A Minority of Childhood Disorders of Gut-Brain Interaction Persist Into Adulthood: A Risk-Factor Analysis.

INTRODUCTION: Disorders of gut-brain interaction (DGBIs) may originate in childhood. There are currently limited data on persistence of DGBI into adulthood and risk factors for persistence. Furthermore, there are no data on this question from general practice, where the majority of DGBIs are diagnosed and managed. This study documents the proportion of childhood-diagnosed DGBIs that persisted into adulthood and what factors were associated with persistence. METHODS: General practice records were obtained for more than 60,000 patients whose medical record spanned both childhood and adulthood years. Patients with diagnosed organic gastrointestinal disorder were excluded. Medical records were also interrogated for potential risk factors. RESULTS: Eleven percent of patients with irritable bowel syndrome (IBS) and 20% of patients with functional dyspepsia (FD) diagnosed in childhood had repeat diagnoses of the same condition in adulthood. Female sex (odds ratio [OR] 2.02) was associated with persistence for IBS, while a childhood diagnosis of gastritis (OR 0.46) was risk-protective. Childhood non-steroidal anti-inflammatory drug use (OR 1.31, 95% confidence interval [CI] 1.09-1.56) was a risk factor for persistence in IBS. For FD, a childhood diagnosis of asthma (OR 1.30, 95% CI 1.00-1.70) was a risk factor, as was anxiety for both IBS (OR 1.24, 95% CI 1.00-1.54) and FD (OR 1.48 95% CI 1.11-1.97) with a similar finding for depression for IBS (OR 1.34, 95% CI 1.11-1.62) and FD (OR 1.88 95% CI 1.47-2.42). DISCUSSION: Childhood DGBIs persist into adulthood in 10%-20% of patients, suggesting that management monitoring should continue into adulthood. Those diagnosed with anxiety or mood disorders in childhood should receive particular attention, and prescription of non-steroidal anti-inflammatory drugs in children should be made judiciously.

Alterations to the duodenal microbiota are linked to gastric emptying and symptoms in functional dyspepsia.

OBJECTIVE: Functional dyspepsia (FD) is a complex disorder, with debilitating epigastric symptoms. Evidence suggests alterations in gastrointestinal (GI) motility, visceral hypersensitivity, permeability and low-level immune activation in the duodenum may play a role. However, we still have a relatively poor understanding of how these factors interact to precipitate the onset of FD symptoms which are frequently meal related. The duodenal microbiota, in combination with specific dietary substrates, may be important mediators in disease pathophysiology; however, these interlinked factors have not been thoroughly investigated in FD. DESIGN: Eighty-six individuals (56 FD, 30 controls) undergoing endoscopy were consecutively recruited and underwent detailed clinical assessment, including upper GI symptoms, gastric emptying and dietary assessment. Duodenal biopsies were obtained aseptically, and the mucosa-associated microbiota (MAM) analysed via 16S rRNA gene amplicon sequencing. RESULTS: The relative abundances of predominant members of the Firmicutes, Bacteroidota and Fusobacteriota phyla were linked to symptom burden in FD. Inverse relationships between the relative abundances of Streptococcus and Prevotella, and the relative abundance of Veillonella spp with gastric emptying time, were also observed. No significant differences in long-term nutrient intake or diet quality were found between FD and controls, and there appeared to be limited association between habitual diet and duodenal MAM profiles. CONCLUSION: This study suggests a link between the duodenal MAM, gastric emptying and FD symptoms, and this is largely independent of long-term dietary intake.

Does the microbiome play a role in the pathogenesis of colonic diverticular disease? A systematic review.

