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Background Increasing evidence suggests that not only genetics, but also environmental factors like gut microbiota dysbiosis play an important role in the pathogenesis of celiac disease (CD). Aim The aim of our study was to investigate the effect of two probiotic strains Bifidobacterium breve BR03 and B. breve B632 on serum production of anti-inflammatory cytokine interleukin 10 (IL-10) and pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α) in children with CD. Methods The study was a double-blinded, placebo-controlled trial that included 49 children with CD on gluten-free diet (GFD) randomized into two groups and 18 healthy children in the control group. The first group (24 children with CD) daily received B. breve BR03 and B632 (2 × 10 9 colony-forming units) and the second group (25 children with CD) received placebo for 3 months. Results TNF-α levels were significantly decreased in the first group after receiving B. breve for 3 months. On follow-up, 3 months after receiving probiotics, TNF-α levels increased again. Children with CD who were on GFD for less than 1 year showed similar baseline TNF-α levels as children who were on GFD for more than 1 year. IL-10 levels were in all groups of patients below detection level. Conclusions Probiotic intervention with B. breve strains has shown a positive effect on decreasing the production of pro-inflammatory cytokine TNF-α in children with CD on GFD.

Depletion of CD4+ T cells from the gut occurs rapidly during acute HIV-1 infection. This has been linked to systemic inflammation and disease progression as a result of translocation of microbial products from the gut lumen into the bloodstream. Combined antiretroviral therapy (cART) substantially restores CD4+ T cell numbers in peripheral blood, but the gut compartment remains largely depleted of such cells for poorly understood reasons. Here, we show that a lack of recruitment of CD4+ T cells to the gut could be involved in the incomplete mucosal immune reconstitution of cART-treated HIV-infected individuals. We investigated the trafficking of CD4+ T cells expressing the gut-homing receptors CCR9 and integrin α4β7 and found that many of these T cells remained in the circulation rather than repopulating the mucosa of the small intestine. This is likely because expression of the CCR9 ligand CCL25 was lower in the small intestine of HIV-infected individuals. The defective gut homing of CCR9+β7+ CD4+ T cells - a population that we found included most gut-homing Th17 cells, which have a critical role in mucosal immune defense - correlated with high plasma concentrations of markers of mucosal damage, microbial translocation, and systemic T cell activation. Our results thus describe alterations in CD4+ T cell homing to the gut that could prevent efficient mucosal immune reconstitution in HIV-infected individuals despite effective cART.

This study was conducted to investigate the effects of aflatoxin B1 (AFB1) on T-cell subsets and mRNA expression of cytokines in the small intestine of broilers. One hundred and fifty-six one-day-old healthy Cobb broilers were randomly divided into control group (0 mg/kg AFB1) and AFB1 group (0.6 mg/kg AFB1) with three replicates per group and 26 birds per replicate for 21 days, respectively. At 7, 14, and 21 days of age, the duodenum, jejunum and ileum were sampled for analyzing T cell subsets (CD3+, CD3+CD4+ and CD3+CD8+) by flow cytometry as well as IL-2, IL-4, IL-6, IL-10, IL-17, IFN-γ and TNF-α mRNA expression by qRT-PCR. The percentages of T-cells in the intra-epithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) of duodenum, jejunum and ileum in the AFB1 group showed a decreased tendency in comparison to the control group. The mRNA expression of cytokines in the three intestinal segments in the AFB1 group presented a general decline compared with the control groups. Our data demonstrated that 0.6 mg/kg AFB1 in the broilers diet could reduce the percentages of T-cell subsets and the expression level of cytokine mRNA in the small intestine, implying that the immune function of the intestinal mucosa might be affected. The reduction of cytokines mRNA expression may be closely associated with the decreased proportions of T cells subsets induced by AFB1.

