Coeliac disease is a strong risk factor for Gastro-oesophageal reflux disease while a gluten free diet is protective: a systematic review and meta-analysis.

Background: Gastro-oesophageal reflux disease (GORD) mechanisms are well described, but the aetiology is uncertain. Coeliac disease (CD), a gluten enteropathy with increased duodenal eosinophils overlaps with GORD. Functional dyspepsia is a condition where duodenal eosinophilia is featured, and a 6-fold increased risk of incident GORD has been observed. Perturbations of the duodenum can alter proximal gastric and oesophageal motor function. We performed a systematic review and meta-analysis assessing the association between CD and GORD. Methods: A systematic search of studies reporting the association of GORD and CD was conducted. CD was defined by combined serological and histological parameters. GORD was defined based on classical symptoms, oesophagitis (endoscopic or histologic) or abnormal 24-h pH monitoring; studies reporting oesophageal motility abnormalities linked with GORD were also included. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated using a random-effects model. Findings: 31 papers were included. Individuals with CD on a gluten containing diet were 3 times more likely to have GORD than controls (OR: 3.37, 95% CI: 2.09-5.44), and over 10 times more likely when compared to those on a gluten free diet (GFD) (OR: 10.20, 95% CI: 6.49-16.04). Endoscopic oesophagitis was significantly associated with CD (OR: 4.96; 95% CI: 2.22-11.06). One year of a GFD in CD and GORD was more efficacious in preventing GORD symptom relapse than treatment with 8 weeks of PPI in non-CD GORD patients (OR: 0.18, 95% CI: 0.08-0.36). Paediatric CD patients were more likely to develop GORD (OR: 3.29, 95% CI: 1.46-7.43), compared to adult CD patients (OR: 2.55, 95% CI: 1.65-3.93). Interpretation: CD is strongly associated with GORD but there was high heterogeneity. More convincingly, a GFD substantially improves GORD symptoms, suggesting a role for duodenal inflammation and dietary antigens in the aetiology of a subset with GORD. Ruling out CD in patients with GORD may be beneficial. Funding: The study was supported by an Investigator Grant from the NHMRC to Dr. Talley.

Faecal microbial transfer and complex carbohydrates mediate protection against COPD.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a major cause of global illness and death, most commonly caused by cigarette smoke. The mechanisms of pathogenesis remain poorly understood, limiting the development of effective therapies. The gastrointestinal microbiome has been implicated in chronic lung diseases via the gut-lung axis, but its role is unclear. DESIGN: Using an in vivo mouse model of cigarette smoke (CS)-induced COPD and faecal microbial transfer (FMT), we characterised the faecal microbiota using metagenomics, proteomics and metabolomics. Findings were correlated with airway and systemic inflammation, lung and gut histopathology and lung function. Complex carbohydrates were assessed in mice using a high resistant starch diet, and in 16 patients with COPD using a randomised, double-blind, placebo-controlled pilot study of inulin supplementation. RESULTS: FMT alleviated hallmark features of COPD (inflammation, alveolar destruction, impaired lung function), gastrointestinal pathology and systemic immune changes. Protective effects were additive to smoking cessation, and transfer of CS-associated microbiota after antibiotic-induced microbiome depletion was sufficient to increase lung inflammation while suppressing colonic immunity in the absence of CS exposure. Disease features correlated with the relative abundance of Muribaculaceae, Desulfovibrionaceae and Lachnospiraceae family members. Proteomics and metabolomics identified downregulation of glucose and starch metabolism in CS-associated microbiota, and supplementation of mice or human patients with complex carbohydrates improved disease outcomes. CONCLUSION: The gut microbiome contributes to COPD pathogenesis and can be targeted therapeutically.

Influence of the bile acid/microbiota axis in ileal surgery: a systematic review.