BACKGROUND AND AIMS: The role of the microbiota in diverticulosis and diverticular disease is underexplored. This systematic review aimed to assess all literature pertaining to the microbiota and metabolome associations in asymptomatic diverticulosis, symptomatic uncomplicated diverticular disease (SUDD), and diverticulitis pathophysiology. METHODS: Seven databases were searched for relevant studies published up to September 28, 2022. Data were screened in Covidence and extracted to Excel. Critical appraisal was undertaken using the Newcastle Ottawa Scale for case/control studies. RESULTS: Of the 413 papers screened by title and abstract, 48 full-text papers were reviewed in detail with 12 studies meeting the inclusion criteria. Overall, alpha and beta diversity were unchanged in diverticulosis; however, significant changes in alpha diversity were evident in diverticulitis. A similar Bacteroidetes to Firmicutes ratio compared with controls was reported across studies. The genus-level comparisons showed no relationship with diverticular disease. Butyrate-producing microbial species were decreased in abundance, suggesting a possible contribution to the pathogenesis of diverticular disease. Comamonas species was significantly increased in asymptomatic diverticulosis patients who later developed diverticulitis. Metabolome analysis reported significant differences in diverticulosis and SUDD, with upregulated uracil being the most consistent outcome in both. No significant differences were reported in the mycobiome. CONCLUSION: Overall, there is no convincing evidence of microbial dysbiosis in colonic diverticula to suggest that the microbiota contributes to the pathogenesis of asymptomatic diverticulosis, SUDD, or diverticular disease. Future research investigating microbiota involvement in colonic diverticula should consider an investigation of mucosa-associated microbial changes within the colonic diverticulum itself.

Increased mucosal eosinophils in colonic diverticulosis and diverticular disease.

AIMS: Eosinophils contribute to tissue homeostasis, damage, and repair. The mucosa of colonic diverticula has not been evaluated for eosinophils by quantitative histology. We aimed to investigate whether mucosal eosinophils and other immune cells are increased in colonic diverticula. METHODS: Hematoxylin and eosin stained sections from colonic surgical resections (n = 82) containing diverticula were examined. Eosinophils, neutrophils, and lymphocytes, in five high power fields in the lamina propria were counted at the base, neck, and ostia of the diverticulum and counts compared to non-diverticula mucosa. The cohort was further subgrouped by elective and emergency surgical indications. RESULTS: Following an initial review of 10 surgical resections from patients with diverticulosis, a total of 82 patients with colonic resections containing diverticula from the descending colon were evaluated (median age 71.5, 42 M/40F). Eosinophil counts for the entire cohort were increased in the base and neck (median 99 and 42, both P = <0.001) compared with the control location (median 16). Eosinophil counts remained significantly increased in the diverticula base (both P = <0.001) and neck (P = 0.01 and <0.001, respectively) in both elective and emergency cases. Lymphocytes were also significantly increased at the diverticula base compared to controls in both elective and emergency subgroups. CONCLUSION: Eosinophils are significantly and most strikingly increased within the diverticulum in resected colonic diverticula. While these observations are novel, the role of eosinophil and chronic inflammation is as yet unclear in the pathophysiology of colonic diverticulosis and diverticular disease.

Duodenal Eosinophils and Mast Cells in Functional Dyspepsia: A Systematic Review and Meta-Analysis of Case-Control Studies.

BACKGROUND & AIMS: This study explored the link between duodenal eosinophils and mast cells in patients with functional dyspepsia (FD). METHODS: MEDLINE (PubMed) and Embase electronic databases were searched until June 2021 for case-control studies reporting duodenal eosinophils and mast cells in FD. Pooled standardized mean difference (SMD), odds ratio, and 95% CIs of duodenal eosinophils and mast cells in FD patients and controls were calculated, using a random-effects model. RESULTS: Twenty-two case-control studies with 1108 FD patients and 893 controls were identified. Duodenal eosinophils (SMD, 1.29; 95% CI, 0.85-1.73; P = .0001) and mast cells (SMD, 2.11; 95% CI, 1.14-3.07; P = .0001) were increased in FD patients compared with controls. Substantial heterogeneity was found (I2 = 93.61, P = .0001; and I2 = 96.69, P = .0001, respectively) and visual inspection of funnel plots confirmed publication bias. Degranulation of duodenal eosinophils was significantly higher in FD patients compared with controls (odds ratio, 3.78; 95% CI, 6.76-4.48; P = .0001), without statistically significant heterogeneity. We conducted a sensitivity analysis for duodenal eosinophils, by including only high-quality studies, and the results remained unchanged (SMD, 1.73; 95% CI, 1.06-2.40; P = .0001), with substantial heterogeneity. Postinfectious FD patients had increased duodenal eosinophils compared with controls (SMD, 3.91; 95% CI, 1.32-6.51; P = .001) and FD patients without any history of infection (SMD, 1.42; 95% CI, 0.88-1.96; P = .001). Helicobacter pylori-negative FD patients had significantly higher duodenal eosinophils compared with controls (SMD, 3.98; 95% CI, 2.13-5.84; P = .0001), with substantial heterogeneity. No significant difference in duodenal eosinophils was seen according to FD subtypes. CONCLUSIONS: This meta-analysis suggests a link between duodenal microinflammation and FD. However, the quality of evidence is very low, largely owing to the unexplained heterogeneity and serious risk of publication bias in all comparative analyses. Thus, causality remains uncertain and further studies are required.

