Probiotic VSL#3-induced TGF-β ameliorates food allergy inflammation in a mouse model of peanut sensitization through the induction of regulatory T cells in the gut mucosa.

SCOPE: Among food allergies, peanut allergy is frequently associated with severe anaphylactic reactions. In the need for safe and effective therapeutic strategies, probiotics may be considered on the basis of their immunomodulatory properties. The aim of the present study was to investigate the immunological mediators involved in the effects of probiotic VSL#3 oral supplementation on Th2 inflammation and anaphylaxis in a mouse model of peanut allergy. METHODS AND RESULTS: VSL#3 supplementation to peanut-sensitized mice was effective in ameliorating anaphylaxis and Th2-mediated inflammation, by promoting regulatory responses in the jejunum mucosa and in the mesenteric lymph node, as evaluated by ELISA, real-time PCR, histologic, and immunohistochemical analysis. Probiotic-induced TGF-β mediates its protective effects through the induction of regulatory T cells expressing FOXP3 and/or latency-associated peptide, as proven by in vivo blockade of TGF-β in VSL#3-treated mice with a neutralizing monoclonal antibody one day before challenge. CONCLUSION: TGF-β, induced in the gut by VSL#3 supplementation, is capable of reducing the Th2 inflammation associated with food anaphylaxis in a mouse model of peanut sensitization. TGF-β acts through the induction/maintenance of regulatory T cells expressing FOXP3 and/or latency-associated peptide. Probiotics supplementation may represent an effective and safe strategy for treating food allergies in adult population

Protective Microbiota: From Localized to Long-Reaching Co-Immunity

Resident microbiota do not just shape host immunity, they can also contribute to host protection against pathogens and infectious diseases. Previous reviews of the protective roles of the microbiota have focused exclusively on colonization resistance localized within a microenvironment. This review shows that the protection against pathogens also involves the mitigation of pathogenic impact without eliminating the pathogens (i.e., “disease tolerance”) and the containment of microorganisms to prevent pathogenic spread. Protective microorganisms can have an impact beyond their niche, interfering with the entry, establishment, growth, and spread of pathogenic microorganisms. More fundamentally, we propose a series of conceptual clarifications in support of the idea of a “co-immunity,” where an organism is protected by both its own immune system and components of its microbiota

Long-Range Activation of Systemic Immunity through Peptidoglycan Diffusion in Drosophila

The systemic immune response of Drosophila is known to be induced both by septic injury and by oral infection with certain bacteria, and is characterized by the secretion of antimicrobial peptides (AMPs) into the haemolymph. To investigate other possible routes of bacterial infection, we deposited Erwinia carotovora (Ecc15) on various sites of the cuticle and monitored the immune response via expression of the AMP gene Diptericin. A strong response was observed to deposition on the genital plate of males (up to 20% of a septic injury response), but not females. We show that the principal response to genital infection is systemic, but that some AMPs, particularly Defensin, are induced locally in the genital tract. At late time points we detected bacteria in the haemolymph of immune deficient RelishE20 flies, indicating that the genital plate can be a route of entry for pathogens, and that the immune response protects flies against the progression of genital infection. The protective role of the immune response is further illustrated by our observation that RelishE20 flies exhibit significant lethality in response to genital Ecc15 infections. We next show that a systemic immune response can be induced by deposition of the bacterial elicitor peptidoglycan (PGN), or its terminal monomer tracheal cytotoxin (TCT), on the genital plate. This immune response is downregulated by PGRP-LB and Pirk, known regulators of the Imd pathway, and can be suppressed by the overexpression of PGRP-LB in the haemolymph compartment. Finally, we provide strong evidence that TCT can activate a systemic response by crossing epithelia, by showing that radiolabelled TCT deposited on the genital plate can subsequently be detected in the haemolymph. Genital infection is thus an intriguing new model for studying the systemic immune response to local epithelial infections and a potential route of entry for naturally occurring pathogens of Drosophila

Leukocyte Attraction by CCL20 and Its Receptor CCR6 in Humans and Mice with Pneumococcal Meningitis

We previously identified CCL20 as an early chemokine in the cerebrospinal fluid (CSF) of patients with pneumococcal meningitis but its functional relevance was unknown. Here we studied the role of CCL20 and its receptor CCR6 in pneumococcal meningitis. In a prospective nationwide study, CCL20 levels were significantly elevated in the CSF of patients with pneumococcal meningitis and correlated with CSF leukocyte counts. CCR6 deficient mice with pneumococcal meningitis and WT mice with pneumococcal meningitis treated with anti-CCL20 antibodies both had reduced CSF white blood cell counts. The reduction in CSF pleocytosis was also accompanied by an increase in brain bacterial titers. Additional in vitro experiments showed direct chemoattractant activity of CCL20 for granulocytes. In summary, our results identify the CCL20-CCR6 axis as an essential component of the innate immune defense against pneumococcal meningitis, controlling granulocyte recruitment

Intestinal microbiota and the innate immune system – a crosstalk in Crohn’s disease pathogenesis

Crohn’s disease (CD) is a chronic, relapsing inflammatory disorder that can occur anywhere along the gastrointestinal tract. The precise etiology of CD is still unclear but it is widely accepted that a complex series of interactions between susceptibility genes, the immune system and environmental factors are implicated in the onset and perpetuation of the disease. Increasing evidence from experimental and clinical studies implies the intestinal microbiota in disease pathogenesis, thereby supporting the hypothesis that chronic intestinal inflammation arises from an abnormal immune response against the microorganisms of the intestinal flora in genetically susceptible individuals. Given that CD patients display changes in their gut microbiota composition, collectively termed “dysbiosis,” the question raises whether the altered microbiota composition is a cause of disease or rather a consequence of the inflammatory state of the intestinal environment. This review will focus on the crosstalk between the gut microbiota and the innate immune system during intestinal inflammation, thereby unraveling the role of the microbiota in CD pathogenesis