Interleukin (IL)-2 is a pleiotropic cytokine that is necessary to prevent chronic inflammation in the gastrointestinal tract 1 – 4 . The protective effects of IL-2 involve the generation, maintenance and function of regulatory T (T reg ) cells 4 – 8 , and the use of low doses of IL-2 has emerged as a potential therapeutic strategy for patients with inflammatory bowel disease 9 . However, the cellular and molecular pathways that control the production of IL-2 in the context of intestinal health are undefined. Here we show, in a mouse model, that IL-2 is acutely required to maintain T reg cells and immunological homeostasis throughout the gastrointestinal tract. Notably, lineage-specific deletion of IL-2 in T cells did not reduce T reg cells in the small intestine. Unbiased analyses revealed that, in the small intestine, group-3 innate lymphoid cells (ILC3s) are the dominant cellular source of IL-2, which is induced selectively by IL-1β. Macrophages in the small intestine produce IL-1β, and activation of this pathway involves MYD88- and NOD2-dependent sensing of the microbiota. Our loss-of-function studies show that ILC3-derived IL-2 is essential for maintaining T reg cells, immunological homeostasis and oral tolerance to dietary antigens in the small intestine. Furthermore, production of IL-2 by ILC3s was significantly reduced in the small intestine of patients with Crohn’s disease, and this correlated with lower frequencies of T reg cells. Our results reveal a previously unappreciated pathway in which a microbiota- and IL-1β-dependent axis promotes the production of IL-2 by ILC3s to orchestrate immune regulation in the intestine. A microbiota- and IL-1β-dependent axis of IL-2 production by group-3 innate lymphoid cells is shown in a mouse model to be necessary to maintain immunological homeostasis and regulatory T cells in the small intestine.

Key Points Intestinal epithelial cells (IECs) provide a physical and biochemical barrier that segregates host tissue and commensal bacteria to maintain intestinal homeostasis. Secretory IECs support this function through the secretion of mucins and antimicrobial peptides. IECs maintain specialized pathways for the delivery of luminal antigens and bacteria to lamina propria-resident antigen-presenting cells. Microbial signals are recognized by IECs to promote intestinal homeostasis. Host–commensal microorganism interactions not only support tissue repair in the setting of injury or acute inflammation but also promote the development of intestinal cancers during chronic inflammation. IECs possess mechanisms for maintaining altered responsiveness to microbial signals that allow for tolerance to continuous exposure to commensal bacteria. IECs convey microbial signals to mucosal immune cells and promote the coordination of appropriate immune responses against commensal bacteria and enteric pathogens. Interactions between antigen-presenting cells and IECs regulate B cell and T cell responses that act on the intestinal barrier. Both innate and adaptive effector cell function and homeostasis are influenced by IEC-derived signals. This allows IECs to locally regulate immune response at the intestinal barrier and promote the maintenance of intestinal homeostasis. Intestinal epithelial cells (IECs) promote gut homeostasis by coordinating the segregation and regulation of commensal microorganisms and the host immune system. This Review highlights the diverse and multifaceted roles of IECs in barrier function, and in their regulation of innate and adaptive immune cell function and homeostasis in response to microbial colonization. The abundance of innate and adaptive immune cells that reside together with trillions of beneficial commensal microorganisms in the mammalian gastrointestinal tract requires barrier and regulatory mechanisms that conserve host–microbial interactions and tissue homeostasis. This homeostasis depends on the diverse functions of intestinal epithelial cells (IECs), which include the physical segregation of commensal bacteria and the integration of microbial signals. Hence, IECs are crucial mediators of intestinal homeostasis that enable the establishment of an immunological environment permissive to colonization by commensal bacteria. In this Review, we provide a comprehensive overview of how IECs maintain host–commensal microbial relationships and immune cell homeostasis in the intestine.

