Introduction

As a gastric bacterium that contributes to the development of peptic ulcer disease and gastric cancer, Helicobacter pylori (H. pylori) appears to transmit from person-to-person, especially among family members. Little is known of the variations of gut and oral microbiome within households and their association with H. pylori infection.

Aims & Methods

We aim to delineate the impact of cohabitation and H. pylori infection on gut and oral microbiota as well as the correlation between gut and oral bacteria. A total of 1271 fecal samples from 522 families and 1469 saliva samples from 524 families were collected during a family-based survey of H. pylori infection from September 2021 to December 2021. The status of H. pylori was examined by 13C urea breath test. 16S rRNA gene sequencing was performed to explore the structure of gut and oral microbiota.

Results

The overall prevalence of H. pylori infection was 33.2%, ranging from 19.8% in children to 36.7% in adults. An H. pylori positive parent as well as at least one infected sibling increase the risk for childhood infection. The redundancy analysis showed that both the gut and oral microbiota were influenced by age, gender, H. pylori, with strong correlations among family income, resident location and living space. Household members shared more of their oral and gut microbiota than individuals from different households, while no significant difference was observed among spouses, parent-child, and siblings. Notably, stratifications into enterotypes of gut microbiota showed that individuals with a Prevotella enterotype (P-type) had significantly higher infection rate compared to individuals with Bacteroides enterotype (B-type). Meanwhile, saliva samples can also be clustered into two broad compositional patterns (stomatotypes), which were distinctly distributed over H. pylori infection. The Serratia stomatotype (Se-type) was more abundant in H. pylori positive subjects whereas the Streptococcus stomatotype (St-type) completely dominated the H. pylori negative samples. Furthermore, paired analysis of oral-gut samples showed that P-type was closely correlated to Se-type and B-type corresponded to St-type. The H. pylori was most prevalent in subjects with P-type&Se-type as compared to other types.

Conclusion

Our findings suggest the stronger effects of co-habitation on oral and fecal microbiota. The characteristic enterotypes and stomatotypes and their crosstalk might play a role in the susceptibility of H. pylori infection.

Introduction

Food-induced mucosal reactions have been visualised in the duodenum of patients with irritable bowel syndrome (IBS) using confocal laser endomicroscopy (CLE). The mechanisms underlying these alterations remain elusive but uncontrolled studies have reported symptomatic improvement in patients on a diet excluding foods that triggered acute alterations.

Aims & Methods

Aim: 1/ elucidate mechanisms underlying food-induced, acute mucosal alterations and 2/ assess whether a diet based on CLE results improves symptoms in patients with IBS.
Methods: Randomised, double-blind, controlled, cross-over study. Patients with ROME IV IBS (non-C), underwent CLE with sequential administration of foods (wheat, soy, milk, egg white, fish mix, and nut mix) in a randomised order ≥2 weeks after index gastroscopy. CLE was terminated after acute reactions or after administration of all foods. In case less than three foods were administered, a second exam was scheduled. Biological measures were compared between index endoscopy and CLE with food administration. Patients excluded food(s) that did (=real diet) and food(s) that did not (=sham diet) cause alterations for 4 weeks each in a blinded, cross-over diet intervention. Clinical response rate (=improvement of ≥50 points IBS-SSS) between real and sham diet was compared. Missing data was replaced using an extreme case approach (missing data on the primary endpoint was considered non-response). Healthy controls underwent CLE to assess disease specificity of observed alterations.

Results

Thirty-three patients were included, of which 21 underwent a second CLE. Alterations were observed in all 54 exams (100%) either at baseline (6/54, 11%) or after administration of food. Acute alterations were not associated with altered permeability (transepithelial electrical resistance 25.6 Ωxcm² after CLE vs 24.6 Ωxcm² at baseline; p = 0.6) nor with tryptase release from duodenal biopsies (1.1 µg/mg tissue vs 0.62 µg/mg tissue; p =0.15) . Two patients dropped out during the diet phase (one due to maladherence to study protocol, one due to acute increase of IBS symptoms during washout). Thirty-one patients completed the diet phase: 13 were clinical responders to the real diet (42%) versus 11 responders to sham (36%). The odds ratio (OR) for clinical response to the real diet was 1.33 (95% confidence interval: 0.46-3.84). The trial was terminated prematurely for futility (predetermined futility threshold OR <1.5). There was no difference in symptom evolution between real and sham diet (median change in IBS-SSS real diet: -30 points, median change sham diet: -20 points ; p = 0.7). No differences were observed between real and sham diet regarding change in pain duration (-0.1 vs +0.1, p =0.5) , in pain severity (-0.1 vs -0.1, p = 0.9), in bloating severity (-0.1 vs -0.4, p=0.6) or in flatulence severity (± 0.0 vs -0.2 p=0.5) based on 10cm VAS scales in symptom diaries. Fifteen healthy volunteers underwent CLE with alterations in all 15 (100%) exams at baseline (2/15, 13%) or after food administration. Distribution of alterations among different foods was similar to that in patients.

