Introduction

Emerging epidemiologic evidence suggested that moderate-to-vigorous physical activity (MVPA) was associated with a lower risk of steatotic liver disease (SLD).¹ However, several issues remain unanswered. First, prospective association between PA and hepatic steatosis was less investigated, with few studies mainly in Western populations,^{2, 3} but not in Chinese populations. Second, since sedentary behavior and PA are interrelated and may jointly affect the health outcomes,⁴ a key concern is whether moderate-to-vigorous physical activity (MVPA) can mitigate the detrimental link between sedentary time and SLD. Moreover, PA was shown to affect the gut microbiome by altering the bile acid profile and promoting the production of metabolites such as short-chain fatty acids^5,6 with benefit to SLD in animal models.⁷ However, PA-related gut microbes and metabolites, as well as their associations with SLD risk were rarely investigated at the population level.

Aims & Methods

We investigated the association between PA and the SLD risk in a cohort of 2,942 adults from the Anhui Liver Disease Study (ALDS), in which PA and SLD were measured using a validated self-reported questionnaire and transient elastography, respectively. In a subset of ALDS (n=330), we further identified gut microbial changes and serum metabolites related to MVPA assessed by accelerometer, and examined their associations with SLD risk. Fecal samples for 16S ribosomal RNA sequencing were collected twice (1-year apart) to evaluate 1-year microbial changes, targeted metabolomics analysis of baseline serum samples was performed using liquid chromatography tandem mass spectrometry, while PA was measured using a wrist-worn accelerometer for 3 consecutive days at baseline. Cox and Logistic regression models were used to calculate hazard ratios (HRs) and odds ratios (ORs) with 95%CIs, respectively.

Results

From 2020 to 2025, 565 SLD cases were newly diagnosed. MVPA levels were inversely (per 1-SD increase HR=0.91, 95%CI: 0.83–0.99) and sedentary hours were positively associated with the risk of SLD (HR=1.13, 95%CI: 1.03–1.24). Relative to long-low group (i.e., participants with long sedentary time and low MVPA level), HRs (95%CIs) for SLD risk were 1.00 (0.78–1.28), 0.93 (0.73–1.19), and 0.75 (0.58–0.97) for long-high, short-low, and short-high group, respectively. The α-diversity decreased in the low MVPA group (p=0.024) and the β-diversity changed in both low and high MVPA groups (all p=0.001). We identified 14 microbial genera whose relative abundance significantly changed in low or high MVPA group (all p_FDR<0.05). Among these genera, Proteus and Synergistes were associated with both low and high MVPA but in opposite directions, and were associated with SLD with ORs (95%CIs) of 1.15 (1.01–1.32) and 0.91 (0.78–1.06), respectively. Targeted metabolomics showed an inverse association between MVPA and serum L-Valine (β=-0.068, p_FDR=0.031), which was positively related to SLD risk (OR=16.40, 95%CI: 2.67–111.94). Significant correlations were also found between PA-associated microbial genera and L-Valine.

Conclusion

MVPA may modify gut microbial diversity and composition, as well as serum metabolite levels, and is associated with lower SLD risk, whereas sedentary behavior is associated with higher SLD risk.

References

[1] European Association for the Study of the Liver . Electronic address eee, European Association for the Study of D, European Association for the Study of O, et al. EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol 2024;81:492-542.
[2] McDonough DJ, Mathew M, Pope ZC, et al. Aerobic and Muscle-Strengthening Physical Activity, Television Viewing, and Nonalcoholic Fatty Liver Disease: The CARDIA Study. Journal of Clinical Medicine 2023;12.
[3] Liu M, Ye Z, Zhang Y, et al. Accelerometer-derived moderate-to-vigorous physical activity and incident nonalcoholic fatty liver disease. BMC Medicine 2024;22.
[4] Ekelund U, Tarp J, Steene-Johannessen J, et al. Dose-response associations between accelerometry measured physical activity and sedentary time and all cause mortality: systematic review and harmonised meta-analysis. Bmj 2019;366:l4570.
[5] Penney N, Barton W, Posma JM, et al. Investigating the Role of Diet and Exercise in Gut Microbe-Host Cometabolism. mSystems 2020;5.
[6] Campaniello D, Corbo MR, Sinigaglia M, et al. How Diet and Physical Activity Modulate Gut Microbiota: Evidence, and Perspectives. Nutrients 2022;14.
[7] Chen J, Vitetta L. Gut Microbiota Metabolites in NAFLD Pathogenesis and Therapeutic Implications. Int J Mol Sci 2020;21.

Introduction

Irritable bowel syndrome (IBS) pathophysiology is multifactorial, with fermentable, oligo, di- and mono-saccharides and polyols (FODMAP) playing a role in symptom induction, presumably through osmotic effects and rapid colonic fermentation. While dietary studies assessed effects on symptoms, few have investigated the direct impact on colonic motility.