AIM: The gastrointestinal bile acid (BA)/microbiota axis has emerged as a potential mediator of health and disease, particularly in relation to pathologies such as inflammatory bowel disease (IBD) and colorectal cancer. Whilst it presents an exciting new avenue for therapies, it has not yet been characterized in surgical resection of the ileum, where BA reabsorption occurs. The identification of BA/microbiota signatures may provide future therapies with perioperative personalized medicine. In this work we conduct a systematic review with the aim of investigating the microbiome and BA changes that are associated with resection of the ileum. METHOD: The databases included were MEDLINE, EMBASE, Web of Science and Cochrane libraries. The outcomes of interest were faecal microbiome and BA signatures after ileal resection. RESULTS: Of the initial 3106 articles, three studies met the inclusion/exclusion criteria for data extraction. A total of 257 patients (46% surgery, 54% nonsurgery controls) were included in the three studies. Two studies included patients with short bowel syndrome and the other included patients with IBD. Large-scale microbiota changes were reported. In general, alpha diversity had decreased amongst patients with ileal surgery. Phylum-level changes included decreased Bacteroidetes and increased Proteobacteria and Fusobacteria in patients with an intestinal resection. Surgery was associated with increased total faecal BAs, cholic acid and chenodeoxycholic acid. There were decreases in deoxycholic acid and glycine and taurine conjugated bile salts. Integrated BA and microbiota data identified correlations with several bacterial families and BA. CONCLUSION: The BA/microbiota axis is still a novel area with minimal observational data in surgery. Further mechanistic research is necessary to further explore this and identify its role in improving perioperative outcomes.

Interferon-epsilon is a novel regulator of NK cell responses in the uterus.

The uterus is a unique mucosal site where immune responses are balanced to be permissive of a fetus, yet protective against infections. Regulation of natural killer (NK) cell responses in the uterus during infection is critical, yet no studies have identified uterine-specific factors that control NK cell responses in this immune-privileged site. We show that the constitutive expression of IFNε in the uterus plays a crucial role in promoting the accumulation, activation, and IFNγ production of NK cells in uterine tissue during Chlamydia infection. Uterine epithelial IFNε primes NK cell responses indirectly by increasing IL-15 production by local immune cells and directly by promoting the accumulation of a pre-pro-like NK cell progenitor population and activation of NK cells in the uterus. These findings demonstrate the unique features of this uterine-specific type I IFN and the mechanisms that underpin its major role in orchestrating innate immune cell protection against uterine infection.

The Impact of Dietary Interventions on the Microbiota in Inflammatory Bowel Disease: A Systematic Review.

BACKGROUND AND AIMS: Diet plays an integral role in the modulation of the intestinal environment, with the potential to be modified for management of individuals with inflammatory bowel disease (IBD). It has been hypothesised that poor "Western-style" dietary patterns select for a microbiota that drives IBD inflammation and that through dietary intervention, a healthy microbiota may be restored. This study aimed to systematically review the literature and assess current available evidence regarding the influence of diet on the intestinal microbiota composition in IBD patients and how this may affect disease activity. METHODS: MEDLINE, EMBASE, Scopus, Web of Science and Cochrane Library were searched from January 2013 to June 2023, to identify studies investigating diet and microbiota in IBD. RESULTS: Thirteen primary studies met the inclusion criteria and were selected for narrative synthesis. Reported associations between diet and microbiota in IBD were conflicting due to the considerable degree of heterogeneity between studies. Nine intervention studies trialled specific diets and did not demonstrate significant shifts in the diversity and abundance of intestinal microbial communities or improvement in disease outcomes, whilst the remaining four cross-sectional studies did not find a specific microbial signature associated with habitual dietary patterns in IBD patients. CONCLUSIONS: Diet modulates the gut microbiota, and this may have implications for IBD; however, the body of evidence does not currently support clear dietary patterns or food constituents that are associated with a specific microbiota profile or disease marker in IBD patients. Further research is required with a focus on robust and consistent methodology to achieve improved identification of associations.

Beyond Eosinophilic Esophagitis: Eosinophils in Gastrointestinal Disease-New Insights, "New" Diseases.

