Luminal Antigens Research Articles

Lactobacillus reuteri and Staphylococcus aureus differentially influence the generation of monocyte-derived dendritic cells and subsequent autologous T cell responses.

IntroductionIn early‐life, the immature mucosal barrier allows contact between the gut microbiota and the developing immune system. Due to their strategic location and their ability to sample luminal antigen, dendritic cells (DC) play a central role in the interaction of microbes and immune cells in the gut. Here, we investigated how two bacteria associated with opposite immune profiles in children, that is, Lactobacillus (L.) reuteri and Staphylococcus (S.) aureus, influenced the differentiation of monocytes in vitro as well how the generated DC impacted T cell responses.MethodsWe exposed monocyte cultures to cell‐free supernatants (CFS) from these bacteria during their differentiation to DC.ResultsThe presence of L. reuteri‐CFS during DC differentiation resulted in DC with a more mature phenotype, in terms of up‐regulated surface markers (HLA‐DR, CD86, CD83, CCR7) and enhanced cytokine production (IL6, IL10, and IL23), but had a reduced phagocytic capacity compared with non‐treated monocyte‐derived DC (Mo‐DC). However, upon LPS activation, L. reuteri‐CFS‐generated DC displayed a more regulated phenotype than control Mo‐DC with notable reduction of cytokine responses both at mRNA and protein levels. In contrast, S. aureus‐CFS‐generated DC were more similar to control Mo‐DC both without and after LPS stimulation, but they were still able to induce responses in autologous T cells, in the absence of further T cell stimulation.ConclusionsWe show that bacterial signals during DC differentiation have a profound impact on DC function and possibly also for shaping the T cell pool.

Fecal microbiota transplantation in inflammatory bowel disease: the quest for the holy grail.

Inflammatory bowel disease (IBD) is due to an aberrant immune response toward luminal antigens, probably commensal bacteria, in genetically susceptible subjects and is also influenced by environmental factors. An imbalanced intestinal microbiota known as "dysbiosis," characterized by an increased proportion of pro-inflammatory microorganisms and a decreased proportion of anti-inflammatory microorganisms, has been repeatedly observed in IBD and is now recognized as a key factor in the gut inflammatory process. Fecal microbiota transplantation (FMT) has gained interest as a novel treatment option in IBD. The goal of FMT in IBD is not only to correct the dysbiosis, but also to restore a normal dialog between the host immune system and the microbiota. Data are still scarce, but the results of the first studies suggest that FMT could be a promising therapy in IBD. More studies are needed to define the best indications, optimal timing, frequency, mode of delivery, and the optimal donor for each patient.

Claudin-based barrier differentiation in the colonic epithelial crypt niche involves Hopx/Klf4 and Tcf7l2/Hnf4-α cascades

ABSTRACTColonic enterocytes form a rapidly renewing epithelium and barrier to luminal antigens. During renewal, coordinated expression of the claudin family of genes is vital to maintain the epithelial barrier. Disruption of this process contributes to barrier compromise and mucosal inflammatory diseases. However, little is known about the regulation of this critical aspect of epithelial cell differentiation. In order to identify claudin regulatory factors we utilized high-throughput gene microarrays and correlation analyses. We identified complex expression gradients for the transcription factors Hopx, Hnf4a, Klf4 and Tcf7l2, as well as 12 claudins, during differentiation. In vitro confirmatory methods identified 2 pathways that stimulate claudin expression; Hopx/Klf4 activation of Cldn4, 7 and 15, and Tcf7l2/Hnf4a up-regulation of Cldn23. Chromatin immunoprecipitation confirmed a Tcf7l2/Hnf4a/Claudin23 cascade. Furthermore, Hnf4a conditional knockout mice fail to induce Cldn23 during colonocyte differentiation. In conclusion, we report a comprehensive screen of colonic claudin gene expression and discover spatiotemporal Hopx/Klf4 and Tcf7l2/Hnf4a signaling as stimulators of colonic epithelial barrier differentiation.

