Dietary fibre fermentation produces short-chain fatty acids (SCFAs) that lower colonic luminal pH, influencing host responses that contribute to blood pressure (BP) regulation. Fibre intake also alters gastrointestinal transit time, which has been linked to hypertension prevalence. Here, we aimed to determine the gastrointestinal pH and transit time in patients with hypertension. Using the SmartPill™ Motility Testing System, we assessed gastrointestinal pH and transit time in 55 participants with normal and elevated BP measured by ambulatory BP monitoring. Participants with hypertension exhibited a higher colonic minimum pH than those with normal BP. This difference was not explained by antihypertensive medication use or BP control, gastrointestinal transit time, nutrient intake or circulating SCFA levels. These findings suggest a potential relationship between colonic pH profiles and BP regulation, underscoring the need for future research into gut pH dynamics as emerging contributors to cardiovascular disease risk and progression.

INTRODUCTION:Specific foods are associated with abdominal bloating, which can significantly affect quality of life. To identify responders to fiber-induced bloating and the mechanisms underpinning clinical and microbial responses. METHODS:Double-blind, placebo-controlled, randomized, 2-period, 2-challenge crossover trial in 41 individuals with functional bloating. Participants were randomized to 8 g/d of fructan or α-galacto-oligosaccharides (α-GOS) for 7 days with a 21-day washout. Clinical, nutritional, microbial (shotgun sequencing, metatranscriptomics), and fermentation (short-chain fatty acids, volatile organic compounds, breath hydrogen) profiles were characterized before each challenge to identify factors predicting response and after the challenge to elucidate mechanisms underpinning food-induced bloating. RESULTS:Thirty-nine participants completed both challenges (39 fructan, 40 α-GOS). Overall, 7 (7/39, 17.9%) participants were fructan responders and 8 (8/40, 20%) were α-GOS responders (experienced fiber-related symptom induction). Clinical metrics indicative of bloating distinguished responders and nonresponders to both challenges, including greater abdominal girth (fructan, P = 0.009; α-GOS, P = 0.030). α-GOS responders had higher breath hydrogen (H 2 ) prechallenge than α-GOS nonresponders ( P = 0.011). Trends were identified within metagenomic and metatranscriptomic gut microbial analyses, with higher carbohydrate active enzyme (CAZyme) diversity in fructan responders (prechallenge, adjusted P -value ( P adj) = 0.024; postchallenge, P adj = 0.042) and greater increase in gene expression for gamma-aminobutyric acid (GABA) degradation in α-GOS responders ( P adj = 0.041). DISCUSSION:A higher burden of GI symptoms predicts clinical response to fermentable fibers in functional bloating, while for α-GOS, higher repeated fasting breath H 2 is also a predictor. Gut microbiome function and fermentation is associated with functional bloating; however, further investigations are required to draw firm conclusions for the microbial influence in this interplay.

BACKGROUND:Gastrointestinal symptoms affect most women with endometriosis, but therapeutic interventions are poorly defined. AIMS:To compare the effects of a 28-day low fermentable oligo-, di- and mono-saccharides and polyols (FODMAP) or control diet on gastrointestinal symptom severity in individuals with endometriosis and poorly controlled gastrointestinal symptoms. METHOD:In this single-blinded randomised, controlled cross-over feeding trial, we randomised women aged ≥ 18 years to 28 days of either a low FODMAP (< 5 g/day FODMAPs) or control diet (20 g/day FODMAPs), both modelled on Australian Dietary Guidelines, before a ≥ 28-day washout and crossover to the alternate diet. The primary outcome was the proportion of responders defined according to the response in overall gastrointestinal symptoms on a 100-mm visual analogue scale. Secondary outcomes included gastrointestinal symptoms, quality of life and psychological status. RESULTS:Of 35 women randomised (mean age 31; 95% confidence interval 29, 33 years), 21 (60%) responded to the low FODMAP diet compared with 9 (26%) to the control diet (p = 0.008). In the 4th week of the dietary intervention, overall symptom scores were 35 (21, 42) mm on the low FODMAP diet and 58 (55, 65) mm on the control diet (p < 0.001). Abdominal pain, bloating, stool form and quality of life for both gastrointestinal and endometriosis-associated scales were significantly better for the low FODMAP diet compared with the control diet, but not overall for perceived stress, anxiety or depression. CONCLUSIONS:The low FODMAP diet ameliorates gastrointestinal symptoms related to endometriosis and improves quality of life. Confirmation of these findings in a real-world setting is required. TRIAL REGISTRATION:The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000153819).

Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction, and diet plays a key role in management of symptoms. The low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet has been widely adopted in clinical practice. However, emerging evidence highlights the potential of other diet interventions for IBS. We recently showed in a 6-week randomized controlled trial in 59 patients with IBS and anxiety or depression symptoms that a Mediterranean diet (MD), rich in whole-grain cereals, vegetables, legumes, fruit, fish and olive oil, was feasible and reduced gastrointestinal (GI) and psychological symptom severity compared with habitual diet controls.1 The gut, mental, and broader health benefits of an MD are proposed to be driven by its enrichment of the microbiome.2.

Abstract Background The regional physicochemical environment of the gut, particularly colonic pH, is a key determinant of microbial composition and metabolic activity. However, how these localised intraluminal physicochemical dynamics interface with systemic immunity in humans remains unknown. Objective We aimed to investigate the relationship between colonic pH, microbial metabolism, and immune tone. Design In a cross-sectional study of 54 healthy adults, we integrated four complementary datasets to enable a systems-level analysis of gut–immune interactions: in vivo real-time colonic pH and transit dynamics via the SmartPill wireless pH–motility capsule; microbial community structure via faecal metagenomic sequencing; microbial metabolic activity via plasma short-chain fatty acid (SCFA) quantification; and 121 circulating immune subsets via deep immunophenotyping of peripheral blood mononuclear cells (PBMCs). Results Lower colonic pH was associated with circulating cytokine-producing CD8 + T cells. Conversely, higher pH correlated with an increase in circulating mature low-density neutrophils (LDNs) and a distinct shift towards PD1-expressing exhaustion-like CD8 + T cells. Metagenomic profiling identified species-level associations within the genus Eubacterium , linked to colonic pH and distinct peripheral immune profiles. Conclusion These findings suggest that gut’s physicochemical microenvironment, driven by pH, may act alongside microbial activity and metabolism to jointly shape systemic immune tone in humans. This supports a functional intraluminal-peripheral axis, suggesting that targeting gut pH and fermentation dynamics could offer novel avenues for exploring immune-targeted interventions. What is already known on this topic Colonic pH is a critical driver of microbial niche selection and metabolic activity in vitro , but how this localised physicochemical environment influences systemic immunity in humans remains unknown. What this study adds? By pairing in vivo real-time wireless pH-capsule transit data with metagenomics, plasma SCFAs, and deep immunophenotyping, we demonstrate specific associations between colonic pH and the peripheral immune landscape, mapping gut–immune interactions in humans Lower colonic pH associates with robust, cytokine-producing CD8 + T cells, whereas a higher pH correlates with a shift toward PD1 exhaustion-like CD8 + T cell phenotypes and elevated systemic mature LDNs. How this study might affect research, practice or policy These findings establish a novel physicochemical-gut-immune axis, suggesting that therapeutic manipulation of colonic pH (via diet, prebiotics, or targeted delivery systems) could serve as a strategy to modulate or support systemic immune tone in inflammatory or metabolic diseases.

The physicochemical environment of the gut, particularly colonic pH, plays a critical role in shaping host-microbe interactions; yet its influence on systemic immunity in humans remains poorly understood. Here, we integrated faecal metagenomics, plasma short-chain fatty acid (SCFA) profiling, SmartPill wireless pH-motility capsule data, and deep immunophenotyping of peripheral blood mononuclear cells in 54 participants to investigate the relationship between colonic pH, microbial metabolism, and immune tone. We found that lower colonic pH was associated with cytokine-producing CD8+ T cells, while higher pH correlated with pre-exhausted CD8+ T cells and elevated neutrophil populations. Metagenomic analyses revealed species-level associations within the genus Eubacterium , linked to colonic pH and peripheral immune profiles. These findings suggest that microbial metabolic activity and gut pH jointly modulate immune tone beyond the gut in humans, establishing a functional axis between microbial fermentation, physicochemical gut conditions, and systemic immunity. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial ACTRN12620000284965 ### Funding Statement This study was supported by a National Heart Foundation Vanguard Grant (102927) and a National Health & Medical Research Council of Australia (NHMRC) Ideas Grant (GTN2017382). F.Z.M. is supported by a Senior Medical Research Fellowship from the Sylvia and Charles Viertel Charitable Foundation, a National Heart Foundation Future Leader Fellowship (105663), and National Health & Medical Research Council (NHMRC) Emerging Leader Fellowship (GNT2017382). J.A.O. is supported by a NHMRC Fellowship (GNT1124288). S.J.T is supported by NHMRC Ideas Grant (GTN2037610). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The pH of Intestines and Blood-pressure Regulation (pHibre) study was approved by the Monash University Human Research Ethics Committee (Study ID: 23336) and followed the Declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Microbiome data are available at https://doi.org/10.5281/zenodo.17645792. We did not obtain patient consent for all the data to be made publicly available. However, the data underlying this article can be shared for selected research questions upon reasonable request to the corresponding author. Please email F.Z.M. at francine.marques{at}monash.edu, who will respond within 4 weeks.