Defects in NLRP6, autophagy and goblet cell homeostasis are associated with reduced duodenal CRH receptor 2 expression in patients with functional dyspepsia.

Functional dyspepsia (FD) affects up to 15% of the population and is characterised by recurring upper gastrointestinal (GI) symptoms occurring in the absence of clinically identifiable pathology. Psychological stress is a key factor associated with the onset of FD and locally acting hypothalamic-pituitary-adrenal (HPA) axis hormones have been implicated in GI motility and barrier dysfunction. Recent pre-clinical work has identified mechanistic pathways linking corticotropin-releasing hormone (CRH) with the innate epithelial immune protein NLRP6, an inflammasome that has been shown to regulate GI mucus secretion. We recruited twelve FD patients and twelve healthy individuals to examine whether dysregulation of hypothalamic-pituitary adrenal (HPA) axis hormones and altered NLRP6 pathways were evident in the duodenal mucosa. Protein expression was assessed by immunoblot and immunohistochemistry in D2 duodenal biopsies. Plasma HPA axis hormones were assayed by ELISA and enteroid and colorectal cancer cell line cultures were used to verify function. FD patients exhibited reduced duodenal CRH-receptor 2, compared to non-GI disease controls, indicating a dysregulation of duodenal HPA signalling. The loss of CRH-receptor 2 correlated with reduced NLRP6 expression and autophagy function, processes critical for maintaining goblet cell homeostasis. In accordance, duodenal goblet cell numbers and mucin exocytosis was reduced in FD patients compared to controls. In vitro studies demonstrated that CRH could reduce NLRP6 in duodenal spheroids and promote mucus secretion in the HT29-MTX-E12 cell line. In conclusion, FD patients exhibit defects in the NLRP6-autophagy axis with decreased goblet cell function that may drive symptoms of disease. These features correlated with loss of CRH receptor 2 and may be driven by dysregulation of HPA signalling in the duodenum of FD patients.

Human intestinal spirochetosis, irritable bowel syndrome, and colonic polyps: A systematic review and meta-analysis.

Human colonic spirochetosis (CS) is usually due toBrachyspira pilosicolior Brachyspira aalborgiinfection. While traditionally considered to be commensal bacteria, there are scattered case reports and case series of gastrointestinal (GI) symptoms in CS and reports of colonic polyps with adherent spirochetes. We performed a systematic review and meta-analysis investigating the association between CS and GI symptoms and conditions including the irritable bowel syndrome (IBS) and colonic polyps. Following PRISMA 2020 guidelines, a systematic search of Medline, CINAHL, EMBASE, and Web of Science was performed using specific keywords for CS and GI disease. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Of 75 studies identified in the search, 8 case-control studies met the inclusion criteria for meta-analysis and 67 case series studies met the inclusion criteria for pooled prevalence analysis. CS was significantly associated with diarrhea (n = 141/127, cases/controls, OR: 4.19, 95% CI: 1.72-10.21, P = 0.002) and abdominal pain (n = 64/65, OR: 3.66, 95% CI: 1.43-9.35, P = 0.007). CS cases were significantly more likely to have Rome III-diagnosed IBS (n = 79/48, OR: 3.84, 95% CI: 1.44-10.20, P = 0.007), but not colonic polyps (n = 127/843, OR: 8.78, 95% CI: 0.75-103.36, P = 0.084). In conclusion, we found evidence of associations between CS and both diarrhea and IBS, but not colonic polyps. CS is likely underestimated due to suboptimal diagnostic methods and may be an overlooked risk factor for a subset of IBS patients with diarrhea.

Concomitant Irritable Bowel Syndrome Does Not Influence the Response to Antimicrobial Therapy in Patients with Functional Dyspepsia.