Aims & Methods

Using high-resolution colonic manometry (HRCM), we examined the effects of intracolonic fructose, fructans (fructo-oligosaccharides), or mannitol infusion on colonic motility in healthy volunteers (HV).
A double-blind three-way crossover study was conducted in 15 HVs, with a ≥ 2-week wash-out period between visits. After three days of a low FODMAP and low fiber diet, subjects came fasted to the hospital's endoscopy unit. They received a 250 mL water enema before advancing a 36-sensor solid state HRCM catheter with perfusion lumen into the ascending colon via colonoscopy under conscious sedation. After a 1 h recovery period, colonic pressures were recorded 1 h in the fasted state, for 20 min during infusion of FODMAP in the ascending colon (200 mL 290 mOsm/kg fructose, fructans, or mannitol), 2 h post-infusion, and 1 h postprandially after a standardized low-calorie meal. Colonic motor patterns were manually identified and compared between the three FODMAPs, with long ones ≥12 cm and high amplitude ones with at least 3 sensors ≥100 mmHg. Gastrointestinal symptoms were recorded every 15 minutes during the 4.5 h measurement. Results are presented as median with minimum and maximum ranges.

Results

Fifteen HV, 40% male (mean age 32 years (range 19-64 y), mean BMI 22.6 kg/m² (range 19.6-33.1)), completed the three study visits. Post FODMAP infusion, a significant difference in long anterograde patterns (p=0.04) was detected (Table). Postprandially, long synchronous (p=0.001) and long anterograde (LA) (p=0.0008) were more frequently observed with fructans, while mannitol tended to induce long retrograde patterns (p=0.07). Many of the long anterograde patterns were pan-colonic interrupted pressurizations (IP; previously described as related to gas transit; Leibbrandt J Clin Med 2023), and these were significantly more frequent after fructans infusion (p=0.004). High-amplitude retrograde-propagating contractions occurred 36 times in five HV: 50% after mannitol, 25% after fructans, and 25% after fructose infusion. There was no significant difference in gastrointestinal symptoms between the three FODMAPs, although flatulence and abdominal cramps were slightly increased after infusion of fructans.

Conclusion

Fructans and mannitol alter colonic motility patterns in distinct ways. Upon fructan infusion, there is a higher frequency of anterograde and synchronous activity, including interrupted pressurizations, which are suggested to be linked to gas transit. However, the frequency of these motor patterns was not altered by mannitol. These responses to different FODMAPs may contribute to symptom generation in IBS.

References

Van den Houte et al. Gastroenterology 2024
Leibbrandt J et al. Clin Med 2023

Introduction

Functional dyspepsia (FD) is a chronic gastrointestinal disorder characterised by meal-related symptoms, which a subset of patients attribute to the consumption of gluten-containing foods [1]. Recent evidence suggests that subtle duodenal immune activation is a feature of FD, as evidenced by elevated eosinophils [2] and impaired epithelial barrier function [3]. FD patients also exhibit an altered duodenal mucosa-associated microbiota (d-MAM) when compared to controls [4]. Given the microbiome’s involvement in the digestion of gluten, we hypothesised that the d-MAM determines the capacity for gluten to disrupt the epithelium and drive immune responses in FD patients.

Aims & Methods

Duodenal biopsies were collected from 10 FD patients and 7 asymptomatic controls. The d-MAM was cultured from biopsies in a habitat simulating media [5] containing 1% wheat-gluten, for up to 48hrs. Microbial cell pellets were frozen for future microbiome sequencing and the cell-free supernatants, containing d-MAM-digested gluten, were collected. Caco2 cells were challenged with the d-MAM-digested gluten, in a Transwell model of the intestinal epithelium (n=3, 2 technical replicates). Transepithelial electrical resistance (TEER) and protein expression of markers of epithelial integrity were measured in Caco2 cells and compared between treatments. Peripheral blood mononuclear cells (PBMCs) from FD patients (n=20) and controls (n=20) were stimulated with pooled samples of FD or control d-MAM-digested gluten, or left untreated, for 44 hours. For comparison to host enzymatic breakdown of gluten, matched PBMCs were also treated with α-chymotrypsin digested, deaminated gluten (CT gluten). The T cell phenotype and presence of activation-induced markers was assessed in PBMCs by flow cytometry.