BACKGROUND:Ingestible wireless motility capsules enable locoregional quantification of luminal pH and concentrations of hydrogen and carbon dioxide in the human colon. AIM:To evaluate these measures in the colon of healthy adults. METHODS:Gas-sensing and pH-sensing wireless motility capsules were ingested tandemly and repeatedly over time. Measurements were analysed and compared in proximal and distal segments of the colon. RESULTS:In paired datasets from 37 participants, colonic pH rose from a median 6.3 (IQR 5.8-6.9) proximally to 7.0 (6.6-7.2) distally (p < 0.001). Concentrations of carbon dioxide rose in nearly all participants from 12.7 (9.1-18.6) proximally to 18.8 (11.9-28.1) %.h/h distally (p < 0.001) with a positive correlation between proximal and distal colon (r = 0.76; p < 0.001). Hydrogen concentrations showed widely varied proximal-to-distal gradients with an increase in 69% of participants, but no correlation between proximal and distal colon measures. No significant correlations between colonic pH, hydrogen concentrations, and carbon dioxide concentrations were observed. Comparison of hydrogen and carbon dioxide concentrations between tandem gas-sensing capsules by Bland-Altman analysis (n = 24) showed minimal (< 1.2%) bias for both measures, and gas metrics on repeat ingestion were similar (n = 20). However, there was greater variance in the distal colon. CONCLUSIONS:Both wireless motility capsules evaluate different yet complementary aspects of colonic fermentation. Carbon dioxide concentrations that most likely reflect overall microbial metabolic activity were consistently greater distally, while proximal-to-distal gradients in hydrogen concentrations varied, likely due to inter-subject variations in dietary carbohydrate and/or methanogenesis. Luminal pH poorly reflects carbohydrate fermentation in the distal colon. TRIAL REGISTRATION:ACTRN12619001219178 and ACTRN12622000422729.

Double-blind, placebo-controlled, randomized controlled trials are the gold standard for clinical trials in nutrition science. For trials of whole diets, dietary counseling is advantageous as they offer clinical translatability although can vary in the fidelity of the intended intervention from participant to participant and across studies. Feeding trials, in which most or all food is provided, offer high precision and can provide proof-of-concept evidence that a dietary intervention is efficacious and can also better evaluate the effect of known quantities of foods and nutrients on physiology. However, they come with additional methodological complexities. Feeding trials also call for a variety of unique methodological considerations, not least of which relate to the design and delivery of diets to participants. This review aims to provide a comprehensive summary of recommendations for design and conduct of feeding trials, encompassing domiciled and nondomiciled feeding trials. Several pertinent aspects of trial design and methodology are discussed, including defining the study population to maximize retention, safety, and generalizability of findings, recommendations for design of control interventions and optimizing blinding, and specific considerations for clinical populations. A detailed stepwise process for menu design, development, validation, and delivery are also presented. These recommendations aim to facilitate methodologic consistency and execution of high-quality feeding trials, ultimately facilitating improved understanding of the role of diet in treating disease and the underpinning mechanisms.