Isolation and Flow Cytometric Characterization of Murine Small Intestinal Lymphocytes

The intestines — which contain the largest number of immune cells of any organ in the body — are constantly exposed to foreign antigens, both microbial and dietary. Given an increasing understanding that these luminal antigens help shape the immune response and that education of immune cells within the intestine is critical for a number of systemic diseases, there has been increased interest in characterizing the intestinal immune system. However, many published protocols are arduous and time-consuming. We present here a simplified protocol for the isolation of lymphocytes from the small-intestinal lamina propria, intraepithelial layer, and Peyer's patches that is rapid, reproducible, and does not require laborious Percoll gradients. Although the protocol focuses on the small intestine, it is also suitable for analysis of the colon. Moreover, we highlight some aspects that may need additional optimization depending on the specific scientific question. This approach results in the isolation of large numbers of viable lymphocytes that can subsequently be used for flow cytometric analysis or alternate means of characterization.

Isolation and Flow Cytometric Characterization of Murine Small Intestinal Lymphocytes.

The intestines - which contain the largest number of immune cells of any organ in the body - are constantly exposed to foreign antigens, both microbial and dietary. Given an increasing understanding that these luminal antigens help shape the immune response and that education of immune cells within the intestine is critical for a number of systemic diseases, there has been increased interest in characterizing the intestinal immune system. However, many published protocols are arduous and time-consuming. We present here a simplified protocol for the isolation of lymphocytes from the small-intestinal lamina propria, intraepithelial layer, and Peyer's patches that is rapid, reproducible, and does not require laborious Percoll gradients. Although the protocol focuses on the small intestine, it is also suitable for analysis of the colon. Moreover, we highlight some aspects that may need additional optimization depending on the specific scientific question. This approach results in the isolation of large numbers of viable lymphocytes that can subsequently be used for flow cytometric analysis or alternate means of characterization.

The intestinal cholinergic anti-inflammatory pathway.

The main task of the immune system is to distinguish and respond accordingly to 'danger' or 'non-danger' signals. This is of critical importance in the gastrointestinal tract in which immune cells are constantly in contact with food antigens, symbiotic microflora and potential pathogens. This complex mixture of food antigens and symbionts are essential for providing vital nutrients, so they must be tolerated by the intestinal immune system to prevent aberrant inflammation. Therefore, in the gut the balance between immune activation and tolerance should be tightly regulated to maintain intestinal homeostasis and to prevent hypersensitivity to harmless luminal antigens. Loss of this delicate equilibrium can lead to abnormal activation of the intestinal immune system resulting in devastating gastrointestinal disorders such as inflammatory bowel disease (IBD). Recent evidence supports the idea that the central nervous system interacts dynamically via the vagus nerve with the intestinal immune system to modulate inflammation through humoral and neural pathways, using a mechanism also referred to as the intestinal cholinergic anti-inflammatory pathway. In this review, we will focus on the current understanding of the mechanisms and neuronal circuits involved in the intestinal cholinergic anti-inflammatory pathway. Further investigation on the crosstalk between the nervous and intestinal immune system will hopefully provide new insights leading to the identification of innovative therapeutic approaches to treat intestinal inflammatory diseases.

Small intestinal Goblet cells and Goblet cell associated antigen passages assist translocation of pathogenic bacteria