BACKGROUND AND AIMS: Antimicrobial therapy improves symptoms in patients with irritable bowel syndrome (IBS), but the efficacy in functional dyspepsia (FD) is largely unknown. While FD and IBS frequently overlap, it is unknown if concomitant IBS in FD alters the response to antimicrobial therapy in FD. Thus, we aimed to assess and compare the effect of antimicrobial therapy on visceral sensory function and symptom improvement in FD patients with and without IBS. METHODS: Adult patients with FD with or without IBS received rifaximin 550 mg BD for 10 days, followed by a 6-week follow-up period. The total gastrointestinal symptom score as measured by the SAGIS (Structured Assessment of Gastrointestinal Symptoms) questionnaire and subscores (dyspepsia, diarrhea, and constipation), symptom response to a standardized nutrient challenge and normalization of the glucose breath tests were measured. RESULTS: Twenty-one consecutive adult patients with FD and 14/21 with concomitant IBS were recruited. Treatment with rifaximin resulted in a significant (p = 0.017) improvement in the total SAGIS score from 34.7 (± 15.4) at baseline to 26.0 (± 16.8) at 2 weeks and 25.6 (± 17.8) at 6 weeks post-treatment. Similarly, compared to baseline there was a statistically significant improvement in SAGIS subscores for dyspepsia and diarrhea (all p < 0.05) and effects persisted for 6 weeks post-treatment. Similarly, the symptom score (and subscores) following a standardized nutrient challenge improved significantly (p < 0.001) 2 weeks post-treatment. The presence of concomitant IBS did not significantly influence the improvement of symptoms after antibiotic therapy (all p > 0.5). CONCLUSIONS: In FD patients, the response to antimicrobial therapy with rifaximin is not influenced by concomitant IBS symptoms.

Physiological mechanisms of unexplained (functional) gastrointestinal disorders.

Functional gastrointestinal disorders (FGIDs) encompass a range of complex conditions with similar clinical characteristics and no overt pathology. Recent recognition of sub-clinical pathologies in FGIDs, in conjunction with physiological and biochemical abnormalities including increased intestinal permeability, microbial profile alterations, differences in metabolites and extra-intestinal manifestations of disease, call into question the designation of these conditions as 'functional'. This is despite significant heterogeneity in both symptom profile and specifics of reported physiological abnormalities hampering efforts to determine defined mechanisms that drive onset and chronicity of symptoms. Instead, the literature demonstrates these conditions are disorders of homeostatic imbalance, with disruptions in both host and microbial function and metabolism. This imbalance is also associated with extraintestinal abnormalities including psychological comorbidities and fatigue that may be a consequence of gastrointestinal disruption. Given the exploitation of such abnormalities will be crucial for improved therapeutic selection, an enhanced understanding of the relationship between alterations in function of the gastrointestinal tract and the response of the immune system is of interest in identifying mechanisms that drive FGID onset and chronicity. Considerations for future research should include the role of sex hormones in regulating physiological functions and treatment responses in patients, as well as the importance of high-level phenotyping of clinical, immune, microbial and physiological parameters in study cohorts. There is opportunity to examine the functional contribution of the microbiota and associated metabolites as a source of mechanistic insight and targets for therapeutic modulation.

Pharmacological HIF-1 stabilization promotes intestinal epithelial healing through regulation of α-integrin expression and function.

Intestinal epithelia are critical for maintaining gastrointestinal homeostasis. Epithelial barrier injury, causing inflammation and vascular damage, results in inflammatory hypoxia, and thus, healing occurs in an oxygen-restricted environment. The transcription factor hypoxia-inducible factor (HIF)-1 regulates genes important for cell survival and repair, including the cell adhesion protein ß1-integrin. Integrins function as αß-dimers, and α-integrin-matrix binding is critical for cell migration. We hypothesized that HIF-1 stabilization accelerates epithelial migration through integrin-dependent pathways. We aimed to examine functional and posttranslational activity of α-integrins during HIF-1-mediated intestinal epithelial healing. Wound healing was assessed in T84 monolayers over 24 h with/without prolyl-hydroxylase inhibitor (PHDi) (GB-004), which stabilizes HIF-1. Gene and protein expression were measured by RT-PCR and immunoblot, and α-integrin localization was assessed by immunofluorescence. α-integrin function was assessed by antibody-mediated blockade, and integrin α6 regulation was determined by HIF-1α chromatin immunoprecipitation. Models of mucosal wounding and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis were used to examine integrin expression and localization in vivo. PHDi treatment accelerated wound closure and migration within 12 h, associated with increased integrin α2 and α6 protein, but not α3. Functional blockade of integrins α2 and α6 inhibited PHDi-mediated accelerated wound closure. HIF-1 bound directly to the integrin α6 promoter. PHDi treatment accelerated mucosal healing, which was associated with increased α6 immunohistochemical staining in wound-associated epithelium and wound-adjacent tissue. PHDi treatment increased α6 protein levels in colonocytes of TNBS mice and induced α6 staining in regenerating crypts and reepithelialized inflammatory lesions. Together, these data demonstrate a role for HIF-1 in regulating both integrin α2 and α6 responses during intestinal epithelial healing.NEW & NOTEWORTHY HIF-1 plays an important role in epithelial restitution, selectively inducing integrins α6 and α2 to promote migration and proliferation, respectively. HIF-stabilizing prolyl-hydroxylase inhibitors accelerate intestinal mucosal healing by inducing epithelial integrin expression.