Functional dyspepsia (FD) is a highly prevalent disorder. Upper endoscopy is normal, and according to the Rome IV criteria, there is no established pathology. Data accumulated over the last 15 years has challenged the notion FD is free of relevant pathology, and in particular, increased duodenal eosinophils have been observed. Intestinal eosinophils play important roles in microbial defence, immune regulation, tissue regeneration and remodelling, and maintaining tissue homeostasis and metabolism; degranulation of eosinophils releases toxic granule products (e.g., major basic protein, eosinophil-derived neurotoxin) which can damage nerves. Normal cut-offs for eosinophil infiltration into the duodenum histologically are less than five eosinophils per high power field (<25 per five high power fields). In clinical practice there is evidence that pathologically increased intestinal eosinophils may often be overlooked. In a meta-analysis duodenal eosinophils were significantly increased in FD although there was substantial heterogeneity; degranulation of duodenal eosinophils was also significantly higher in FD without significant heterogeneity. In addition, increased duodenal permeability, systemic immune activation, and an altered mucosa-associated duodenal microbiome have been identified that may help explain why symptoms arise, often occur after food with exposure to food antigens, and typically fluctuate. Several potentially reversible risk factors for FD have now been identified. We evaluate the current evidence linking duodenal microinflammation and immune activation with FD and disorders of gut-brain interactions that overlap with FD. We propose a two-hit disease model for eosinophilic functional dyspepsia (EoFD) with management implications.

Crosstalk between DNA methylation and hypoxia in acute myeloid leukaemia.

BACKGROUND: Acute myeloid leukaemia (AML) is a deadly disease characterised by the uncontrolled proliferation of immature myeloid cells within the bone marrow. Altered regulation of DNA methylation is an important epigenetic driver of AML, where the hypoxic bone marrow microenvironment can help facilitate leukaemogenesis. Thus, interactions between epigenetic regulation and hypoxia signalling will have important implications for AML development and treatment. MAIN BODY: This review summarises the importance of DNA methylation and the hypoxic bone marrow microenvironment in the development, progression, and treatment of AML. Here, we focus on the role hypoxia plays on signalling and the subsequent regulation of DNA methylation. Hypoxia is likely to influence DNA methylation through altered metabolic pathways, transcriptional control of epigenetic regulators, and direct effects on the enzymatic activity of epigenetic modifiers. DNA methylation may also prevent activation of hypoxia-responsive genes, demonstrating bidirectional crosstalk between epigenetic regulation and the hypoxic microenvironment. Finally, we consider the clinical implications of these interactions, suggesting that reduced cell cycling within the hypoxic bone marrow may decrease the efficacy of hypomethylating agents. CONCLUSION: Hypoxia is likely to influence AML progression through complex interactions with DNA methylation, where the therapeutic efficacy of hypomethylating agents may be limited within the hypoxic bone marrow. To achieve optimal outcomes for AML patients, future studies should therefore consider co-treatments that can promote cycling of AML cells within the bone marrow or encourage their dissociation from the bone marrow.

TRAV26-2 T-Cell Receptor Expression Is Associated With Mucosal Lymphocyte Response to Wheat Proteins in Patients With Functional Dyspepsia.

INTRODUCTION: An association between functional dyspepsia (FD) and wheat-containing foods has been reported in observational studies; however, an adaptive response has not been demonstrated. We examined whether antigens present in wheat could provoke a response from FD duodenal lymphocytes. METHODS: Lamina propria mononuclear cells (LPMCs) were isolated from duodenal biopsies from 50 patients with FD and 23 controls. LPMCs were exposed to gluten (0.2 mg/mL) or gliadin (0.2 mg/mL) for 24 hours. Flow cytometry was performed to phenotype lymphocytes. Quantitative PCR was used to measure the expression of gliadin-associated T-cell receptor alpha variant ( TRAV ) 26-2. RESULTS: In response to gliadin (but not gluten) stimulation, the effector Th2-like population was increased in FD LPMCs compared with that in controls and unstimulated FD LPMCs. Duodenal gene expression of TRAV26- 2 was decreased in patients with FD compared with that in controls. We identified a positive association between gene expression of this T-cell receptor variant and LPMC effector Th17-like cell populations in patients with FD, but not controls after exposure to gluten, but not gliadin. DISCUSSION: Our findings suggest that gliadin exposure provokes a duodenal effector Th2-like response in patients with FD, supporting the notion that food antigens drive responses in some patients. Furthermore, these findings suggest that altered lymphocyte responses to wheat proteins play a role in FD pathogenesis.