Results

Challenge of Caco2 cells with gluten digested by the FD d-MAM resulted in a significant increase in Zonula occludens-1 (p=0.007), and reduction in Myd88 (p=0.03), compared to Caco2 cells challenged with control d-MAM-digested gluten. However, TEER readings were not altered between treatment groups in Caco2 experiments. In PBMC experiments, in response to stimulation with FD or control d-MAM-digested gluten, both FD and control PBMCs exhibited heightened expression of activation markers (CD4⁺OX40⁺CD25⁺), when compared to their respective unstimulated cells (p<0.05). When assessing the T-cell phenotype we observed that FD d-MAM-digested gluten promoted an increase in T-helper (Th) 2 cells in both FD (p=0.007) and control (p=0.0001) PBMCs. Meanwhile, control d-MAM-digested gluten stimulation resulted in elevated Th17.1 cells in FD (p<0.0001) and control (p=0.02) PBMCs, when compared to unstimulated cells. Alternatively, CT gluten stimulation did not alter any of the assessed lymphocyte populations in FD or control PBMCs when compared to unstimulated cells, suggesting host digestion of gluten isn’t sufficient to induce immune responses in FD.

Conclusion

Our findings suggest that the d-MAM of FD patients digest gluten in a way that promotes epithelial barrier remodelling and altered immune responses compared to the d-MAM from asymptomatic individuals. The promotion of a Th2 T-cell phenotype by the FD d-MAM is consistent with reports of increased Th2-associated cells, such as eosinophils, in FD patients [6]. These results highlight the likely role of microbiome-gluten interactions in FD, indicating the potential for novel dietary therapies and microbial approaches to management.

References

1. Potter, M., et al., Incidence and prevalence of self-reported non-coeliac wheat sensitivity and gluten avoidance in Australia. Med J Aust, 2020. 212(3): p. 126-131.
2. Shah, A., et al., Duodenal Eosinophils and Mast Cells in Functional Dyspepsia: A Systematic Review and Meta-Analysis of Case-Control Studies. Clinical Gastroenterology and Hepatology, 2022. 20(10): p. 2229-2242.e29.
3. Puthanmadhom Narayanan, S., et al., Duodenal Mucosal Barrier in Functional Dyspepsia. Clin Gastroenterol Hepatol, 2022. 20(5): p. 1019-1028.e3.
4. Shanahan, E.R., et al., Alterations to the duodenal microbiota are linked to gastric emptying and symptoms in functional dyspepsia. Gut, 2023. 72(5): p. 929-938.
5. Schooth, L., Defining the Role of the Mucosa-Associated Microbiota in Digestive Health and Disease Using Novel ex-vivo Combinations of Microbe Culture with Metagenomics. 2024 [Doctoral thesis, The University of Queensland], UQ eSpace.
6. Burns, G.L., et al., Type 2 and type 17 effector cells are increased in the duodenal mucosa but not peripheral blood of patients with functional dyspepsia. Front Immunol, 2022. 13: p. 1051632.

Disclosure

JP, EH, CN, SS, SR, MS, KH, GB, and KD have no disclosures to report.
NT: Financial support from: BluMaiden (microbiome advisory board) (2021), Comvita Mānuka Honey (2021) (digestive health), Biocodex (functional dyspepsia tool), Microba (microbiome advisory board) outside the submitted work. In addition, Dr. Talley has a patent Nepean Dyspepsia Index (NDI) 1998, Biomarkers of IBS licensed, a patent Licensing Questionnaires Talley Bowel Disease Questionnaire licensed to Mayo/Talley, a patent issued, “Diagnostic marker for functional gastrointestinal disorders” Australian Patent Application WO2022256861A1via the University of Newcastle and UniQuest (University of Queensland) and ”Methods and compositions for treating age-related neurodegenerative disease associated with dysbiosis” US Application No. 63/537,725. Dr. Talley is supported by funding from the National Health and Medical Research Council (NHMRC) to the Centre for Research Excellence in Digestive Health and he holds an NHMRC Investigator grant.
SK: Grants from National Health and Medical Research Council (Ideas Grant and Centre for Research Excellence), grants from Viscera Labs (Research contract), grants from Microba Life Science (Research contract), personal fees from Gossamer Bio, personal fees from Anatara Lifescience, personal fees from Immuron, personal fees from Microba Life Science.

Introduction

PTEN Hamartoma Tumor Syndrome (PHTS) is a rare condition caused by PTEN disease-causing variants and characterized by a complex phenotype including gastrointestinal-hamartomas and an increased lifetime risk for malignancies. Current genetic testing enables carriers identification and cascade testing

Aims & Methods

To describe a large cohort of PHTS carriers including unique clinical presentation, genetic diagnosis and treatment approach.
We conducted a retrospective, comprehensive review of medical charts was conducted for individuals with PHTS who were under surveillance at specialized high-risk clinics in Israel. The diagnosis of PHTS was based on the revised diagnostic criteria, which include identification of disease-causing variants in the PTEN gene mutation and/or a combination of major and minor clinical features *.

