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This Perspective presents the potential of the Small Intestinal Axis, a sub-division of the Gut-immune Axis, to modulate systemic inflammation based on sensing contents of the gut lumen. Gut mucosal immunity regulates tolerance to food and gut contents and is a significant factor in maintaining systemic homeostasis without compromising immunity to pathogens. This is achieved through anatomical structures and signaling pathways that link the tolerogenic potential of the proximal small intestine to systemic immunity. Non-live preparations of microbes isolated from human small intestinal mucosa, and the extracellular vesicles (EVs) which they shed, can resolve systemic inflammation without systemic exposure after oral delivery. The mechanism involves primary interactions with pattern recognition receptors followed by trafficking of immune cells through mesenteric lymph nodes. This generates in the periphery a population of circulating CD4 + T cells which have regulatory function but an atypical FoxP3 - phenotype. There is no modification of the resident gut microbiome. Discoveries using this novel approach of targeting mucosal microbial elements to the tolerogenic proximal regions of the small intestine are revealing some of the mysteries of the relationship between the gut and immune system.

Although the presentation of peptide–major histocompatibility complex class II (pMHC class II) complexes to CD4 T cells has been studied extensively in vitro , knowledge of this process in vivo is limited. Unlike the in vitro situation, antigen presentation in vivo takes place within a complex microenvironment in which the movements of antigens, antigen-presenting cells (APCs) and T cells are governed by anatomic constraints. Here we review developments in the areas of lymph node architecture, APC subsets and T cell activation that have shed light on how antigen presentation occurs in the lymph nodes.

spp. has been associated with promising immunomodulatory results in preclinical trials. The aim of this study was to investigate the pharmacodynamic (PD) effects of three monoclonal microbial formulations of spp. (EDP1066) on the immune response to keyhole limpet hemocyanin (KLH). Potential effects on the gut microbiota were also investigated. The trial was registered on Netherlands Trial Register (trial ID NL7519, https://trialsearch.who.int). Eighty-one healthy subjects (median 28, range 18-59 years) were randomized to 28 days of enteric-coated capsules at five doses (n = 13) (1.5 * 10 total cells daily), freeze-dried powder at one dose (n = 12) (3.0 * 10 total cells daily) or five doses (n = 12), minitablets at one dose (n = 12) or five doses (n = 12), or placebo (n = 20) prior to KLH immunization. Antibody responses and circulating regulatory T cells (Tregs) were measured after KLH immunization, and skin responses were evaluated after a KLH rechallenge by laser speckle contrast imaging and multispectral imaging. lymphocyte (phytohemagglutinin) and monocyte (lipopolysaccharide (LPS)) cytokine release assays were explored in the minitablet-treated groups only. The prevalence of spp. in the gastrointestinal tract and the impact on the fecal microbiota were assessed by qPCR and 16S rRNA sequencing, respectively. Repeated-measures analysis of covariances revealed no significant treatment effects on the antibody responses to KLH, number of Tregs, or KLH skin rechallenge outcomes. LPS-driven cytokine responses in whole blood were lower in the low dose minitablet group compared to placebo: tumor necrosis factor (estimated difference (ED) from placebo: -44.2%, 95% confidence interval (CI) -65.3% to -10.3%), interleukin (IL)-1β (ED -41.4%, 95% CI -63.5% to -5.8%), and IL-6 (ED -39.2%, 95% CI -56.8% to -14.5%). The fecal presence of spp. increased during treatment by all EDP1066 formulations and normalized 5 days after the last dose. Microbiome α-diversity did not change by the treatments compared to placebo. The EDP1066 formulations did not affect the immune response to KLH immunization in healthy individuals. However, exposure to spp. in minitablet formulation impacted whole blood LPS cytokine response. The clinical impact of these effects awaits further investigations. trialsearch.who.int, trial ID NL7519.

