BACKGROUND: Subtle histopathologic features such as eosinophilia and increased mast cells have been observed in functional gastrointestinal disorders (FGIDs), including functional dyspepsia (FD) and the irritable bowel syndrome (IBS). The mechanisms that drive recruitment of these cells to the gastrointestinal tract remain unexplained, largely due to the heterogeneity in phenotypes among patients diagnosed with such conditions. We aimed to systematically review the literature and collate the evidence for immune activation in FD and IBS, and where possible, detail the nature of activation. METHODS: Seven literature databases were searched using the keywords: ‘functional gastrointestinal disorder’, FGID, ‘functional dyspepsia’, ‘non-ulcer dyspepsia’, ‘idiopathic dyspepsia’, ‘irritable bowel syndrome’, IBS and ‘immun*’. RESULTS: Fifty-one papers reporting discordant immune features met the selection criteria for this review. Changes in lymphocyte populations, including B and T lymphocyte numbers and activation status were reported in IBS and FD, in conjunction with duodenal eosinophilia in FD and increased colonic mast cells in IBS. Increases in circulating α4+β7+ gut-homing T cells appear to be linked to the pathophysiology of both FD and IBS. Studies in the area are complicated by poor phenotyping of patients into subgroups and the subtle nature of the immune activity involved in FD and IBS. CONCLUSIONS: Alterations in proportions of gut-homing T lymphocytes in both FD and IBS indicate that a loss of mucosal homeostasis may drive the symptoms of FD and IBS. There is indirect evidence that Th17 responses may play a role in FGIDs, however the evidence for a Th2 immune phenotype in FD and IBS is limited. Although immune involvement is evident, large, well-characterised patient cohorts are required to elucidate the immune mechanisms driving the development of FGIDs.

Inflammatory bowel disease (IBD) is a progressive disease that includes Crohn's diseases and ulcerative colitis. Over one third of IBD patients have secondary organ pathologies and pulmonary manifestations are common. The platelet activating factor receptor (PAFR) plays a critical role in regulating inflammation and it is expressed on epithelial cells and neutrophils in both colon and lung. Having identified increased expression of PAFR in both the gastrointestinal (GI) tract and lungs of mice with dextran sulfate sodium (DSS) colitis, we hypothesised that PAFR was a mediator of the pulmonary inflammation associated with colitis. We aimed to elucidate the role of PAFR in gut‐lung inflammatory cross‐talk using of the DSS‐induced experimental model of colitis (7 days). DSS mice were treated with PAFR antagonist CV6209 both intranasally and intravenously and lung, colon and blood were assessed for inflammatory cells and mediators by qPCR, immunoblot, immunohistochemistry and flow cytometry. We demonstrated that DSS‐induced colitis resulted in inflammation in mouse bronchoalveolar lavage fluid (BALF) and lungs, as well as increased PAFR protein levels in lungs and colons. Pulmonary neutrophils in DSS animals showed increased PAFR staining. Bacterial 16S mRNA expression were also increased in mouse lungs after 7 days DSS challenge. Both intravenous and intranasal inhibition of PAFR by CV6209 reduced colitis‐induced numbers of neutrophils, but not macrophages, in mouse lungs. Inhibition of PAFR also reduced levels of TNF and IL‐1b proteins and bacterial 16S expression in mouse lungs. Importantly, intravenous administration of CV6209 reduced colitis pathology, TNF and IL‐1b protein levels in mouse colons after 7 days DSS challenge. In the DSS model, increased PAFR protein expression was associated with inflammasome activation, characterized by increased NLRP3 and mature caspase‐1 proteins, however inhibition of PAFR by CV6209 reduced NLRP3 and caspase‐1 levels after DSS challenge in mouse lungs. In vitro, NLRP3, activated caspase‐1 and secreted IL‐1b protein levels were increased in human alveolar epithelial cell culture (A549) after 24h LPS stimulation, and this was inhibited by treatment with CV6209. These data suggest that PAFR regulates colitis‐induced lung inflammation by IL‐1b protein activation via the NLRP3 inflammasome signalling pathway. PAFR may act as an inflammasome‐activating pattern recognition receptor during mucosal inflammation thus is a potential therapeutic target for lung inflammation associated with colitis and bacteraemia. Support or Funding Information This study was supported by a grant from National Health Medical Research Council (NHMRC) Australia This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Inflammatory bowel disease (IBD) is associated with several immune-mediated extraintestinal manifestations. More than half of all IBD patients have some form of respiratory pathology, most commonly neutrophil-mediated diseases, such as bronchiectasis and chronic bronchitis. Using murine models of colitis, we aimed to identify the immune mechanisms driving pulmonary manifestations of IBD. We found increased neutrophil numbers in lung tissue associated with the pulmonary vasculature in both trinitrobenzenesulfonic acid- and dextran sulfate sodium-induced models of colitis. Analysis of systemic inflammation identified that neutrophilia was associated with bacteremia and pyrexia in animal models of colitis. We further identified IL-6 as a systemic mediator of neutrophil recruitment from the bone marrow of dextran sulfate sodium animals. Functional inhibition of IL-6 led to reduced systemic and pulmonary neutrophilia, but it did not attenuate established colitis pathology. These data suggest that systemic bacteremia and pyrexia drive IL-6 secretion, which is a critical driver for pulmonary manifestation of IBD. Targeting IL-6 may reduce neutrophil-associated extraintestinal manifestations in IBD patients.

