Background:
Epidemiologic data suggest a protective effect of Helicobacter pylori infection against the development of autoimmune disease. Laboratory data illustrate H. pylori's ability to induce ...immune tolerance and limit inflammatory responses. Numerous observational studies have investigated the association between H. pylori infection and inflammatory bowel disease (IBD). Our aim was to perform a systematic review and meta‐analysis of this association.
Methods:
Medline, EMBASE, bibliographies, and meeting s were searched by 2 independent reviewers. Of 369 s reviewed, 30 promising articles were reviewed in detail. Twenty‐three studies met our inclusion criteria (subject N = 5903). Meta‐analysis was performed with the metan command in Stata 10.1.
Results:
Overall, 27.1% of IBD patients had evidence of infection with H. pylori compared to 40.9% of patients in the control group. The estimated relative risk of H. pylori infection in IBD patients was 0.64 (95% confidence interval CI: 0.54–0.75). There was significant heterogeneity in the included studies that could not be accounted for by the method of IBD and H. pylori diagnosis, study location, or study population age.
Conclusions:
These results suggest a protective benefit of H. pylori infection against the development of IBD. Heterogeneity among studies and the possibility of publication bias limit the certainty of this finding. Further studies investigating the effect of eradication of H. pylori on the development of IBD are warranted. Because environmental hygiene and intestinal microbiota may be strong confounders, further mechanistic studies in H. pylori mouse models are also necessary to further define the mechanism of this negative association. (Inflamm Bowel Dis 2009;)
The host immune response to gastrointestinal (GI) infections, hypersensitivity reactions, or GI cancers comprises numerous pathways that elicit responses on different host cells. Some of these ...include (1) the stimulation of mast cells
their IgE receptor, (2) the production of antibodies leading to antibody-mediated cytotoxic T/natural killer cell killing, (3) the activation of the complement pathway, and (4) the activation of the adaptive immune response
antigen-presenting cell, T cell, and B cell interactions. Within the plethora of these different responses, several host immune cells represent major key players such as those of myeloid lineage (including neutrophils, macrophages, myeloid-derived suppressor cells) or lymphoid lineage (including T and B cells). In this review, we focus on newly identified metabolites and metabolite receptors that are expressed by either myeloid or lymphoid lineages. Irrespective of their source, these metabolites can in certain instances elicit responses on a wide range of cell types. The myeloid-expressed metabolic enzymes and receptors which we will discuss in this review include arginase 2 (Arg2), indoleamine-2,3-dioxygenase 1 (IDO1), hydroxycarboxylic acid receptor 2 (Hcar2; also called GPR109A), and immunoresponsive gene 1 (Irg1). We will also review the role of the lymphoid-expressed metabolite receptor that binds to the sphingosine-1-phosphate (S1P) sphingolipid. Moreover, we will describe the synthesis and metabolism of retinoic acid, and its effect on T cell activation. The review will then discuss the function of these metabolites in the context of GI disease. The review provides evidence that metabolic pathways operate in a disease- and context-dependent manner-either independently or concomitantly-in the GI tract. Therefore, an integrated approach and combinatorial analyses are necessary to devise new therapeutic strategies that can synergistically improve prognoses.
The epithelial layer of the gastrointestinal tract contains invaginations, called glands or crypts, which are colonized by symbiotic and pathogenic microorganisms and may function as designated ...niches for certain species. Factors that control gland colonization are poorly understood, but bacterial chemotaxis aids occupation of these sites. We report here that a
cytoplasmic chemoreceptor, TlpD, is required for gland colonization in the stomach.
mutants demonstrate gland colonization defects characterized by a reduction in the percentage of glands colonized but not in the number of bacteria per gland. Consistent with TlpD's reported role in reactive oxygen species (ROS) avoidance,
mutants showed hallmarks of exposure to high ROS. To assess the role of host-generated ROS in TlpD-dependent gland colonization, we utilized mice that lack either the ability to generate epithelial hydrogen peroxide or immune cell superoxide.
gland colonization defects were rescued to wild-type
levels in both of these mutants. These results suggest that multiple types of innate immune-generated ROS production limit gland colonization and that bacteria have evolved specific mechanisms to sense and direct their motility in response to this signal and thus spread throughout tissue.