The gastrointestinal tract represents one of the largest body surfaces that is exposed to the outside world. It is the only mucosal surface that is required to simultaneously recognize and defend against pathogens, while allowing nutrients containing foreign antigens to be tolerated and absorbed. It differentiates between these foreign substances through a complex system of pattern recognition receptors expressed on the surface of the intestinal epithelial cells as well as the underlying immune cells. These immune cells actively sample and evaluate microbes and other particles that pass through the lumen of the gut. This local sensing system is part of a broader distributed signaling system that is connected to the rest of the body through the enteric nervous system, the immune system, and the metabolic system. While local tissue homeostasis is maintained by commensal bacteria that colonize the gut, colonization itself may not be required for the activation of distributed signaling networks that can result in modulation of peripheral inflammation. Herein, we describe the ability of a gut-restricted strain of commensal bacteria to drive systemic anti-inflammatory effects in a manner that does not rely upon its ability to colonize the gastrointestinal tract or alter the mucosal microbiome. Orally administered EDP1867, a gamma-irradiated strain of Veillonella parvula , rapidly transits through the murine gut without colonization or alteration of the background microbiome flora. In murine models of inflammatory disease including delayed-type hypersensitivity (DTH), atopic dermatitis, psoriasis, and experimental autoimmune encephalomyelitis (EAE), treatment with EDP1867 resulted in significant reduction in inflammation and immunopathology.  Ex vivo  cytokine analyses revealed that EDP1867 treatment diminished production of pro-inflammatory cytokines involved in inflammatory cascades. Furthermore, blockade of lymphocyte migration to the gut-associated lymphoid tissues impaired the ability of EDP1867 to resolve peripheral inflammation, supporting the hypothesis that circulating immune cells are responsible for promulgating the signals from the gut to peripheral tissues. Finally, we show that adoptively transferred T cells from EDP1867-treated mice inhibit inflammation induced in recipient mice. These results demonstrate that an orally-delivered, non-viable strain of commensal bacteria can mediate potent anti-inflammatory effects in peripheral tissues through transient occupancy of the gastrointestinal tract, and support the development of non-living bacterial strains for therapeutic applications.

EDP1815 is a non-colonizing pharmaceutical preparation of a single stain of isolated from the duodenum of a human donor. We report here preclinical and clinical studies showing that the action of EDP1815, an orally delivered and gut restricted single strain of commensal bacteria can regulate inflammatory responses throughout the body. Supported by evidence for anti-inflammatory activity in three preclinical mouse models of Th1-, TH2-, and Th17-mediated inflammation, EDP1815 was tested clinically in three Phase 1b studies in patients with psoriasis, patients with atopic dermatitis, and healthy volunteers in a KLH skin challenge model. Preclinically, EDP1815 was efficacious in all three mouse models of inflammation, showing reduction in skin inflammation as well as related tissue cytokines. In the Phase 1b studies, EDP1815 was found to be well tolerated by participants, with a safety profile comparable to placebo, including no severe or consistent side-effects reported, and no evidence of immunosuppression with no opportunistic infection occurring in these studies. In psoriasis patients, signs of clinical efficacy were seen after 4 weeks of treatment, which continued beyond the treatment period in the higher-dose cohort. In atopic dermatitis patients, improvements were seen throughout the key physician-and patient-reported outcomes. In a healthy-volunteer study of a KLH-induced skin inflammatory response, consistent anti-inflammatory effects were seen in two cohorts through imaging-based measures of skin inflammation. This is the first report demonstrating clinical effects from targeting peripheral inflammation with a non-colonizing gut-restricted single strain of commensal bacteria, providing proof of concept for a new class of medicines. These clinical effects occur without systemic exposure of EDP1815 or modification of the resident gut microbiota, and with placebo-like safety and tolerability. The breadth of these clinical effects of EDP1815, combined with its excellent safety and tolerability profile and oral administration, suggests the potential for a new type of effective, safe, oral, and accessible anti-inflammatory medicine to treat the wide range of diseases driven by inflammation. : EudraCT # 2018-002807-32; EudraCT # 2018-002807-32; NL8676; https://clinicaltrials.gov/ct2/show/NCT03733353; http://www.trialregister.nl.

The contribution of CCR6 and phagocyte recruitment to the initiation of T cell responses to a local pathogen is unclear. CD4 T cell activation to an injected soluble antigen occurred rapidly and was completely CCR6-independent. In marked contrast, the tempo of pathogen-specific CD4 T cell activation depended on whether the antigen was secreted or cell-associated. Furthermore, lymph node pathogen-specific CD4 T cell activation required CCR6 and cell migration from the site of infection. Surprisingly, adoptive transfer of wild-type blood phagocytes rescued bacteria-specific T cell activation in CCR6-deficient mice, even when these cells were unable to participate in direct antigen presentation. These data demonstrate that T cell responses to a local bacterial infection follow a distinct tempo, largely determined by bacterial protein secretion, and that CCR6-mediated blood phagocyte recruitment to the site of infection is a critical step in the initiation of pathogen-specific immune responses in skin draining lymph nodes.