Innate Immune Molecule NLRC5 Protects Mice From Helicobacter-induced Formation of Gastric Lymphoid Tissue.

BACKGROUND & AIMS: Helicobacter pylori induces strong inflammatory responses that are directed at clearing the infection, but if not controlled, these responses can be harmful to the host. We investigated the immune-regulatory effects of the innate immune molecule, nucleotide-binding oligomerization domain-like receptors (NLR) family CARD domain-containing 5 (NLRC5), in patients and mice with Helicobacter infection. METHODS: We obtained gastric biopsies from 30 patients in Australia. We performed studies with mice that lack NLRC5 in the myeloid linage (Nlrc5møKO) and mice without Nlrc5 gene disruption (controls). Some mice were gavaged with H pylori SS1 or Helicobacter felis; 3 months later, stomachs, spleens, and sera were collected, along with macrophages derived from bone marrow. Human and mouse gastric tissues and mouse macrophages were analyzed by histology, immunohistochemistry, immunoblots, and quantitative polymerase chain reaction. THP-1 cells (human macrophages, controls) and NLRC5-/- THP-1 cells (generated by CRISPR-Cas9 gene editing) were incubated with Helicobacter and gene expression and production of cytokines were analyzed. RESULTS: Levels of NLRC5 messenger RNA were significantly increased in gastric tissues from patients with H pylori infection, compared with patients without infection (P < .01), and correlated with gastritis severity (P < .05). H pylori bacteria induced significantly higher levels of chemokine and cytokine production by NLRC5-/- THP-1 macrophages than by control THP-1 cells (P < .05). After 3 months of infection with H felis, Nlrc5mø-KO mice developed gastric hyperplasia (P < .0001), splenomegaly (P < .0001), and increased serum antibody titers (P < .01), whereas control mice did not. Nlrc5mø-KO mice with chronic H felis infection had increased numbers of gastric B-cell follicles expressing CD19 (P < .0001); these follicles had features of mucosa-associated lymphoid tissue lymphoma. We identified B-cell-activating factor as a protein that promoted B-cell hyperproliferation in Nlrc5mø-KO mice. CONCLUSIONS: NLRC5 is a negative regulator of gastric inflammation and mucosal lymphoid formation in response to Helicobacter infection. Aberrant NLRC5 signaling in macrophages can promote B-cell lymphomagenesis during chronic Helicobacter infection.

Small Intestinal Bacterial Overgrowth in Functional Dyspepsia: A Systematic Review and Meta-Analysis.

INTRODUCTION: This systematic review and meta-analysis aimed to determine the role of small intestinal bacterial overgrowth (SIBO) in patients with functional dyspepsia (FD). METHODS: Electronic databases were searched until July 2020 for studies reporting prevalence of SIBO in FD. The prevalence rates, odds ratio, and 95% confidence intervals (CIs) of SIBO in FD and controls were calculated. RESULTS: Seven studies with 263 patients with FD and 84 controls were identified. The odds for SIBO in patients with FD were significantly higher as compared to that in controls (odds ratio = 4.3, 95% CI, 1.1-17.5, 4 studies, 234 participants); however, there was moderate heterogeneity in this analysis. Including high-quality, case-control studies (all using glucose breath tests [GBTs]), the risk of SIBO in patients with FD as compared to controls was 2.8 higher (95% CI 0.8-10.0, 3 studies, 200 participants) with minimal heterogeneity in this analysis. Using the lactulose breath test, SIBO prevalence in FD was significantly higher (53.4%, 95% CI 33.9-71.9, 3 studies, 110 participants) as compared to that with GBT (17.2%, 95% CI 8.6-31.6, 4 studies, 153 participants). Substantial heterogeneity was found in studies using the lactulose breath test but not in studies using GBT. There was no significant difference in SIBO prevalence in patients with FD according to FD subtype. DISCUSSION: This meta-analysis suggests a link between FD and SIBO. The quality of evidence is low and can be largely attributed to the type of breath test for SIBO diagnosis and clinical heterogeneity. More appropriately designed studies are required to confirm the link between SIBO and FD.