Abstract Diet therapy in disorders of gut–brain interaction (DGBI) is rapidly advancing, with accumulating evidence to support two innovative therapies—manipulation of dietary fibers and enzyme supplementation—that target specific DGBI pathophysiology and modulate digestion. Dietary fibers escape digestion in the upper gastrointestinal tract and can influence gut function by impacting digestion, improving laxation, and interacting with the microbiota. A more nuanced understanding of different fiber types and their ability to impact gut function in highly specific ways has shown that fibers can impact distinct gut symptoms and pathophysiology. By considering their functional characteristics of bulking, gel‐forming, and fermentability, restriction or supplementation of specific fibers can offer clinical value in DGBI. Similarly to fiber specificity, emerging evidence suggests that supplemental digestive enzymes may be targeted to known food triggers with consideration that enzymes are substrate specific. Limited evidence supports use of lactase to target lactose, and α‐galactosidase to target galacto‐oligosaccharides. Application of enzymes during manufacturing of food products may prove to be an additional strategy, although evidence is scant. Both innovative therapies may be utilized in isolation or in combination with other diet and nondiet therapies. Implementation can be guided by the principles that fiber modulation can be targeted to specific symptomology or requirement for alterations to gut function, and digestive enzymes can be targeted to known food triggers. This review aims to summarize recent literature of these two innovative concepts and provide practical suggestions for their implementation in clinical practice.

Purpose of review The gastrointestinal (GI) microbiome has been implicated in the pathogenesis of inflammatory bowel disease (IBD) and has been linked with irritable bowel syndrome (IBS). The aim of this article is to critically review the emerging evidence for the mechanisms and effectiveness of probiotics in the management of these conditions. Recent findings The GI microbiome is strongly influenced by ageing, diet and disease. Probiotics may confer health effects to the host by modulating the metabolic activities of the microbiome to propagate anti-inflammatory effects and reinforce the intestinal barrier, and are considered to be safe to use. Many short-term studies have demonstrated the effectiveness of probiotics overall in IBS, with meta-analyses demonstrating efficacy across specific strains albeit with relatively small effect sizes. Within IBD, some probiotics appear to offer clinical benefit in ulcerative colitis but strain-specific effects are unclear. Evidence for the use of probiotics in Crohn's disease remains limited. Summary Probiotics offer considerable potential for the management of IBS and possibly in IBD, however, any benefits conferred appear to be strain-specific. High quality trials of specific probiotics in IBS and IBD, as well as laboratory investigations of their mechanism of action, are required in order to fully understand their potential therapeutic value.

Summary Background Carbohydrate fermentation plays a pivotal role in maintaining colonic health with excessive proximal and deficient distal fermentation being detrimental. Aims To utilise telemetric gas‐ and pH‐sensing capsule technologies for defining patterns of regional fermentation following dietary manipulations, alongside conventional techniques of measuring fermentation. Methods In a double‐blind crossover trial, 20 patients with irritable bowel syndrome were fed low FODMAP diets that included no extra fibre (total fibre content 24 g/day), or additional poorly fermented fibre, alone (33 g/day) or with fermentable fibre (45 g/day) for 2 weeks. Plasma and faecal biochemistry, luminal profiles defined by tandem gas‐ and pH‐sensing capsules, and faecal microbiota were assessed. Results Plasma short‐chain fatty acid (SCFA) concentrations (μmol/L) were median (IQR) 121 (100–222) with fibre combination compared with 66 (44–120) with poorly fermented fibre alone ( p = 0.028) and 74 (55–125) control ( p = 0.069), but no differences in faecal content were observed. Luminal hydrogen concentrations (%), but not pH, were higher in distal colon (mean 4.9 [95% CI: 2.2–7.5]) with fibre combination compared with 1.8 (0.8–2.8) with poorly fermented fibre alone ( p = 0.003) and 1.9 (0.7–3.1) control ( p = 0.003). Relative abundances of saccharolytic fermentative bacteria were generally higher in association with supplementation with the fibre combination. Conclusions A modest increase in fermentable plus poorly fermented fibres had minor effects on faecal measures of fermentation, despite increases in plasma SCFA and abundance of fermentative bacteria, but the gas‐sensing capsule, not pH‐sensing capsule, detected the anticipated propagation of fermentation distally in the colon. The gas‐sensing capsule technology provides unique insights into localisation of colonic fermentation. Trial registration: ACTRN12619000691145.

Background and Aim: Gut – brain dysregulation and microbiome dysfunction are central to the pathogenesis of irritable bowel syndrome (IBS). Depressive and anxiety symptoms are highly prevalent and contribute to disease burden but are not commonly addressed in practice. The low-FODMAP diet is ef fi cacious for managing gastrointestinal symptoms but may not be appropriate for those with psychological comorbidity, due to its complexity. A Mediterranean diet (MD), rich in vegetables, pulses, wholegrains, and olive oil, has potential bene fi t in IBS, as it leads to positive shifts in microbiome composition and function, and randomized controlled trials (RCTs) have demonstrated antidepressant effects. The TANDIM trial aimed to assess the feasibility of an MD in patients with IBS and psychological comorbidity. Methods: Adults aged 18 – 65 years with Rome IV IBS and mild or moderate anxiety and/or depressive symptoms were recruited to a 6-week RCT. Patients with signi fi cant medical or mental health conditions (e.g. in fl am-matory bowel disease, bipolar disorder) and recent change in IBS or psychotropic treatment were excluded. Patients were randomized to receive MD advice from a dietitian or advice to continue habitual diet. Diet adherence was measured using an MD adherence screener (MEDAS). Data on gastrointestinal symptoms