Conclusion

In this double-blind controlled cross-over trial, trigger foods identified based on CLE responses were not associated with superior clinical improvement following a targeted exclusion diet compared to a sham diet. Acute alterations in healthy controls suggest these alterations are not specific for IBS. The underling physiological or pathophysiological mechanism requires further studies.

Introduction

A marked decrease of Faecalibacterium prausnitzii is a well-established hallmark of Crohn’s disease (CD)-associated dysbiosis and predicts disease relapse (1-2). Several strains of F. prausnitzii exhibit anti-inflammatory effects in vitro and in rodents colitis models, positioning this species as a promising therapeutic candidate (3-4). However, it has never been administered to humans. Here, we present the development and first-in-human evaluation of F. prausnitzii strain EXL01 for CD treatment.

Aims & Methods

F. prausnitzii EXL01, isolated from a healthy donor, was selected based on strict safety and preliminary in vitro efficacy criteria. Its anti-inflammatory effect was tested in trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats and dextran sodium sulfate (DSS)-induced colitis in mice. After favorable toxicological studies, a first-in-human, open-label, single-arm study (Part A) was conducted in patients with mild to moderate ileal CD (CDAI 180–350), following clinical remission (CDAI <150) or response (CDAI decrease ≥70) after corticosteroids (CS). EXL01 (10¹⁰ total cell count/day) was administered orally for 24 weeks, with a 6-week CS taper. Colonoscopies were performed at baseline and week 24. The primary endpoint was safety; secondary endpoints included clinical efficacy, blood/fecal biomarkers, transcriptomic analysis, and gut microbiota profiling. Part B, initially planned as a placebo-controlled phase, was not pursued due to low recruitment.

Results

According to classical evaluation endpoints, EXL01 demonstrated dose-dependent anti-inflammatory effects in both TNBS and DSS models. Between March 2023 and October 2024, 8 patients were enrolled across Belgium and Poland. Baseline characteristics were consistent with the target CD population. After corticosteroid induction, the parameters were as follow: CDAI = 78.1 (42-105); SES-CD= 6.9 (2-17); CRP = 5.7mg/l (3-13). EXL01 was well tolerated; no treatment-related serious adverse events or safety signals were observed. Six participants (75%) completed the 24-week treatment; two discontinued due to disease flare. Compared to patients who remained in remission, those who flared during the study showed higher baseline systemic inflammation markers (CRP, neutrophils, platelets) and innate immunity gene expression, with limited corticosteroid response. While gut microbiota composition remained largely stable, transcriptomic analyses revealed distinct changes in ileal gene expression following EXL01 treatment, notably modulation of immune-related genes and upregulation of energy metabolism pathways, similar to what we saw previously in vitro (bioRxiv 2024.10.06.616495).

Conclusion

EXL01, administered during and after CS tapering, was safe and well tolerated for up to 24 weeks in patients with CD. Though limited by small sample size, the study supports the biological activity of EXL01, notably through its impact on ileal gene expression. A phase 2 randomized controlled trial is ongoing to further assess efficacy.

References

1. Rajca S, Grondin V, Louis E, et al. Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn's disease. Inflamm Bowel Dis. 2014 Jun;20(6):978-86. doi: 10.1097/MIB.0000000000000036. PMID: 24788220.
2. Pascal V, Pozuelo M, Borruel N, et al. A microbial signature for Crohn's disease. Gut. 2017;66(5):813-22.
3. Sokol H, Pigneur B, Watterlot L, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A. 2008;105(43):16731-6.
4. Martin R, Chain F, Miquel S, et al. The commensal bacterium Faecalibacterium prausnitzii is protective in DNBS-induced chronic moderate and severe colitis models. Inflamm Bowel Dis. 2014;20(3):417-30.

Disclosure

HS, PhL and BH are co-founder of Exeliom. PR, DS, BH are employees of Exeliom Biosciences

Introduction

Some patients with inflammatory bowel disease require subtotal colectomy with ileostomy electively or in emergency as the first step of surgical treatment. Secondary proctectomy with ileal pouch anal anastomosis or ileorectal anastomosis can be considered for bowel continuity restoration. However, recent literature reports a significant number of patients who do not undergo subsequent surgery and are resigned to live with a definitive end ileostomy.