An Increasing Incidence of Upper Gastrointestinal Disorders Over 23 Years: A Prospective Population-Based Study in Sweden.

INTRODUCTION: We hypothesized that the prevalence of functional dyspepsia and gastroesophageal reflux disease in the community may be increasing. METHODS: Randomly selected adults were surveyed on 4 occasions: 1988 (n = 1,151, 21-79 years, response rate [rr] = 90%), 1989 (n = 1,097, 22-80 years, rr = 87%), 1995 (n = 1,139, 20-85 years, rr = 76%), and 2011 (n = 1,175, 20-93 years, rr = 63%). RESULTS: In functional dyspepsia, the odds of postprandial distress syndrome tripled over 23 years' follow-up (odds ratio [OR]: 3.55; 95% confidence interval [CI]: 2.60-4.84, mixed-effect regression analysis), whereas a small decrease in epigastric pain syndrome was observed (OR: 0.65, 95% CI: 0.42-1.00). The odds of reporting gastroesophageal reflux disease doubled (OR: 2.02; 95% CI: 1.50-2.73). DISCUSSION: The underlying mechanisms behind the increase in postprandial distress syndrome and gastroesophageal reflux disease remain to be determined.

Clinicopathological Significance of Nerves in Esophageal Cancer.

Nerves are emerging promoters of cancer progression, but the innervation of esophageal cancer and its clinicopathologic significance remain unclear. In this study, nerves were analyzed by immunohistochemistry in a cohort of 260 esophageal cancers, including 40 matched lymph node metastases and 137 normal adjacent esophageal tissues. Nerves were detected in 38% of esophageal cancers and were more associated with squamous cell carcinomas (P = 0.04). The surrounding or invasion of nerves by cancer cells (perineural invasion) was detected in 12% of esophageal cancers and was associated with reduced survival (P = 0.04). Nerves were found to express the following receptors for nerve growth factor (NGF): neurotrophic receptor tyrosine kinase 1 and nerve growth factor receptor. An association was suggested between high production of NGF by cancer cells and the presence of nerves (P = 0.02). In vitro, NGF production in esophageal cancer cells was shown by Western blot, and esophageal cancer cells were able to induce neurite outgrowth in the PC12 neuronal cells. The neurotrophic activity of esophageal cancer cells was inhibited by anti-NGF blocking antibodies. Together, these data suggest that innervation is a feature in esophageal cancers that may be driven by cancer cell-released NGF.

Functional Dyspepsia and Duodenal Eosinophil Count and Degranulation: A Multiethnic US Veteran Cohort Study.

BACKGROUND: Duodenal eosinophilia may play a role in functional dyspepsia (FD), but existing study results are conflicted. We investigated the association between duodenal eosinophils (count and degranulation) and FD symptoms, accounting for atopic conditions, medications, and seasonal variations. METHODS: In a cross-sectional study conducted in the Michael E. DeBakey VA Medical Center in Houston, Texas, we analyzed duodenal histopathology of 436 patient samples from a prospective cohort with a validated symptom survey data and chart reviews. FD was defined using Rome II symptom criteria. Eosinophil count was number per 5 high-power fields (HPF), and eosinophil degranulation was eosinophilic granules in the stroma both determined by two independent investigators. RESULTS: The study cohort was predominantly male (87.4%) with a mean age of 59.3 (standard deviation (SD) ± 9.8). Mean and median eosinophil counts were 75.5 (± 47.8) and 63 (IQR: 43, 101) per five HPF, respectively. Duodenal eosinophilia (defined as ≥ 63 per 5 HPF) and eosinophil degranulation were present in 50.5% and 23.1% of patient samples, respectively. FD was observed in 178 patients (41.7%), but neither the mean eosinophil count nor duodenal eosinophilia was associated with FD. Eosinophil degranulation was independently associated with FD overall (OR 1.74; 95% CI 1.08, 2.78; p = 0.02) and early satiety (OR 2.04; 95% CI 1.26, 3.30; p = 0.004). CONCLUSIONS: In this large, ethnically diverse cohort of adult patients, we found no significant association between duodenal eosinophilia and FD. However, the presence of duodenal eosinophilic degranulation, an activated eosinophil marker, was significantly associated with FD, especially early satiety.