Results

A total of 53 individuals were included in the study (43% female; median age at diagnosis: 38 years, IQR 29, range 25-75). Pathogenic or likely pathogenic variants in the PTEN gene were identified in 40 individuals (75%), (52% missense, 17% nonsense, and 25% frameshift mutations). Common clinical presentations included gastrointestinal polyps, observed in 75% (n = 40), with five patients having adenomas and one presenting with a ganglion cell polyp. Malignancies were reported in 62% (n = 33), most commonly breast cancer (20%) and thyroid cancer (9%). Macrocephaly was observed in 35% (n = 20), and developmental delay, including autism spectrum disorder, in 8 patients (15%). There were three cases of soft tissue tumors (5.6%): One individual with abdominal desmoid tumor at age 18, one individual with axillary osteosarcoma followed by bilateral chest liposarcoma and one case with a rare soft tissue sarcoma, at the base of the skull.
One case of PHTS with PTEN mosaicism was identified through sequencing of endometrial, salivary, and thyroid tissue samples, following a negative result from blood-based genetic testing. Five individuals (9.4%) received Sirolimus for severe clinical manifestations (multiple thyroid nodules, colonic polyps, gastrointestinal symptoms, and early-onset malignancies). Of them, two patients had substantial reduction in polyp burden and improvement in gastrointestinal symptoms.

Conclusion

In this substantial series we found that PTHS exhibits a wide range of phenotypic presentations, high overall cancer rates and a relatively high prevalence of soft tissue malignancies, which have been rarely described in PHTS. Constitutional mosaicism should be sought in a clinical picture suggestive of PHTS with negative germline genetic testing.

References

* Pilarski R et al: Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst. 2013
1. Hendricks LAJ et al: PTEN Study Group; Mensenkamp AR, Vos JR. Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort. Eur J Med Genet. 2022 Dec;65(12):104632. doi: 10.1016/j.ejmg.2022.104632. Epub 2022 Oct 18. PMID: 36270489.
2. Dhawan A et al: Cancer and Overgrowth Manifestations of PTEN Hamartoma Tumour Syndrome: Management Recommendations from the International PHTS Consensus Guidelines Working Group. Clin Cancer Res. 2025 Feb 12;31(9):1754–65. doi: 10.1158/1078-0432.CCR-24-3819. Epub ahead of print. PMID: 39937242; PMCID: PMC12010961.
3.Dhawan A, et al: Cancer and Overgrowth Manifestations of PTEN Hamartoma Tumour Syndrome: Management Recommendations from the International PHTS Consensus Guidelines Working Group. Clin Cancer Res. 2025 Feb 12;31(9):1754–65. doi: 10.1158/1078-0432.CCR-24-3819. Epub ahead of print. PMID: 39937242; PMCID: PMC12010961.

Introduction

Eosinophilic Esophagitis (EoE) is a clinicopathological disease that requires an integrated assessment combining clinical, endoscopic, and histological findings. Despite this, treatment decisions often remain symptom based. A treat-to-target strategy has recently been proposed to guide EoE management.

Aims & Methods

Retrospective single-center study of EoE patients followed between March 2012 and January 2024, with ≥12 months of follow-up. Clinical, endoscopic, histological data, and complications were assessed using the I-SEE score.

Results

A total of 82 patients with EoE were evaluated [75.6% (n=62) male, mean age 29 ± 13 years], with 37.8% (n=31) diagnosed during childhood. The most frequent symptom was food impaction (74.4%), and atypical symptoms were more common in pediatric patients (p=0.014). At baseline, 55.1% (n=43) presented with a fibrostenotic phenotype, more frequently in adults (p=0.012), and 32.9% (n=27) had moderate-to-severe disease based on the I-SEE score.
During follow-up, 56.1% (n=46) developed complications, most commonly food impaction requiring endoscopy. The presence of a fibrostenotic phenotype on initial endoscopy was a predictor of complications (OR 3.122; 95% CI 1.210–8.055; p=0.019). Both fibrostenotic phenotype (p=0.018) and moderate-to-severe I-SEE scores (p=0.004) were associated with increased need for therapeutic switching.
At 12 months, 50.0% (n=41) were asymptomatic; however, only 12.2% (n=10) had endoscopic healing and 9.8% (n=8) histologic remission. Throughout the study period, the rates of endoscopic and histologic healing remained below 25%.

Conclusion

The authors highlight the clinical dissociation of inflammatory activity and emphasize the importance of endoscopic and histologic healing to prevent disease progression.

References

Dellon, Evan S., et al. "A clinical severity index for eosinophilic esophagitis: development, consensus, and future directions." Journal of Allergy and Clinical Immunology 150.1 (2022): 33-47.