Aims & Methods

Assess the rate and cumulative incidence of secondary reconstructive surgery after subtotal colectomy for inflammatory bowel disease and identify the risk factors associated with the absence of a completion procedure in a large national cohort study.
A national retrospective study from 2013 and 2021 was conducted on prospective collected data from the French Medical Information System Database (PMSI). All patients undergoing subtotal colectomy in France for inflammatory bowel disease were included. Cumulative incidence of reconstruction surgery either with proctectomy and ileal pouch anal anastomosis or with ileorectal anastomosis was calculated by means of a Kaplan-Meier survival curve. The association between the absence of a subsequent intervention and potential risk factors was studied using univariate and multivariate analyses.

Results

1860 patients were included (45 +/-19 years old), with a median follow-up of 30­ months. 77% (n=1442) presented an ulcerative colitis and 23% (n=418) a Crohn’s disease. Mortality and morbidity at 90 days after subtotal colectomy were 5% (n=100) and 47% (n=868). Reconstructive surgery was identified in 1255 patients (67%) with a mean time of 7 months. 74% (n=932) underwent a completion proctectomy with ileal pouch anal anastomosis and 26% (n=323) an ileorectal anastomosis. Among patients with a permanent ileostomy who did not have bowel continuity restorative surgery (33%, n=605), 19% (n=114) had an abdominoperineal resection and 81% (n=491) did not had any further surgical procedure after subtotal colectomy. Independent risk factors for definitive end ileostomy identified in multivariate analysis were older age, Crohn’s disease, colic neoplasia, postoperative complication after subtotal colectomy, laparotomy, and low volume centre.

Conclusion

In this large national cohort study, 67% of patients undergoing subtotal colectomy with ileostomy for inflammatory bowel disease were treated with reconstructive surgery. This rate is higher than previously reported in other population-based studies. Absence of reconstructive surgery is associated with age, Crohn’s disease, colic neoplasia, post-operative morbidity, laparotomy, and low volume centre.

Introduction

Inflammatory bowel disease (IBD) is a chronic systemic condition of unknown etiology. Dysregulated T-cell responses play a fundamental role in perpetuating intestinal inflammation in IBD. Unconventional T cells are a diverse subset of T cells with innate and adaptive characteristics including: Gamma Delta T cells (GDT), mucosa-associated invariant T (MAIT) cells, and invariant natural killer T (iNKT) cells. As new studies emerge, unconventional T cells’ role in IBD pathogenesis has been increasingly recognized, but their role in the pathogenesis and possible clinical application remains to be elucidated.

Aims & Methods

The aim of the study is to characterize the immune profile of IBD patients and controls in a large well-characterized cohort with focus on Unconventional T cells. We performed an in-depth, multidimensional flow cytometry analysis of unconventional T cells and plasma proteins from patinets´samples collected from the IBD biobank in Norway.
We used immunophenotyping from isolated PBMC to study both conventional T cells and unconventional T cells and evaluated their gut-homing -a4 and b7 expression-, activation and senescence markers. A 65-plex Luminex assay was used to quantify soluble plasma proteins. We studied the variations of T cell profiles within the different disease phenotypes and their correlation with disease activity. A subset of patients was followed-up clinically for 6 (+/-2) years to evaluate the association with disease outcomes.
Statistical analysis was performed using GraphPad Prism (San Diego, CA). Two-tailed Mann-Whitney U test was used to compare two independent groups and ROC analysis was used for diagnostic accuracy; p≤ 0.05 was considered statistically significant. Ethical approvals were obtained and all patients gave written informed consent.

Results

A total of 184 individuals (106 F) were included: 149 IBD (84 UC and 65 CD) and 25 healthy controls. We found important quantitative and phenotypical differences in unconventional T cells and plasma protein in IBD and between UC and CD patients. Patients with IBD had a significant reduction in MAIT cells, and increase in GDT VD3+ and CD8+ cells (p< 0.05). MAIT cells from IBD patients had lower a4+ and b7+ expression than controls. (p<0.05, p<0.001). Interestingly, Macrophage Migration Inhibitor Factor (MIF) was significantly reduced in patients with UC but not in CD (p<0.0001).
Patients with total colitis presented a significant increase in platelet count, MIG, IL-2R, and CD30 (p<0.001,p<0.01 and p<0.05,respectively). CD patients with colonic affection (L2) had a significant increase in TNF-b, FGF-2, G-CSF compared with patients with ileal (L1) or ileocolonic (L3) CD (p<0.01). Interestingly, MAIT cells were the only immune cells significantly reduced in patients with extraintestinal manifestations. The combination of 6 parameters: IL-4, IL-5, IL-8, MIG, CD30 and Eotaxin-3 showed a good diagnostic accuracy in ROC curves (CI:0.759-1.000; p=0.0005) to distinguish patients with mucosal healing vs those with biochemical and clinical remission alone. A decrease in GDT VD2 cells was found in UC patients with worse outcomes (p<0.01). CD patients with bad prognosis showed a significant increase in platelet counts and a decrease in: FABP2, CXCL10 and APRIL (p<0.05).