Novel concepts in the pathophysiology and treatment of functional dyspepsia.

Emerging data increasingly point towards the duodenum as a key region underlying the pathophysiology of functional dyspepsia (FD), one of the most prevalent functional GI disorders. The duodenum plays a major role in the control and coordination of gastroduodenal function. Impaired duodenal mucosal integrity and low-grade inflammation have been associated with altered neuronal signalling and systemic immune activation, and these alterations may ultimately lead to dyspeptic symptoms. Likely luminal candidates inducing the duodenal barrier defect include acid, bile, the microbiota and food antigens although no causal association with symptoms has been convincingly demonstrated. Recognition of duodenal pathology in FD will hopefully lead to the discovery of new biomarkers and therapeutic targets, allowing biologically targeted rather than symptom-based therapy. In this review, we summarise the recent advances in the diagnosis and treatment of FD with a focus on the duodenum.

Small Intestinal Bacterial Overgrowth in Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis of Case-Control Studies.

INTRODUCTION: We conducted a systematic review and meta-analysis to compare the prevalence of small intestinal bacterial overgrowth (SIBO) in patients with irritable bowel syndrome (IBS) and controls. METHODS: Electronic databases were searched up to December 2018 for studies reporting SIBO prevalence in patients with IBS. Prevalence rates, odds ratios (ORs), and 95% confidence intervals (CIs) of SIBO in patients with IBS and controls were calculated. RESULTS: We included 25 studies with 3,192 patients with IBS and 3,320 controls. SIBO prevalence in patients with IBS was significantly increased compared with controls (OR = 3.7, 95% CI 2.3-6.0). In studies using only healthy controls, the OR for SIBO in patients with IBS was 4.9 (95% CI 2.8-8.6). With breath testing, SIBO prevalence in patients with IBS was 35.5% (95% CI 33.6-37.4) vs 29.7% (95% CI 27.6-31.8) in controls. Culture-based studies yielded a SIBO prevalence of 13.9% (95% CI 11.5-16.4) in patients with IBS and 5.0% (95% CI 3.9-6.2) in controls with a cutoff value of 10 colony-forming units per milliliter vs 33.5% (95% CI 30.1-36.9) in patients with IBS and 8.2% (95% CI 6.8-9.6) in controls with a cutoff value of 10 colony-forming unit per milliliter, respectively. SIBO prevalence diagnosed by lactulose breath test is much greater in both patients with IBS (3.6-fold) and controls (7.6-fold) compared with glucose breath test. Similar difference is seen when lactulose breath test is compared with culture methods. OR for SIBO in patients with IBS-diarrhea compared with IBS-constipation was 1.86 (95% CI 1.83-2.8). Methane-positive breath tests were significantly more prevalent in IBS-constipation compared with IBS-diarrhea (OR = 2.3, 95% CI 1.2-4.2). In patients with IBS, proton pump inhibitor was not associated with SIBO (OR = 0.8, 95% CI 0.5-1.5, P = 0.55). DISCUSSION: This systematic review and meta-analysis suggests a link between IBS and SIBO. However, the overall quality of the evidence is low. This is mainly due to substantial "clinical heterogeneity" due to lack of uniform selection criteria for cases and controls and limited sensitivity and specificity of the available diagnostic tests.

Duodenal eosinophils as predictors of symptoms in coeliac disease: a comparison of coeliac disease and non-coeliac dyspeptic patients with controls.