Abstract The intestinal epithelium forms an essential physicochemical barrier that separates luminal bacteria from underlying immune cells of the intestinal mucosa. Appropriate exposure of the immune cells to luminal antigens is crucial to ensure intestinal homeostasis and to respond to enteric infections. We recently demonstrated a previously unappreciated role of small intestinal (SI) Goblet cells (GCs) in delivering luminal antigens across the epithelium by forming goblet-cell associated antigen passages (GAPs) in the steady state. How pathogenic bacteria affect the formation of SI GAPs and the ability of pathogens to use GAPs as a portal of entry is largely unexplored. Here we report that in conventionally housed mice, luminal exposure to invasive Salmonella typhimurium, but not mutant non-invasive S. typhimurium, results in inhibition of SI GAPs within minutes. Moreover, overriding the ability of GCs to sense the pathogen by deleting MyD88 in GCs or inhibiting EGFR activation downstream of MyD88 during S. typhimurium infection allowed GAP formation, suggesting that GC intrinsic sensing of an invasive pathogen to shut off GAPs is a host defense mechanism. Fluorescent wildtype S. typhimurium preferentially localized around and within GCs forming GAPs. Deletion of GCs prevented the translocation of wildtype S. typhimurium to the SI draining mesenteric lymph node following oral infection, indicating that S. typhimurium uses GCs as a portal of entry. These findings identify a role of GC sensing of an invasive pathogen in inhibiting antigen delivery to the immune system and in limiting the translocation of pathogenic bacteria.

Maternal control of dietary and gut microbial antigen exposure promotes enhanced tolerance and prevents allergic responses

Abstract The incidence of allergic disorders is rapidly increasing in children in Western societies, and is linked to allergen avoidance diets and decreased exposure to microbes and microbial antigens in early life. Exposure to dietary antigens and the microbiota via the gastrointestinal tract early in life is associated with a reduced risk of allergic disorders, however the optimal time to introduce these antigens, where the immune system encounters these antigens, and what controls the immune systems exposure to define this time in early life is largely unknown. We identified a window of time in early life in which luminal antigens are shunted to the colonic lamina propria (LP) immune system to induce enhanced tolerogenic responses. Delivery of luminal antigens to the colonic immune system during this time in life was mediated by the formation of goblet cell-associated antigen passages (GAPs), which were regulated by goblet cell (GC) intrinsic sensing of breast milk derived epidermal growth factor (EGF) and the blooming gut microbiota. Disruption of GAP formation and antigen delivery during this time in early life abrogated tolerance to dietary antigens, decreased regulatory T cells, and induced a skewing of the immune system toward systemic Th2 responses. We propose that maternal control of antigen delivery during infancy allows for the proper education of the immune system against dietary and microbial antigens, and induction of regulatory T cells necessary to suppress inappropriate Th2 responses later in life.

Gut bacteria modulate dendritic cell priming of diabetogenic T cell effector functions in a mouse model of autoimmune diabetes

Abstract Increasing evidence implicates a contribution of the microbiome, within the gastrointestinal tract, in the initiation and progression of type 1 diabetes (T1D). Notably, our understanding of mechanisms whereby gut flora interaction with the host immune system can influence T1D pathogenesis remain poorly understood. Comparison of stool samples from the non-obese diabetic (NOD) mouse model of spontaneous T1D and non-obese resistant (NOR) mice revealed distinct bacterial flora communities present within the two strains correlated to a Th17 bias. Given that dendritic cells (DC) are critical in sampling luminal antigens and priming naïve T lymphocyte effector functions, we next interrogated the populations of CD11c+ DC within the lamina propria (LP) of NOD and NOR mice. Phenotypic characterization of LP DC revealed that NOR mice possessed more mature DC denoted by a higher frequency of CD11c+ MHCII+ cells and CD103+ CD86+ cells. We have previously shown that the oral administration of a gut bacterium Lactobaccillus johnsonii (LjN6.2), present in diabetes resistant rodents, was capable of conferring diabetes resistance to diabetes prone rodents while another strain Lactobacillus reuterii (LrTD1) had no effect. Notably, T1D resistance was correlated to a Th17 bias. Hence, we sought to investigate the influence of LjN6.2 on NOD and NOR DC in comparison to LrTD1 in vitro. We found that LjN6.2, but not LrTD1 mediated an increase in IL6 and IL10 cytokine production by DC. Together, these data suggest that gut bacteria have the important ability to shape the maturation and priming abilities of DC. These results could have critical implications regarding the ability of bacterial flora to regulate the generation of a diabetogenic immune repertoire.