Accumulating evidence indicates that gut microorganisms have a pathogenic role in autoimmune diseases, including in multiple sclerosis 1 . Studies of experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis) 2 , 3 , as well as human studies 4 – 6 , have implicated gut microorganisms in the development or severity of multiple sclerosis. However, it remains unclear how gut microorganisms act on the inflammation of extra-intestinal tissues such as the spinal cord. Here we show that two distinct signals from gut microorganisms coordinately activate autoreactive T cells in the small intestine that respond specifically to myelin oligodendrocyte glycoprotein (MOG). After induction of experimental autoimmune encephalomyelitis in mice, MOG-specific CD4 + T cells are observed in the small intestine. Experiments using germ-free mice that were monocolonized with microorganisms from the small intestine demonstrated that a newly isolated strain in the family Erysipelotrichaceae acts similarly to an adjuvant to enhance the responses of T helper 17 cells. Shotgun sequencing of the contents of the small intestine revealed a strain of Lactobacillus reuteri that possesses peptides that potentially mimic MOG. Mice that were co-colonized with these two strains showed experimental autoimmune encephalomyelitis symptoms that were more severe than those of germ-free or monocolonized mice. These data suggest that the synergistic effects that result from the presence of these microorganisms should be considered in the pathogenicity of multiple sclerosis, and that further study of these microorganisms may lead to preventive strategies for this disease. Germ-free mice co-colonized with two bacterial strains from the small intestinal flora showed increased susceptibility to experimental autoimmune encephalomyelitis, implicating the synergistic effects of these microorganisms in this mouse model of multiple sclerosis.

Epithelial tuft cells are shown to be the source of intestinal interleukin (IL)-25 that is required for activation of type 2 innate lymphoid cells (ILC2s), ILC2-regulated tuft and goblet cell expansion, and control of parasite infection. Epithelial tuft cells in type 2 immunity The 'weep-and-sweep' response to parasitic helminths and allergens, in which parasites are ejected by increased propulsive activity of the gut combined with fluid and mucus secretion, is a manifestation of type 2 (or allergic) immunity involving the activation of group 2 innate lymphoid cells (ILC2s). The epithelium in the small intestine consists of five or more distinct cellular lineages, including tuft cells, whose functions remain unclear. Two papers in this issue of Nature demonstrate a role for tuft cells in the response to parasites. Richard Locksley and colleagues show that tuft cells are the source of the interleukin 25 (IL-25) that is required for activation of ILC2s, ILC2-regulated tuft and goblet cell expansion, and control of parasite infection. Philippe Jay and colleagues show that tuft cells secrete IL-25 via an IL-13/IL-4R -dependent feedback loop. Parasitic helminths and allergens induce a type 2 immune response leading to profound changes in tissue physiology, including hyperplasia of mucus-secreting goblet cells 1 and smooth muscle hypercontractility 2 . This response, known as ‘weep and sweep’, requires interleukin (IL)-13 production by tissue-resident group 2 innate lymphoid cells (ILC2s) and recruited type 2 helper T cells (T H 2 cells) 3 . Experiments in mice and humans have demonstrated requirements for the epithelial cytokines IL-33, thymic stromal lymphopoietin (TSLP) and IL-25 in the activation of ILC2s 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , but the sources and regulation of these signals remain poorly defined. In the small intestine, the epithelium consists of at least five distinct cellular lineages 12 , including the tuft cell, whose function is unclear. Here we show that tuft cells constitutively express IL-25 to sustain ILC2 homeostasis in the resting lamina propria in mice. After helminth infection, tuft-cell-derived IL-25 further activates ILC2s to secrete IL-13, which acts on epithelial crypt progenitors to promote differentiation of tuft and goblet cells, leading to increased frequencies of both. Tuft cells, ILC2s and epithelial progenitors therefore comprise a response circuit that mediates epithelial remodelling associated with type 2 immunity in the small intestine, and perhaps at other mucosal barriers populated by these cells.

Alterations in the gut microbiota affect stroke outcomes via modulation of T cells, suggesting a gut-brain axis linking commensal microbes with the CNS. Commensal gut bacteria impact the host immune system and can influence disease processes in several organs, including the brain. However, it remains unclear whether the microbiota has an impact on the outcome of acute brain injury. Here we show that antibiotic-induced alterations in the intestinal flora reduce ischemic brain injury in mice, an effect transmissible by fecal transplants. Intestinal dysbiosis alters immune homeostasis in the small intestine, leading to an increase in regulatory T cells and a reduction in interleukin (IL)-17–positive γδ T cells through altered dendritic cell activity. Dysbiosis suppresses trafficking of effector T cells from the gut to the leptomeninges after stroke. Additionally, IL-10 and IL-17 are required for the neuroprotection afforded by intestinal dysbiosis. The findings reveal a previously unrecognized gut-brain axis and an impact of the intestinal flora and meningeal IL-17 + γδ T cells on ischemic injury.