Conclusion

These results demonstrate the potential of the characterization of Unconventional T cells and soluble plasma proteins as biomarkers in IBD and as markers of disease progression. Further investigation is warranted to elucidate the use of Unconventional T cells in precision medicine and as potential therapeutic targets in IBD.

References

1. Catalan-Serra I, Sandvik AK, Bruland T et al. Gammadelta T Cells in Crohn's Disease: A New Player in the Disease Pathogenesis? J Crohns Colitis. 2017;11:1135-1145.
2. Hinks TSC, Zhang XW. MAIT Cell Activation and Functions. Front Immunol. 2020 May 27;11:1014. doi: 10.3389/fimmu.2020.01014.

Disclosure

No

Introduction

Many prospective studies conducted in healthy volunteers have shown that diet is associated with the risk of developing IBD. By contrast, data are scarce on the role of diet in disease activity in patients with IBD. The aim of the present study was to find dietary factors associated with the risk of IBD relapses.

Aims & Methods

The “Mikinautes” e-cohort is a nationwide French prospective study recruiting IBD patients older than 6 years at inclusion and followed in private practice and public hospitals. French Crohn and Colitis Patients’ association was also involved in the design, funding and recruitment. Patients filled in online questionnaires about their dietary habits and health status. Validated food frequency questionnaires (FFQ) recorded average intakes of 230 food items over the past 12 months. Patients were followed for at least one year and medical records were prospectively collected. Relapse was defined by i) an increased disease activity reported monthly by the patients and/or a clinical report mentioning a relapse, together with ii) a documented consultation with a doctor and iii) a change in IBD therapy, either drug, enteral nutrition and/or surgery).
A posteriori dietary patterns (DPs) were identified using principal component analysis (PCA) performed on 31 food groups. Primary analysis was a Cox model among patients in remission at inclusion to reduce potential reverse causality. Secondary analyses included: i) a Cox model conducted among all patients, which measured the time between the onset of the last relapse before inclusion (or the ongoing relapse at inclusion) and the first relapse during follow-up and ii) a logistic model comparing inactive versus active patients (defined as patients who had at least one relapse at inclusion or over the first year of follow-up). Models were adjusted for age, sex, smoking status and energy intake.

Results

After exclusion of 14 patients with implausible dietary intakes, 693 patients were retained for analyses, comprising 66% of females, 59% Crohn Disease (CD) patients, 34% ulcerative colitis (UC) patients and 7% indeterminate colitis (IC). Median follow-up [Q1-Q3] was 2.1 years [1.6;2.7]. 77% of patients were in remission at inclusion. Their cumulative probability (95% CI) of flare were 18% [15%; 21%] at 1 year and 25% [22%; 29%] at 2 years. In total, 36% of patients had an active disease after one year of follow-up (including active patients at inclusion).
Four DPs were identified through PCA. In CD, primary Cox analysis revealed an association between the second DP and disease activity (HR 95% CI: 0.42 [0.22;0.80] for 3^rdvs 1^st tertile of consumption, p-trend=0.050). This DP was characterized by high intakes of vegetables, fruit, nuts, legumes, cereals, eggs and unsweetened beverages and by a low consumption of dairy products and desserts, bread, sweet/fat or salty/fat products. Secondary analyses confirmed this association (HR: 0.37 [0.18;0.78] for 3^rdvs 1^st tertile, p-trend=0.010; OR: 0.42 [0.22;0.80] for 3^rdvs 1^st tertile, p-trend=0.010). In UC, fruit consumption was protective toward relapse in primary (HR: 0.46 [0.26;0.82] for 3^rdvs 1^st tertile, p-trend=0.009) together with secondary analyses; no dietary pattern was associated with relapse.

Conclusion

A diet characterized by a high consumption of fruit, vegetables, legumes and nuts is associated with a reduction in the risk of relapse by half in patients with CD. High fruit consumption is associated with the same decreased risk of relapse in patients with UC. These results inform dietary counseling in IBD.

References

Acknowledgements: This study was funded by the French association AFA Crohn-RCH France. It was supported by the networks of the Pediatric GETAID, the GETAID, the CREGG, the ANGH and EPIMAD. We thank Nutrinet-Santé, IBD patients and their doctors who contributed to this study.

Disclosure

FC reports receiving research grants from Alpha Wassermann, MaaT pharma, Mayoly Spindler, Medtronic, Nestlé; receiving payment for lectures from AbbVie, AlphaSigma, Ferring, Janssen, Eli Lilly,
Nestlé Health Sciences, Pierre Fabre, Pileje, Takeda, Tillots, Viatris ; receiving consulting fees from AbbVie, Janssen, MaaT pharma, Tillots. HS, SA, CGR, AB, LD and JPH have nothing to declare.