In It for the Long Haul: Managing the Complexity of Crohn’s Disease

The challenges of, and opportunities for optimal long-term management of Crohn’s disease (CD) and real-world experience of managing CD and its application in clinical practice were discussed at this symposium. CD is a complex disease, which requires effective treatment options to improve the quality of life for patients, both in terms of intestinal and extraintestinal manifestations (EIMs). Increased gut permeability of luminal antigens may play a primary role in the pathogenesis of CD, leading to dysregulation of the host’s immune response, and resulting in increased levels of tumour necrosis factor (TNF)-α and interferon (IFN)-γ in the inflamed mucosa of patients. Appropriate management goals need to be established by the physician and patient together. Anti-TNF therapy is not suitable for all patients, and a significant proportion of patients will be primary non-responders. Safety must also be considered as part of a patient-tailored assessment. Vedolizumab is a gut-selective antibody to α4β7 integrin for the treatment of ulcerative colitis (UC) and CD. An integrated Phase II and III safety analysis showed that vedolizumab exposure was not associated with increased risk of any infection or serious infection, or any cases of progressive multifocal leukoencephalopathy (PML), a rare and usually fatal viral disease characterised by progressive damage of the white matter of the brain at multiple locations. Data from the GEMINI trials with vedolizumab showed it to be effective versus placebo, in terms of eliciting both initial and sustained responses, and inducing remission in CD. The real-world studies with vedolizumab in >800 CD patients, most of whom failed ≥1 anti-TNF therapy, confirmed the efficacy and safety reported in clinical trials. Up to 30% of CD patients are receiving vedolizumab as a first biologic in the real-world setting.

Endocytosis in enterocytes.

Endocytosis is a fundamental cell biological process, which carries out essential functions in a polarized epithelial cell such as enterocytes provided with a huge surface area of the brush border membrane. Major tasks of enterocytes, which are regulated by endocytic signals, are digestion and absorption of nutrients and drugs/pharmacological agents, barrier permeability to microorganism, toxins and antigens, and transcytotic crosstalk between intestinal lumen and lamina propria cells with access to the circulation.Investigations on inflammatory bowel diseases such as food allergy, celiac disease, Crohn's disease, and ulcerative colitis focus on immune processes originating within enterocytes as antigen presenting cells. Thus the initiation of oral tolerance, that is, the binding of food antigens to MHC class II proteins, might be localized within late endosomes of enterocytes. Furthermore, the late endosomal compartment of enterocytes seems to be involved in the processing of luminal antigens during the pathogenesis of celiac disease and inflammatory bowel diseases. Investigations of inherited diseases such as microvillus inclusion disease have revealed a pathogenetic defect in the autophagocytotic and/or recycling pathway of enterocytes.Our progress in the cell and molecular biological understanding of the endocytosis and the methodical opportunities of translational research offer now new therapeutic options for patients suffering from endocytosis-related diseases of enterocytes.

P-128 Ven120, A Plant Derived Human Protein, Attenuates Murine Ileitis Through Activation of Treg Function