CONTEXT:Dietary fibers hold potential to influence depressive and anxiety outcomes by modulating the microbiota-gut-brain axis, which is increasingly recognized as an underlying factor in mental health maintenance. OBJECTIVE:Evidence for the effects of fibers on depressive and anxiety outcomes remains unclear. To this end, a systematic literature review and a meta-analysis were conducted that included observational studies and randomized controlled trials (RCTs). DATA SOURCES:The PubMed, Embase, CENTRAL, CINAHL, and PsychINFO databases were searched for eligible studies. DATA EXTRACTION:Study screening and risk-of-bias assessment were conducted by 2 independent reviewers. DATA ANALYSIS:Meta-analyses via random effects models were performed to examine the (1) association between fiber intake and depressive and anxiety outcomes in observational studies, and (2) effect of fiber intervention on depressive and anxiety outcomes compared with placebo in RCTs. A total of 181 405 participants were included in 23 observational studies. In cross-sectional studies, an inverse association was observed between fiber intake and depressive (Cohen's d effect size [d]: -0.11; 95% confidence interval [CI]: -0.16, -0.05) and anxiety (d = -0.25; 95%CI, -0.38, -0.12) outcomes. In longitudinal studies, there was an inverse association between fiber intake and depressive outcomes (d = -0.07; 95%CI, -0.11, -0.04). In total, 740 participants were included in 10 RCTs, all of whom used fiber supplements. Of note, only 1 RCT included individuals with a clinical diagnosis of depression. No difference was found between fiber supplementation and placebo for depressive (d = -0.47; 95%CI, -1.26, 0.31) or anxiety (d = -0.30; 95%CI, -0.67, 0.07) outcomes. CONCLUSION:Although observational data suggest a potential benefit for higher fiber intake for depressive and anxiety outcomes, evidence from current RCTs does not support fiber supplementation for improving depressive or anxiety outcomes. More research, including RCTs in clinical populations and using a broad range of fibers, is needed. SYSTEMATIC REVIEW REGISTRATION:PROSPERO registration no. CRD42021274898.

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Summary Background Diet is fundamental to the care of irritable bowel syndrome (IBS). However, some approaches are not appropriate for individuals experiencing psychological symptoms. Aims To assess feasibility of a Mediterranean diet in IBS and its impact on gastrointestinal and psychological symptoms. Methods We recruited adults with Rome IV IBS and mild or moderate anxiety and/or depressive symptoms to an unblinded 6‐week randomised controlled trial. Patients were randomised to Mediterranean diet counselling or habitual diet. We collected gastrointestinal and psychological symptom data, dietary data and stool samples for metagenomic sequencing. Results We randomised 59 individuals (29 Mediterranean diet, 30 control); 48 completed the study. The Mediterranean Diet Adherence Screener score was higher in the Mediterranean diet group than controls at week 6 (7.5 [95% CI: 6.9–8.0] vs. 5.7 [5.2–6.3], p < 0.001), and there was a greater score increase than controls (2.1 [95% CI: 1.3–2.9] vs. 0.5 [95% CI: 0.1–1.0], p = 0.004), demonstrating Mediterranean diet feasibility. There was a greater proportion of gastrointestinal symptom responders in the Mediterranean diet group than controls (24/29, 83% vs. 11/30, 37%, p < 0.001) and depression responders (15/29, 52% vs. 6/30 20%, p = 0.015). There was no difference in FODMAP intake at week 6 ( p = 0.51). Gastrointestinal adverse events were similar ( p = 0.588). There were no differences in change in microbiome parameters between groups. Conclusions A Mediterranean diet is feasible in IBS and leads to improvement in gastrointestinal and psychological symptoms. Although this study was unblinded, these findings together with the broader benefits of the Mediterranean diet, provide strong impetus for future research in IBS. Australia New Zealand Clinical Trials Registry: ACTRN12620001362987.