Probiotics, gut microbiota and their influence on host health and disease

The gastrointestinal tract (GIT) of mammals hosts a high and diverse number of different microorganisms, known as intestinal microbiota. Many probiotics were originally isolated from the GIT, and they were defined by the FAO/WHO as live microorganisms which when administered in adequate amounts confer a health benefit on the host. Probiotics exert their beneficial effects on the host through four main mechanisms: interference with potential pathogens, improvement of barrier function, immunomodulation and production of neurotransmitters, and their host targets vary from the resident microbiota to cellular components of the gut-brain axis. However, in spite of the wide array of beneficial mechanisms deployed by probiotic bacteria, relatively few effects have been supported by clinical data. In this regard, different probiotic strains have been effective in Antibiotic-Associated Diarrhea or Inflammatory Bowel Disease for instance. The aim of this review was to compile the molecular mechanisms underlying the beneficial effects of probiotics, mainly through their interaction with the intestinal microbiota and with the intestinal mucosa. The specific benefits discuss in this paper include among others those elicited directly through dietary modulation of the human gut microbiota.This article is protected by copyright. All rights reservedResearch in our lab is funded by Grants AGL2013-44039R and AGL2013-44761-P from the Spanish “Plan Estatal de I+D+I.” Part of the authors is also partially funded by the [15VI013] Contract-Programme from the University of Vigo and the Agrupamento INBIOMED from DXPCTSUG-FEDER unha maneira de facer Europa (2012/273). B. S. was recipient of a Ramón y Cajal postdoctoral contract from the Spanish Ministry of Economy and Competitiveness

Stromal Fibroblasts in Tertiary Lymphoid Structures: A Novel Target in Chronic Inflammation.

Tertiary lymphoid structures (TLS) are organized aggregates of lymphocytes, myeloid, and stromal cells that provide ectopic hubs for acquired immune responses. TLS share phenotypical and functional features with secondary lymphoid organs (SLO); however, they require persistent inflammatory signals to arise and are often observed at target sites of autoimmune disease, chronic infection, cancer, and organ transplantation. Over the past 10 years, important progress has been made in our understanding of the role of stromal fibroblasts in SLO development, organization, and function. A complex and stereotyped series of events regulate fibroblast differentiation from embryonic life in SLOs to lymphoid organ architecture observed in adults. In contrast, TLS-associated fibroblasts differentiate from postnatal, locally activated mesenchyme, predominantly in settings of inflammation and persistent antigen presentation. Therefore, there are critical differences in the cellular and molecular requirements that regulate SLO versus TLS development that ultimately impact on stromal and hematopoietic cell function. These differences may contribute to the pathogenic nature of TLS in the context of chronic inflammation and malignant transformation and offer a window of opportunity for therapeutic interventions in TLS associated pathologies

'Gut health': a new objective in medicine?

'Gut health' is a term increasingly used in the medical literature and by the food industry. It covers multiple positive aspects of the gastrointestinal (GI) tract, such as the effective digestion and absorption of food, the absence of GI illness, normal and stable intestinal microbiota, effective immune status and a state of well-being. From a scientific point of view, however, it is still extremely unclear exactly what gut health is, how it can be defined and how it can be measured. The GI barrier adjacent to the GI microbiota appears to be the key to understanding the complex mechanisms that maintain gut health. Any impairment of the GI barrier can increase the risk of developing infectious, inflammatory and functional GI diseases, as well as extraintestinal diseases such as immune-mediated and metabolic disorders. Less clear, however, is whether GI discomfort in general can also be related to GI barrier functions. In any case, methods of assessing, improving and maintaining gut health-related GI functions are of major interest in preventive medicine

Gut microbiota, NLR proteins, and intestinal homeostasis

The gastrointestinal tract harbors a highly complex microbial community, which is referred to as gut microbiota. With increasing evidence suggesting that the imbalance of gut microbiota plays a significant role in the pathogenesis of multiple diseases, interactions between the host immune system and the gut microbiota are now attracting emerging interest. Nucleotide-binding and leucine-rich repeat-containing receptors (NLRs) encompass a large number of innate immune sensors and receptors, which mediate the activation of Caspase-1 and the subsequent release of mature interleukin-1β and interleukin-18. Several family members have been found to restrain rather than activate inflammatory cytokines and immune signaling. NLR family members are central regulators of pathogen recognition, host immunity, and inflammation with utmost importance in human diseases. In this review, we focus on the potential roles played by NLRs in controlling and shaping the microbiota community and discuss how the functional axes interconnecting gut microbiota with NLRs impact the modulation of colitis, inflammatory bowel diseases, and colorectal cancer.The authors acknowledge many investigators in the field whose primary data could not be cited in this review because of space limitations. This work was supported by grants from the National Institute of Allergy and Infectious Diseases (grant R01-AI029564), National Institutes of Health (grant R35CA232109), National Institute of Diabetes and Digestive and Kidney Diseases (grant P01-DK094779), and RadCCORE (grant AI067798 to J.P.Y. Ting) and ITCMS T32 (grant 5T32CA009156 to S.A. Gibson). Author contributions: H. Guo wrote the initial draft, prepared and created the figures and tables, and revised the paper. S.A. Gibson wrote the initial draft and prepared and created the figures and Table 2. J.P.Y. Ting provided oversight and leadership responsibility for this paper and edited the manuscript. Disclosures: J.P.Y. Ting reported a patent to University of North Carolina, currently pending, and is the cofounder of GoldCrest Bio, a company that is looking at the role of the microbiota in radiation sickness. H. Guo holds equity shares in GoldCrest Bio. No other disclosures were reported