Current hypotheses suggest that Crohns disease (CD) may develop through a dysregulated mucosal immune response toward the commensal enteric flora in genetically susceptible individuals. Multiple animal studies indicate that regulatory T cells (Treg) regulate the immune response in normal intestinal mucosa and thereby prevent colitis development. A breakdown of this tolerance to luminal antigens plays a pivotal role in IBD development. We hypothesize that a plant produced human milk protein, Ven120, can modulate the adaptive immune system in Crohn's disease to ameliorate inflammation. We aimed to validate this hypothesis using a TNF-driven model of CD the TNFDARE mouse model, in which a 69bp deletion of the AU-rich element confers increased TNF mRNA stability leading to spontaneous chronic murine ileitis. The Ven120 was provided by oral gavage or by subcutaneous Alzet pump to 10-12 week old TNFDARE mice with ileitis. After 2 weeks these mice were evaluated for intestinal permeability by FITC dextran flux, inflammation by histology, cell isolation and flow cytometry as well as Treg function. Finally, IL-10 and IL17 output was measured both by ELISA and by intracellular cytokine staining. Isolated CD4+CD25− T cells had decreased proliferation in the presence of Ven120. These cells produced increased quantities of IL-10. In the TNFDARE mouse model of IBD after 2 weeks of treatment with Ven120 versus vehicle there was a significant drop in influx of Naive CD44lowCD62Lhi T cells into the lamina propria of the intestine. In addition to this there was a significant increase in Treg numbers and these cells produced increased quantities of IL-10. Histology of the intestines from these mice was evaluated by a pathologist in blinded fashion and all indices of inflammation were improved. Similar studies were carried out in the DSS model of colitis and similar anti-inflammatory effects were noted. Our studies have effectively demonstrated the therapeutic potential of Ven120 in murine models of inflammatory bowel disease. Specifically, Ven120 administration significantly decreased naive T cell infiltration and proliferation in the intestinal lamina propria, mesenteric lymph nodes and spleen of 12 weeks old TNFDARE mice. An increase in CD4+Foxp3+ regulatory T cells was noted in the Ven120-treated mice. These Ven120 treated mice also exhibited improved histological indices and had improved intestinal barrier function, indicating efficacy for Ven120 to decrease inflammation in a preclinical model of CD.

Neutralization of pro-inflammatory monocytes by targeting TLR2 dimerization ameliorates colitis.

Monocytes have emerged as critical driving force of acute inflammation. Here, we show that inhibition of Toll-like receptor 2(TLR2) dimerization by a TLR2 transmembrane peptide (TLR2-p) ameliorated DSS-induced colitis by interfering specifically with the activation of Ly6C(+) monocytes without affecting their recruitment to the colon. We report that TLR2-p directly interacts with TLR2 within the membrane, leading to inhibition of TLR2-TLR6/1 assembly induced by natural ligands. This was associated with decreased levels of extracellular signal-regulated kinases (ERK) signaling and reduced secretion of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-23, IL-12, and IL-1β. Altogether, our study provides insights into the essential role of TLR2 dimerization in the activation of pathogenic pro-inflammatory Ly6C(hi) monocytes and suggests that inhibition of this aggregation by TLR2-p might have therapeutic potential in the treatment of acute gut inflammation.

Development of Functional Microfold (M) Cells from Intestinal Stem Cells in Primary Human Enteroids.

Background & AimsIntestinal microfold (M) cells are specialized epithelial cells that act as gatekeepers of luminal antigens in the intestinal tract. They play a critical role in the intestinal mucosal immune response through transport of viruses, bacteria and other particles and antigens across the epithelium to immune cells within Peyer’s patch regions and other mucosal sites. Recent studies in mice have demonstrated that M cells are generated from Lgr5+ intestinal stem cells (ISCs), and that infection with Salmonella enterica serovar Typhimurium increases M cell formation. However, it is not known whether and how these findings apply to primary human small intestinal epithelium propagated in an in vitro setting.MethodsHuman intestinal crypts were grown as monolayers with growth factors and treated with recombinant RANKL, and assessed for mRNA transcripts, immunofluorescence and uptake of microparticles and S. Typhimurium.ResultsFunctional M cells were generated by short-term culture of freshly isolated human intestinal crypts in a dose- and time-dependent fashion. RANKL stimulation of the monolayer cultures caused dramatic induction of the M cell-specific markers, SPIB, and Glycoprotein-2 (GP2) in a process primed by canonical WNT signaling. Confocal microscopy demonstrated a pseudopod phenotype of GP2-positive M cells that preferentially take up microparticles. Furthermore, infection of the M cell-enriched cultures with the M cell-tropic enteric pathogen, S. Typhimurium, led to preferential association of the bacteria with M cells, particularly at lower inoculum sizes. Larger inocula caused rapid induction of M cells.ConclusionsHuman intestinal crypts containing ISCs can be cultured and differentiate into an epithelial layer with functional M cells with characteristic morphological and functional properties. This study is the first to demonstrate that M cells can be induced to form from primary human intestinal epithelium, and that S. Typhimurium preferentially infect these cells in an in vitro setting. We anticipate that this model can be used to generate large numbers of M cells for further functional studies of these key cells of intestinal immune induction and their impact on controlling enteric pathogens and the intestinal microbiome.