A primordial gut-epithelial innate defense response is the release of hydrogen peroxide by dual NADPH oxidase (DUOX). In inflammatory bowel disease (IBD), a condition characterized by an imbalanced ...gut microbiota-immune homeostasis, DUOX2 isoenzyme is the highest induced gene. Performing multiomic analyses using 2872 human participants of a wellness program, we detected a substantial burden of rare protein-altering DUOX2 gene variants of unknown physiologic significance. We identified a significant association between these rare loss-of-function variants and increased plasma levels of interleukin-17C, which is induced also in mucosal biopsies of patients with IBD. DUOX2-deficient mice replicated increased IL-17C induction in the intestine, with outlier high Il17c expression linked to the mucosal expansion of specific Proteobacteria pathobionts. Integrated microbiota/host gene expression analyses in patients with IBD corroborated IL-17C as a marker for epithelial activation by gram-negative bacteria. Finally, the impact of DUOX2 variants on IL-17C induction provided a rationale for variant stratification in case control studies that substantiated DUOX2 as an IBD risk gene. Thus, our study identifies an association of deleterious DUOX2 variants with a preclinical hallmark of disturbed microbiota-immune homeostasis that appears to precede the manifestation of IBD.
Intestinal IL-17-producing T helper (Th17) cells are dependent on adherent microbes in the gut for their development. However, how microbial adherence to intestinal epithelial cells (IECs) promotes ...Th17 cell differentiation remains enigmatic. Here, we found that Th17 cell-inducing gut bacteria generated an unfolded protein response (UPR) in IECs. Furthermore, subtilase cytotoxin expression or genetic removal of X-box binding protein 1 (Xbp1) in IECs caused a UPR and increased Th17 cells, even in antibiotic-treated or germ-free conditions. Mechanistically, UPR activation in IECs enhanced their production of both reactive oxygen species (ROS) and purine metabolites. Treating mice with N-acetyl-cysteine or allopurinol to reduce ROS production and xanthine, respectively, decreased Th17 cells that were associated with an elevated UPR. Th17-related genes also correlated with ER stress and the UPR in humans with inflammatory bowel disease. Overall, we identify a mechanism of intestinal Th17 cell differentiation that emerges from an IEC-associated UPR.
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•ER stress in intestinal epithelial cells (IEC) drives gut Th17 differentiation•Th17 cells induced by IEC-ER stress require H2O2 generated by DUOX2/DUOXA2•IEC-ROS induce Th17 differentiation through purine metabolites, including xanthine•IEC-ER stress drives microbial Th17 induction even under germ-free conditions
Intestinal epithelial cell (IEC)-adherent microbes are important for generation of intestinal Th17 cells. Duan et al. report that microbial adhesion drives IEC-ER stress and unfolded protein response (UPR). The UPR enhances IEC production of reactive oxygen species and purine metabolites that subsequently promote Th17 differentiation in the gut.
Dendritic cells (DCs) are essential mediators of the host immune response to surrounding microbes. In this study, we investigate the role of DCs in the pathogenesis of a widely used colitis model, ...dextran sulfate sodium-induced colitis. The effect of dextran sulfate sodium on the production of proinflammatory cytokines and chemokines by bone marrow-derived DCs (BM-DCs) was analyzed. BM-DCs were adoptively transferred into C57BL/6 mice or DCs were ablated using transgenic CD11c-DTR/GFP mice before treatment with 5% dextran sulfate sodium in drinking water. We found that dextran sulfate sodium induced production of proinflammatory cytokines (IL-12 and TNF-alpha) and chemokines (KC, MIP-1alpha, MIP-2, and MCP-1) by DCs. Adoptive transfer of BM-DCs exacerbated dextran sulfate sodium colitis while ablation of DCs attenuated the colitis. We conclude that DCs are critical in the development of acute dextran sulfate sodium colitis and may serve a key role in immune balance of the gut mucosa.
Purpose
Light is known to induce histidine (His) oxidation and His-His crosslinking in proteins. The crosslinking is resulted from the nucleophilic attack of a His to a photooxidized His from another ...protein. The goal of this work is to understand if covalent buffer adducts on His residues can be generated by light through similar mechanisms in nucleophilic buffers such as Tris and His.