Introduction: Duodenal eosinophilia is a key feature of functional dyspepsia, particularly in those with early satiety. Duodenal eosinophilia is also recognised in coeliac disease, although its relevance to symptoms is not understood. We aimed to determine if duodenal eosinophilia is present in patients with coeliac disease presenting with dyspepsia, and whether other histological characteristics were associated with clinical features on presentation.Methods: The coeliac study population comprised 61 patients with a new presentation of coeliac disease to a single centre from 2003 to 2013. A standard symptom assessment was documented for all patients. The control population (55 adults) presenting for endoscopy without coeliac disease was drawn from the same centre with similar demographics for age and gender. Duodenal biopsies from both groups were assessed for eosinophil counts and histological features.Results: Dyspepsia was present in 18.0% of coeliac patients and early satiety in 24.6%. The eosinophil counts were significantly higher in the stomach (12.1/mm2 vs. 4.0/mm2, p < .001) and duodenum (60.4/mm2 vs. 18.0/mm2, p < .001) of coeliac patients compared with controls. There was no significant difference in the mean duodenal eosinophil count in coeliac disease with and without early satiety (55.4/mm2 vs. 66.9/mm2, p = .51). Duodenal eosinophilia was not associated with the severity of coeliac enteropathy. The degree of villous atrophy was associated with iron deficiency at presentation (p = .01), but not symptoms.Conclusions: Although duodenal eosinophil counts are higher in coeliac disease than controls, we were not able to demonstrate an association with presenting symptoms or markers of disease severity.

Incidence and prevalence of self-reported non-coeliac wheat sensitivity and gluten avoidance in Australia.

OBJECTIVES: To determine the incidence of self-reported non-coeliac wheat sensitivity (SR-NCWS) and factors associated with its onset and resolution; to describe the prevalence of factors associated with gluten avoidance. DESIGN: Longitudinal cohort study; analysis of responses to self-administered validated questionnaires (Digestive Health and Wellbeing surveys, 2015 and 2018). SETTING, PARTICIPANTS: Subset of an adult population sample randomly selected in 2015 from the electoral rolls for the Newcastle and Gosford regions of New South Wales. MAIN OUTCOME MEASURES: Prevalence of SR-NCWS (2015, 2018) and incidence and resolution of SR-NCWS, each by demographic and medical factors; prevalence of gluten avoidance and reasons for gluten avoidance (2018). RESULTS: 1322 of 2185 eligible participants completed the 2018 survey (response rate, 60.5%). The prevalence of SR-NCWS was similar in 2015 (13.8%; 95% CI, 12.0-15.8%) and 2018 (13.9%; 95% CI, 12.1-15.9%); 69 of 1301 respondents (5.3%) reported developing new onset (incident) SR-NCWS between 2015 and 2018 (incidence, 1.8% per year). Incident SR-NCWS was significantly associated with a diagnosis of functional dyspepsia, and negatively associated with being male or older. Gluten avoidance was reported in 2018 by 24.2% of respondents (20.5% partial, 3.8% complete avoidance); general health was the most frequent reason for avoidance (168 of 316 avoiders, 53%). All 13 participants with coeliac disease, 56 of 138 with irritable bowel syndrome (41%), and 69 of 237 with functional dyspepsia (29%) avoided dietary gluten. CONCLUSIONS: The prevalence of SR-NCWS was similar in 2015 and 2018. Baseline (2015) and incident SR-NCWS (2018) were each associated with functional gastrointestinal disorders. The number of people avoiding dietary gluten exceeds that of people with coeliac disease or SR-NCWS, and general health considerations and abdominal symptoms are the most frequently reported reasons for avoidance.

Functional Dyspepsia and Food: Immune Overlap with Food Sensitivity Disorders.

PURPOSE OF REVIEW: Functional dyspepsia (FD) is a chronic functional gastrointestinal disorder characterised by upper gastrointestinal symptoms. Here, we aimed to examine the evidence for immune responses to food in FD and overlap with food hypersensitivity conditions. RECENT FINDINGS: A feature of FD in a subset of patients is an increase in mucosal eosinophils, mast cells, intraepithelial cytotoxic T cells and systemic gut-homing T cells in the duodenum, suggesting that immune dysfunction is characteristic of this disease. Rates of self-reported non-celiac wheat/gluten sensitivity (NCW/GS) are higher in FD patients. FD patients commonly report worsening symptoms following consumption of wheat, fermentable oligosaccharides, disaccharides, monosaccharides, or polyols (FODMAPs), high-fat foods and spicy foods containing capsaicin. Particularly, wheat proteins and fructan in wheat may drive symptoms. Immune mechanisms that drive responses to food in FD are still poorly characterised but share key effector cells to common food hypersensitivities including non-IgE-mediated food allergy and eosinophilic oesophagitis.