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.

Understanding food allergy through neuroimmune interactions in the gastrointestinal tract.

Food allergies are adverse immune reactions to food proteins in the absence of oral tolerance, and the incidence of allergies to food, including peanut, cow's milk, and shellfish, has been increasing globally. Although advancements have been made toward understanding the contributions of the type 2 immune response to allergic sensitization, crosstalk between these immune cells and neurons of the enteric nervous system is an area of emerging interest in the pathophysiology of food allergy, given the close proximity of neuronal cells of the enteric nervous system and type 2 effector cells, including eosinophils and mast cells. At mucosal sites, such as the gastrointestinal tract, neuroimmune interactions contribute to the sensing and response to danger signals from the epithelial barrier. This communication is bidirectional, as immune cells express receptors for neuropeptides and transmitters, and neurons express cytokine receptors, allowing for the detection of and response to inflammatory insults. In addition, it seems that neuromodulation of immune cells including mast cells, eosinophils, and innate lymphoid cells is critical for amplification of the type 2 allergic immune response. As such, neuroimmune interactions may be critical targets for future food allergy therapies. This review evaluates the contributions of local enteric neuroimmune interactions to the underlying immune response in food allergy and discusses considerations for future investigations into targeting neuroimmune pathways for treatment of food allergies.

Clinical and Pathologic Factors Associated With Colonic Spirochete (Brachyspira pilosicoli and Brachyspira aalborgi) Infection: A Comprehensive Systematic Review and Pooled Analysis.

OBJECTIVES: This study aims to determine what pathologic and clinical factors differentiate Brachyspira species that may be useful to clinicians and pathologists. METHODS: We identified 21 studies of Brachyspira infection with individual patient information (n = 113) and conducted a pooled analysis comparing each species. RESULTS: There were differences in the pathologic and clinical profiles of each Brachyspira species. Patients infected with Brachyspira pilosicoli infection were more likely to have diarrhea, fever, HIV, and immunocompromised conditions. Those patients infected with Brachyspira aalborgi were more likely to have lamina propria inflammation. CONCLUSIONS: Our novel data provide potential insights into the pathogenic mechanism(s) and the specific risk factor profile of Brachyspira species. This may be clinically useful when assessing and managing patients.

A pilot study: intraoperative 16S rRNA sequencing versus culture in predicting colorectal incisional surgical site infection.

BACKGROUND: Surgical Site Infection (SSI) of the abdominal incision is a dreaded complication following colorectal surgery. Identifying the intraoperative surgical site microbes may provide clarity in the pathogenesis of SSIs. Genomic sequencing has revolutionized the ability to identify microbes from clinical samples. Utilization of 16S rRNA amplicon sequencing to characterize the intraoperative surgical site may provide the critical information required to predict and prevent infection in colorectal surgery. METHODS: This is a pilot, prospective observational study of 50 patients undergoing elective colorectal resection. At completion of surgery, prior to skin closure, swabs were taken from the subcutaneous tissue of the abdominal incision to investigate the microbial profile. Dual swabs were taken to compare standard culture technique and 16S rRNA sequencing to establish if a microbial profile was associated with postoperative SSI. RESULTS: 8/50 patients developed an SSI, which was more likely in those undergoing open surgery (5/15 33.3% versus 3/35, 8.6%; P = 0.029). 16S rRNA amplicon sequencing was more sensitive in microbial detection compared to traditional culture. Both culture and 16S rRNA demonstrated contamination of the surgical site, predominantly with anaerobes. Culture was not statistically predictive of infection. 16S rRNA amplicon sequencing was not statistically predictive of infection, however, it demonstrated patients with an SSI had an increased biodiversity (not significant) and a greater relative abundance (not significant) of pathogens such as Bacteroidacaea and Enterobacteriaceae within the intraoperative site. CONCLUSIONS: 16S rRNA amplicon sequencing has demonstrated a potential difference in the intraoperative microbial profile of those that develop an infection. These findings require validation through powered experiments to determine the overall clinical significance.