Mucin-Microbiota Interaction During Postnatal Maturation of the Intestinal Ecosystem: Clinical Implications.

The mucus layer and gut microbiota interplay contributes to host homeostasis. The mucus layer serves as a scaffold and a carbon source for gut microorganisms; conversely, gut microorganisms, including mucin degraders, influence mucin gene expression, glycosylation, and secretion. Conjointly they shield the epithelium from luminal pathogens, antigens, and toxins. Importantly, the mucus layer and gut microbiota are established in parallel during early postnatal life. During this period, the development of gut microbiota and mucus layer is coupled with that of the immune system. Developmental changes of different mucin types can impact the age-dependent patterns of intestinal infection in terms of incidence and severity. Altered mucus layer, dysbiotic microbiota, and abnormal mucus-gut microbiota interaction have the potential for inducing systemic effects, and accompany several intestinal diseases such as inflammatory bowel disease, colorectal cancer, and radiation-induced mucositis. Early life provides a pivotal window of opportunity to favorably modulate the mucus-microbiota interaction. The support of a health-compatible mucin-microbiota maturation in early life is paramount for long-term health and serves as an important opportunity for clinical intervention.

Overview of cytokines and nitric oxide involvement in immuno-pathogenesis of inflammatory bowel diseases.

Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis are complex disorders with undetermined etiology. Several hypotheses suggest that IBDs result from an abnormal immune response against endogenous flora and luminal antigens in genetically susceptible individuals. The dysfunction of the mucosal immune response is implicated in the pathogenesis of IBD. The balance between pro-inflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, and IL-17A], anti-inflammatory cytokines (IL-4 and IL-13), and immunoregulatory cytokines (IL-10 and transforming growth factors β) is disturbed. Moreover, evidence from animal and clinical studies demonstrate a positive correlation between an increased concentration of nitric oxide (NO) and the severity of the disease. Interestingly, proinflammatory cytokines are involved in the up-regulation of inducible oxide synthase (iNOS) expression in IBD. However, anti-inflammatory and immunoregulatory cytokines are responsible for the negative regulation of iNOS. A positive correlation between NO production and increased pro-inflammatory cytokine levels (TNF-α, IL-6, IL-17, IL-12, and interferon-γ) were reported in patients with IBD. This review focuses on the role of cytokines in intestinal inflammation and their relationship with NO in IBD.

Abnormal Barrier Function in Gastrointestinal Disorders.

There is increasing concern in identifying the mechanisms underlying the intimate control of the intestinal barrier, as deregulation of its function is strongly associated with digestive (organic and functional) and a number of non-digestive (schizophrenia, diabetes, sepsis, among others) disorders. The intestinal barrier is a complex and effective defensive functional system that operates to limit luminal antigen access to the internal milieu while maintaining nutrient and electrolyte absorption. Intestinal permeability to substances is mainly determined by the physicochemical properties of the barrier, with the epithelium, mucosal immunity, and neural activity playing a major role. In functional gastrointestinal disorders (FGIDs), the absence of structural or biochemical abnormalities that explain chronic symptoms is probably close to its end, as recent research is providing evidence of structural gut alterations, at least in certain subsets, mainly in functional dyspepsia (FD) and irritable bowel syndrome (IBS). These alterations are associated with increased permeability, which seems to reflect mucosal inflammation and neural activation. The participation of each anatomical and functional component of barrier function in homeostasis and intestinal dysfunction is described, with a special focus on FGIDs.

Segmental Differences in Radiation-Induced Alterations of Tight Junction-Related Proteins in Non-Human Primate Jejunum, Ileum and Colon.

