20]. There is Firmicutes species and Staphylococcus species, dominate a growing tendency to consider humans as superorganisms in the first few days as shown by the analysis of the new- consisting of cells and genes of eukaryotic and prokaryotic born’s meconium [40]. When oxygen is deprived, the an- origin. Both prokaryotic and eukaryotic factors affect our aerobic bacteria, such as Bacteroides, Clostridium and Bi- behaviour and physiological processes (uptake and meta- fidobacterium, replace E. coli, Firmicutes species and Sta- bolism of food products, utilisation of vitamins, defence phylococcus species [40]. At the time when the baby is against pathogens). Throughout most of our life this su- weaned from the mother’s milk and regular food