Methods
A model protein (DNase) was buffer exchanged into nucleophilic buffers before light exposure. Photogenerated products were characterized by tryptic peptide mapping with mass spectrometry (MS) analysis. Several buffer adductions on His residues were identified after light exposure. To understand the influencing factors of such reactions, the levels of adducts were measured for six nucleophilic buffers on all His residues in DNase.
Results
The levels of adducts were found to correlate with the solvent accessibility of the His residue. The levels of adducts also correlate with the structure of the nucleophile, especially the steric restrictions of the nucleophile. The levels of adducts can be higher than that of other His photoreaction products, including photooxidation and crosslinking.
Conclusions
In nucleophilic buffers, light can induce covalently-linked adducts to His residues.
The exact mechanism by which VSL#3 prevents UC-associated carcinogenesis remains unclear. ...we used a mouse model of AOM/DSS-induced UC-associated carcinogenesis to verify the effect of VSL#3 in ...preventing UC-associated carcinogenesis and explored the specific mechanism of action. Considering the differences between mice and humans, we further explored how probiotics influence the Wnt/β-catenin pathway at the human cellular level. Since cultivating multiple probiotics simultaneously is challenging, we used Bifidobacterium to explore the effects and mechanisms of VSL#3 on UC-associated carcinogenesis in mice and cells. ...VSL#3 and 5-ASA inhibited NF-kB transcriptional activity in the mouse colonic tissue. ...VSL#3 and 5-ASA effectively prevented UC-associated carcinogenesis in mice, and supplementing VSL#3 and co-culturing cells with Bifidobacterium may downregulate the proinflammatory factors TNF-α and IL-6, inhibit NF-κB transcriptional activity, and finally downregulate the Wnt/β-catenin pathway, consequently preventing the progression from inflammation to carcinogenesis.
The worldwide incidence of inflammatory bowel disease (IBD) is increasing. Abundant literature has suggested that an imbalance between harmful and protective bacteria, or dysbiosis, of the intestine ...is largely responsible for the rising incidence of IBD. In this review, data supporting dysbiosis as a cause of IBD are presented. A comparison of the number of scientific publications in the US versus Europe on intestinal dysbiosis and microbiota revealed the US scientific community has a lower level of interest in studying dysbiosis and microbiota compared the research community in Europe. The rising trend of antibiotic use in the US provides further evidence of the lack of concern for the effect of dysbiosis on human health. Further research to understand the causal relationship between dysbiosis and IBD are needed to better guide clinical practice in using probiotics.
Background
Helicobacter pylori infection leads to regulatory T‐cell (Treg) induction in infected mice, which contributes to H. pylori immune escape. However, the mechanisms responsible for H. pylori ...induction of Treg and immune tolerance remain unclear. We hypothesized DC‐produced TGF‐β may be responsible for Treg induction and immune tolerance.
Materials and Methods
To test this hypothesis, we generated TGF‐β∆DC mice (CD11c+ DC‐specific TGF‐β deletion) and assessed the impact of DC‐specific TGF‐β deletion on DC function during Helicobacter infection in vitro and in vivo. To examine the T cell–independent DC function, we crossed TGF‐β∆DC mice onto Rag1KO background to generate TGF‐β∆DCxRag1KO mice.
Results
When stimulated with H. pylori, TGF‐β∆DC BMDC/splenocyte cocultures showed increased levels of proinflammatory cytokines and decreased levels of anti‐inflammatory cytokines compared to control, indicating a proinflammatory DC phenotype. Following 6 months of H. felis infection, TGF‐β∆DC mice developed more severe gastritis and a trend toward more metaplasia compared to TGF‐βfl/fl with increased levels of inflammatory Th1 cytokine mRNA and lower gastric H. felis colonization compared to infected TGF‐βfl/fl mice. In a T cell–deficient background using TGF‐β∆DCxRag1KO mice, H. felis colonization was significantly lower when DC‐derived TGF‐β was absent, revealing a direct, innate function of DC in controlling H. felis infection independent of Treg induction.
Conclusions
Our findings indicate that DC‐derived TGF‐β mediates Helicobacter‐induced Treg response and attenuates the inflammatory Th1 response. We also demonstrated a previously unrecognized innate role of DC controlling Helicobacter colonization via a Treg‐independent mechanism. DC TGF‐β signaling may represent an important target in the management of H. pylori.
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