The physiological functions of mast cells remain largely an enigma. In the context of barrier damage, mast cells are integrated in type 2 immunity and, together with immunoglobulin E (IgE), promote allergic diseases. Allergic symptoms may, however, facilitate expulsion of allergens, toxins and parasites and trigger future antigen avoidance 1 – 3 . Here, we show that antigen-specific avoidance behaviour in inbred mice 4 , 5 is critically dependent on mast cells; hence, we identify the immunological sensor cell linking antigen recognition to avoidance behaviour. Avoidance prevented antigen-driven adaptive, innate and mucosal immune activation and inflammation in the stomach and small intestine. Avoidance was IgE dependent, promoted by Th2 cytokines in the immunization phase and by IgE in the execution phase. Mucosal mast cells lining the stomach and small intestine rapidly sensed antigen ingestion. We interrogated potential signalling routes between mast cells and the brain using mutant mice, pharmacological inhibition, neural activity recordings and vagotomy. Inhibition of leukotriene synthesis impaired avoidance, but overall no single pathway interruption completely abrogated avoidance, indicating complex regulation. Collectively, the stage for antigen avoidance is set when adaptive immunity equips mast cells with IgE as a telltale of past immune responses. On subsequent antigen ingestion, mast cells signal termination of antigen intake. Prevention of immunopathology-causing, continuous and futile responses against per se innocuous antigens or of repeated ingestion of toxins through mast-cell-mediated antigen-avoidance behaviour may be an important arm of immunity. Mast cells are shown to function as sensor cells linking antigen recognition in type 2 immunity to antigen-specific avoidance behaviour, preventing immune activation and inflammation.

Maternal immune activation (MIA)-mediated abnormal behavioural phenotypes require defined gut commensal bacteria for the induction of IL-17-producing T helper 17 cells. Gut bacteria behind behaviour anomalies Epidemiological studies have suggested an association between the activation of the maternal immune system (MIA) against viral infections during pregnancy and behavioural abnormalities in the offspring. Earlier studies in mice have demonstrated a role for interleukin-17 (IL-17) in autism spectrum disorder (ASD)-like phenotypes and abnormal cortical development. Here, Gloria Choi, Jun Huh and colleagues provide evidence that MIA-mediated abnormal behavioural phenotypes require defined gut commensal bacteria for the induction of IL-17-producing T helper 17 (T H 17) cells. In a related study published this week, Gloria Choi, Jun Huh and colleagues identify a specific cortical subregion of the somatosensory cortex as a critical region of dysfunction related to MIA, and show that the presence and size of cortical patches correlate with specific social behaviours. Maternal immune activation (MIA) contributes to behavioural abnormalities associated with neurodevelopmental disorders in both primate and rodent offspring 1 , 2 , 3 , 4 . In humans, epidemiological studies suggest that exposure of fetuses to maternal inflammation increases the likelihood of developing autism spectrum disorder 5 , 6 , 7 . In pregnant mice, interleukin-17a (IL-17a) produced by T helper 17 (T H 17) cells (CD4 + T helper effector cells involved in multiple inflammatory conditions) induces behavioural and cortical abnormalities in the offspring exposed to MIA 8 . However, it is unclear whether other maternal factors are required to promote MIA-associated phenotypes. Moreover, the underlying mechanisms by which MIA leads to T cell activation with increased IL-17a in the maternal circulation are not well understood. Here we show that MIA phenotypes in offspring require maternal intestinal bacteria that promote T H 17 cell differentiation. Pregnant mice that had been colonized with mouse commensal segmented filamentous bacteria or human commensal bacteria that induce intestinal T H 17 cells were more likely to produce offspring with MIA-associated abnormalities. We also show that small intestine dendritic cells from pregnant, but not from non-pregnant, females secrete IL-1β, IL-23 and IL-6 and stimulate T cells to produce IL-17a upon exposure to MIA. Overall, our data suggest that defined gut commensal bacteria with a propensity to induce T H 17 cells may increase the risk of neurodevelopmental disorders in the offspring of pregnant mothers undergoing immune system activation owing to infections or autoinflammatory syndromes.