The gut microbiome can modulate systemic inflammation and is therefore target for immunomodulation. Immunomodulating effects of EDP1815, a bacterial commensal strain of Prevotella histicola, were studied in healthy participants. Effects on adaptive immunity were evaluated by a neo-antigen challenge with keyhole limpet haemocyanin (KLH), while effects on innate immunity were evaluated by topical toll-like receptor 7 (TLR7) agonist imiquimod. Capsules with two enteric coating levels (EC1, EC2) were compared. Thirty-six healthy participants were included and received a daily dose of 8 × 1010 cells EDP1815-EC1, EDP1815-EC2 or placebo (randomization 1:1:1) for 60 days. They received KLH vaccinations at days 8, 24 and 36, with intradermal skin challenge at day 57. KLH challenge outcomes were antibody levels, and skin blood flow and erythema after skin challenge, measured by imaging techniques. Imiquimod administration started at day 57, for 72 h. Outcomes consisted of imaging measurements similar to the KLH challenge, and the influx of inflammatory cells and cytokines in blister fluid. There was no effect of EDP1815 treatment on the KLH challenge, neither on the imaging outcomes of the imiquimod challenge. There was a consistently lower influx of inflammatory cells in the blister fluid of EDP1815-treated participants (neutrophils, p = 0.016; granulocytes, p = 0.024), more pronounced in EC1. There was a lower influx of interleukin [IL]-1β, IL-6, IL-8, IL-10, interferon [IFN]-γ and tumour necrosis factor in blister fluid of EDP1815-treated participants. EDP1815 had immunomodulatory effects on the innate immune response driven by imiquimod, but no effect on the KLH challenge was observed. Trial registration number: NCT05682222; date: 22 July 2022.

Physical detection of antigen-specific CD4 T cells has revealed features of the in vivo immune response that were not appreciated from in vitro studies. In vivo, antigen is initially presented to naïve CD4 T cells exclusively by dendritic cells within the T cell areas of secondary lymphoid tissues. Anatomic constraints make it likely that these dendritic cells acquire the antigen at the site where it enters the body. Inflammation enhances in vivo T cell activation by stimulating dendritic cells to migrate to the T cell areas and display stable peptide-MHC complexes and costimulatory ligands. Once stimulated by a dendritic cell, antigen-specific CD4 T cells produce IL-2 but proliferate in an IL-2-independent fashion. Inflammatory signals induce chemokine receptors on activated T cells that direct their migration into the B cell areas to interact with antigen-specific B cells. Most of the activated T cells then die within the lymphoid tissues. However, in the presence of inflammation, a population of memory T cells survives. This population is composed of two functional classes. One recirculates through nonlymphoid tissues and is capable of immediate effector lymphokine production. The other recirculates through lymph nodes and quickly acquires the capacity to produce effector lymphokines if stimulated. Therefore, antigenic stimulation in the presence of inflammation produces an increased number of specific T cells capable of producing effector lymphokines throughout the body.

The mechanism by which an initially uncommitted cell chooses between alternative fates is a central issue in developmental biology. In the mammalian thymus, CD4 helper T cells and CD8 cytotoxic T cells arise from a common precursor that expresses both CD4 and CD8. The choice between the CD4 and CD8 lineage is linked to the specificity of the T-cell antigen receptor expressed by a thymocyte, but whether lineage commitment is stochastic or instructed has not been definitively resolved. We present evidence that expression of a constitutive CD8 transgene during thymic selection permits development of mature CD4 cells bearing the class I-restricted F5 T-cell antigen receptor. These results suggest that there is a stochastic component to the development of class I major histocompatibility complex-restricted T cells.

Although CD4+ and CD8+ T cells have very different peripheral effector functions, both cell types are derived from a common progenitor cell that develops in the thymus. This precursor, which expresses both CD4 and CD8, must at some point choose between the CD4 and CD8 lineages. In order to elucidate the mechanism by which thymocytes choose between the CD4 and CD8 lineages, we undertook a kinetic analysis of the generation of mature T cells in TCR and co-receptor transgenic mice using BrdU labeling. We observed a surprisingly high efficiency of selection of mature cells. Our findings support an instructional mechanism of lineage commitment in which signals through the T cell antigen receptor bias developing thymocytes towards one lineage or the other. Recent experiments have demonstrated that the Notch signaling pathway is also involved in both the CD4/CD8 lineage choice as well as the earlier fate choice between the γδ and αβ T lineages, and have suggested that Notch and TCR signals are integrated by the developing thymocytes during lineage commitment. In order to better understand the role of Notch in thymic development, we characterized the thymic development in mice mutant for Jagged 2 and Delta 3, two Notch ligands expressed in the thymus. We determined that the previously observed reduction in γδ T cells in mice deficient for Jagged 2 was due to a specific block in the development of Vγ3 + γδ T cells in the thymus. Delta 3 may also contribute to the generation of these cells. Our observations demonstrate that Notch signaling is involved in the development of a fetal lineage of γδ T cells. In addition to characterizing the effects of mutations in Notch ligands, we generated transgenic mice constitutively expressing full-length and truncated forms of Jagged 2 under the control of a thymocyte specific promoter. We observed no alteration of either the γδ/αβ or CD4/CD8 lineage choices, as well as normal numbers of Vγ3+ cells, in mice expressing high levels of either a full-length or truncated Jagged 2 protein. These results are possibly explained by the involvement of down-stream modulators of Notch signaling, such as Numb or Fringe, in thymic development.