Dysfunction of the intestinal epithelial barrier and leakage of luminal antigens and bacteria across the barrier have been linked to various human diseases. Intestinal permeability is regulated by intercellular structures, termed "tight junction" (Tj), which are disrupted after total-body irradiation (TBI). In this study, we investigated radiation-induced alterations in Tj-related proteins in the jejunum, ileum and colon of a non-human primate (NHP) model. NHPs were total-body irradiated with 6.7 and 7.4 Gy and intestines were procured at day 4, 7 and 12. Radiation exposure was found to induce significant increases in claudin-10 mRNA early (day 4) in all three gut segments and claudin-4 mRNA levels were repressed through day 12. TNF-alpha was highly induced in the jejunum and colon at early time points, but little induction was found in the ileum. Claudin-1 was induced only in the colon on day 4 postirradiation. Unlike the colon and jejunum, the ileum levels of claudin-7 were significantly downregulated through day 12 postirradiation. Western blot analysis revealed increased levels of claudin-2 on day 4 and of JAM-1 on day 7 postirradiation in all three gut segments. E-cadherin was downregulated on day 4 postirradiation in all segments, but remained reduced in the jejunum only until day 12. Taken together, these data suggest that exposure to radiation causes segment-specific alterations in the expression of Tj-related proteins. Interruption of Tjs may be a key factor contributing to injury to the intestinal mucosal barrier and increased intestinal permeability.

Nutritional Keys for Intestinal Barrier Modulation.

The intestinal tract represents the largest interface between the external environment and the human body. Nutrient uptake mostly happens in the intestinal tract, where the epithelial surface is constantly exposed to dietary antigens. Since inflammatory response toward these antigens may be deleterious for the host, a plethora of protective mechanisms take place to avoid or attenuate local damage. For instance, the intestinal barrier is able to elicit a dynamic response that either promotes or impairs luminal antigens adhesion and crossing. Regulation of intestinal barrier is crucial to control intestinal permeability whose increase is associated with chronic inflammatory conditions. The cross talk among bacteria, immune, and dietary factors is able to modulate the mucosal barrier function, as well as the intestinal permeability. Several nutritional products have recently been proposed as regulators of the epithelial barrier, even if their effects are in part contradictory. At the same time, the metabolic function of the microbiota generates new products with different effects based on the dietary content. Besides conventional treatments, novel therapies based on complementary nutrients are now growing. Fecal therapy has been recently used for the clinical treatment of refractory Clostridium difficile infection instead of the classical antibiotic therapy. In the present review, we will outline the epithelial response to nutritional components derived from dietary intake and microbial fermentation focusing on the consequent effects on the integrity of the epithelial barrier.

The Neuromodulation of the Intestinal Immune System and Its Relevance in Inflammatory Bowel Disease.

One of the main tasks of the immune system is to discriminate and appropriately react to “danger” or “non-danger” signals. This is crucial in the gastrointestinal tract, where the immune system is confronted with a myriad of food antigens and symbiotic microflora that are in constant contact with the mucosa, in addition to any potential pathogens. This large number of antigens and commensal microflora, which are essential for providing vital nutrients, must be tolerated by the intestinal immune system to prevent aberrant inflammation. Hence, the balance between immune activation versus tolerance should be tightly regulated to maintain intestinal homeostasis and to prevent immune activation indiscriminately against all luminal antigens. Loss of this delicate equilibrium can lead to chronic activation of the intestinal immune response resulting in intestinal disorders, such as inflammatory bowel diseases (IBD). In order to maintain homeostasis, the immune system has evolved diverse regulatory strategies including additional non-immunological actors able to control the immune response. Accumulating evidence strongly indicates a bidirectional link between the two systems in which the brain modulates the immune response via the detection of circulating cytokines and via direct afferent input from sensory fibers and from enteric neurons. In the current review, we will highlight the most recent findings regarding the cross-talk between the nervous system and the mucosal immune system and will discuss the potential use of these neuronal circuits and neuromediators as novel therapeutic tools to reestablish immune tolerance and treat intestinal chronic inflammation.