A Systematic Review and Meta-Analysis of Intra-Operative Surgical Site Sampling: Culture versus Culture-Independent Techniques in Predicting Downstream Surgical Site Infection.

Background: Surgical site infection remains a significant cause of morbidity and mortality. Traditionally, the causation has been inferred from the organism(s) detected in the post-operative setting. However, the intra-operative surgical site and the bacteria it harbors have been scarcely studied. Compared with culture-dependent methods, the development of genomic technology provides a new sensitive tool that could aid in characterizing the bacteria within the surgical site. The purpose of this literature review is to establish if there is a predictive role of sampling the intra-operative surgical site. Methods: A systematic literature review was conducted identifying relevant literature reporting on studies that sampled the intra-operative surgical site of any specialty, using either traditional culture or a culture-independent genomic sequencing-based technique and correlation with infection was attempted. The review identified studies between 1959 and 2021 in MEDLINE, EMBASE and Cochrane. Results: The initial search identified 7,835 articles; 36 remained after screening. Thirty-one articles focused on culture-dependent techniques, five on culture-independent. Subgroup meta-analysis demonstrates that a positive intra-operative culture carries a risk of downstream infection with an odds ratio of 8.6, however limited by a high false-positive and inability to correlate the intra-operative culture with the post-operative infection. In contrast, culture-independent studies through genomic sequencing are not predictive but suggest that the surgical incision is a complex microbial community with a shift toward dysbiosis in certain patients. Conclusion: The intra-operative surgical site clearly harbors bacteria. Both techniques give rise to separate explanations underpinning the role of bacteria in surgical site infection. It is possible there is a more complex dynamic community within the incision that makes a patient susceptible to infection. Characterizing this microbial community in large scale studies, including patients with infections may enhance our ability to predict and prevent incisional surgical site infections in patients undergoing surgical procedures.

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.

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.

The duodenal mucosa associated microbiome, visceral sensory function, immune activation and psychological comorbidities in functional gastrointestinal disorders with and without self-reported non-celiac wheat sensitivity.

Frequently, patients with functional gastrointestinal disorders (FGIDs) report intolerance of wheat products. We compared gastrointestinal symptoms, sensory function, psychiatric comorbidities, gut-homing immune cells, and duodenal mucosa-associated microbiome (d-MAM) in FGID patients and controls with and without self-reported wheat sensitivity (SR-NCWS). We recruited 40 FGID patients and 20 controls referred by GPs for treatment. Gastrointestinal/extraintestinal symptoms, visceral sensory function, psychological comorbidities, and SR-NCWS were assessed in a standardized approach. Peripheral gut homing T-cells (CD4+α4+ß7+CCR9+/CD8+α4+ß7+CCR9+) were quantified, and the d-MAM was assessed by DNA sequencing for 46 subjects. Factors of bacterial genera were extracted utilizing factor analysis with varimax rotation and factors univariately associated with FGID or SR-NCWS included in a subsequent multivariate analysis of variance to identify statistically independent discriminators. Anxiety scores (p < .05) and increased symptom responses to a nutrient challenge (p < .05) were univariately associated with FGID. Gut homing T-cells were increased in FGID patients with SR-NCWS compared to other groups (p all <0.05). MANOVA revealed that anxiety (p = .03), visceral sensory function (p = 0.007), and a d-MAM factor comprise members of the Alloprevotella, Prevotella, Peptostreptococcus, Leptotrichia, and Veillonella lineages were significantly (p = .001) associated with FGID, while gut homing CD4+α4+ ß7+CCR9+ T-cells were associated (p = .002) with SR-NCWS. Compared to controls, patients with and without SR-NCWS show that there are shifts in the amplicon sequence variants within specific bacterial genera between the FGID subgroups (particularly Prevotella and Streptococcus) as well as distinct bacterial taxa discriminatory for the two different FGID subtypes. Compared to controls, both FGID patients with and without SR-NCWS have an increased symptom response to a standardized nutrient challenge and increased anxiety scores. The FGID patients with SR-NCWS - as compared to FGID without SR-NCWS (and controls without SR-NCWS) - have increased gut homing T-cells. The d-MAM profiles suggest species and strain-based variations between the two FGID subtypes and in comparison to controls.