Functional dyspepsia (FD) is a common disorder of gut-brain interaction, characterised by upper gastrointestinal symptom profiles that differentiate FD from the irritable bowel syndrome (IBS), although the two conditions often co-exist. Despite food and eating being implicated in FD symptom induction, evidence-based guidance for dietetic management of FD is limited. The aim of this narrative review is to collate the possible mechanisms for eating-induced and food-related symptoms of FD for stratification of dietetic management. Specific carbohydrates, proteins and fats, or foods high in these macronutrients have all been reported as influencing FD symptom induction, with removal of ‘trigger’ foods or nutrients shown to alleviate symptoms. Food additives and natural food chemicals have also been implicated, but there is a lack of convincing evidence. Emerging evidence suggests the gastrointestinal microbiota is the primary interface between food and symptom induction in FD, and is therefore a research direction that warrants substantial attention. Objective markers of FD, along with more sensitive and specific dietary assessment tools will contribute to progressing towards evidence-based dietetic management of FD.

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OBJECTIVES: Anti-cytolethal distending toxin B (CdtB) and anti-vinculin antibodies have been proposed as biomarkers that discriminate irritable bowel syndrome (IBS) diarrhea from inflammatory bowel disease; however, it is unknown whether they can also discriminate patients with IBS and IBS subtypes and functional dyspepsia (FD) from healthy individuals in the general population. We aimed to determine whether anti-CdtB and anti-vinculin can discriminate IBS and FD from health and from organic gastrointestinal (GI) disease. METHODS: Adults were enrolled from 2 Australian studies: (i) a random, population-based study (n = 331) with subjects diagnosed with IBS (n = 63) or FD (n = 61) by modified Rome III criteria or healthy control subjects (n = 246) who did not meet criteria for IBS and/or FD and (ii) an outpatient-based study with subjects diagnosed with IBS (n = 256) and/or FD (n = 55) or organic GI disease (n = 182) by an independent clinician. Serum levels of anti-CdtB/anti-vinculin antibodies were determined by enzyme-linked immunosorbent assay. RESULTS: There was a significantly higher mean value of anti-CdtB in FD vs healthy controls (mean = 2.46 [SD = 0.72] vs mean = 2.14 [SD = 0.77]; P = 0.005) and IBS/FD overlap vs healthy controls (mean = 2.47 [SD = 0.78] vs mean = 2.14 [SD = 0.77]; P = 0.02). There were no significant differences in anti-CdtB in IBS and FD outpatients or IBS/FD subgroups compared with patients with organic GI disease. In terms of anti-vinculin, there were no significant differences between IBS and FD and healthy controls or between IBS and FD and organic GI disease controls. DISCUSSION: We did not confirm that anti-CdtB/anti-vinculin discriminated IBS diarrhea from organic GI disease in Australian subjects. However, we did find higher anti-CdtB in FD and IBS/FD overlap vs healthy controls. Postinfectious FD may be more common than currently recognized.

Intestinal inflammatory lesions are inherently hypoxic, due to increased metabolic demands created by cellular infiltration and proliferation, and reduced oxygen supply due to vascular damage. Hypoxia stabilizes the transcription factor hypoxia-inducible factor-1α (HIF) leading to a coordinated induction of endogenously protective pathways. We identified IL12B as a HIF-regulated gene and aimed to define how the HIF-IL-12p40 axis influenced intestinal inflammation. Intestinal lamina propria lymphocytes (LPL) were characterized in wild-type and IL-12p40 murine colitis treated with vehicle or HIF-stabilizing prolyl-hydroxylase inhibitors (PHDi). IL12B promoter analysis was performed to examine hypoxia-responsive elements. Immunoblot analysis of murine and human LPL supernatants was performed to characterize the HIF/IL-12p40 signaling axis. We observed selective induction of IL-12p40 following PHDi-treatment, concurrent with suppression of Th1 and Th17 responses in murine colitis models. In the absence of IL-12p40, PHDi-treatment was ineffective. Analysis of the IL12B promoter identified canonical HIF-binding sites. HIF stabilization in LPLs resulted in production of IL-12p40 homodimer which was protective against colitis. The selective induction of IL-12p40 by HIF-1α leads to a suppression of mucosal Th1 and Th17 responses. This HIF-IL12p40 axis may represent an endogenously protective mechanism to limit the progression of chronic inflammation, shifting from pro-inflammatory IL-12p70 to an antagonistic IL-12p40 homodimer.

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