Enteric nervous system and intestinal epithelial regulation of the gut-brain axis.

The gut-brain axis describes a bidirectional interplay within the enteric environment between the intestinal epithelium, the mucosal immune system, and the microbiota with the enteric nervous system. This interplay provides a link between exogenous environmental stimuli such as nutrient sensing, and nervous system function, as well as a mechanism of feedback from cortical and sensory centers of the brain to enteric activities. The intestinal epithelium is one of the human body's largest sources of hormones and neurotransmitters, which have critical effects on neuronal function. The influence of the gut microbiota on these processes appears to be profound; yet to date, it has been insufficiently explored. Disruption of the intestinal microbiota is linked not only to diseases in the gut but also to brain symptomatology, including neurodegenerative and behavioral disorders (Parkinson disease, Alzheimer disease, autism, and anxiety and/or depression). In this review we discuss the cellular wiring of the gut-brain axis, with a particular focus on the epithelial and neuronal interaction, the evidence that has led to our current understanding of the intestinal role in neurologic function, and future directions of research to unravel this important interaction in both health and allergic disease.

Eosinophils, Hypoxia-Inducible Factors, and Barrier Dysfunction in Functional Dyspepsia.

Functional dyspepsia (FD) is a highly prevalent disorder of gut-brain interaction (DGBI), previously known as a functional gastrointestinal disorder. Characterized by early satiety, postprandial fullness, and/or epigastric pain or burning, diagnosis depends on positive symptomatology and exclusion of obvious structural diseases. A subtle inflammatory phenotype has been identified in FD patients, involving an increase in duodenal mucosal eosinophils, and imbalances in the duodenal gut microbiota. A dysregulated epithelial barrier has also been well described in FD and is thought to be a contributing factor to the low-grade duodenal inflammation observed, however the mechanisms underpinning this are poorly understood. One possible explanation is that alterations in the microbiota and increased immune cells can result in the activation of cellular stress response pathways to perpetuate epithelial barrier dysregulation. One such cellular response pathway involves the stabilization of hypoxia-inducible factors (HIF). HIF, a transcriptional protein involved in the cellular recognition and adaptation to hypoxia, has been identified as a critical component of various pathologies, from cancer to inflammatory bowel disease (IBD). While the contribution of HIF to subtle inflammation, such as that seen in FD, is unknown, HIF has been shown to have roles in regulating the inflammatory response, particularly the recruitment of eosinophils, as well as maintaining epithelial barrier structure and function. As such, we aim to review our present understanding of the involvement of eosinophils, barrier dysfunction, and the changes to the gut microbiota including the potential pathways and mechanisms of HIF in FD. A combination of PubMed searches using the Mesh terms functional dyspepsia, functional gastrointestinal disorders, disorders of gut-brain interaction, duodenal eosinophilia, barrier dysfunction, gut microbiota, gut dysbiosis, low-grade duodenal inflammation, hypoxia-inducible factors (or HIF), and/or intestinal inflammation were undertaken in the writing of this narrative review to ensure relevant literature was included. Given the findings from various sources of literature, we propose a novel hypothesis involving a potential role for HIF in the pathophysiological mechanisms underlying FD.