Introduction

Advances in non-celiac wheat sensitivity (NCWS) have proved that it should be considered a protean condition in which several potential triggers [e.g. gluten, wheat amylase-trypsin inhibitors, etc.] might determine an intestinal mucosal damage with increased permeability and exposure of foods/microbial peptides to immune cells (1,2), resulting in both a local and systemic inflammatory activation responsible for its gastrointestinal and extraintestinal manifestations (3,4). Up to 75% of NCWS subjects complain of multiple foods hypersensitivities (MFH) (5). These patients usually have clinical, immunological and histological features similar to wheat allergy patients, although without positive gluten/wheat IgE assays, allowing to hypothesize the existence of a non-IgE mediated hypersensitivity. In addition, several studies have reported an association between atopic diseases and NCWS.

Aims & Methods

This study aimed to define the presence and features of atopic diseases and other hypersensitivities (primarily food allergies/intolerances) in NCWS compared with celiac disease (CD) and irritable bowel syndrome/functional dyspepsia (IBS/FD) and to analyze a possible correlation between these diseases and NCWS clinical manifestations. This retrospective, multicenter study included NCWS patients diagnosed by double-blind placebo-controlled challenge with wheat. Their clinical, laboratory and histology data at diagnosis (i.e. before the start of a wheat-free diet) were analyzed and compared to control subjects with CD and IBS/FD. Specific allergology data, other than clinical/laboratory features typical of NCWS, were collected and analyzed: family and personal history of atopic diseases, type of allergens responsible, positivity of skin prick tests (SPT), patch tests and total and food-specific IgE.

Results

Atopic disease prevalence was higher in NCWS (32.8%) than in CD (19.3%) and IBS/FD (21.5%) (P=.001 for both). Similarly, NCWS subjects had a higher frequency of MFH (39.8%) and self-reported milk intolerance (SRMI) (65.9%) compared to the controls (P <.001 for both). Allergic asthma, either alone (P=.03) or associated with allergic rhinitis (P=.005), was more prevalent in NCWS compared to IBS/FD, which was more often associated with allergic conjunctivitis (P=.004) or allergic rhinitis alone (P=.02). Graminaceae hypersensitivity and nickel allergic contact dermatitis (Ni-ACD) were more frequent in patients with NCWS (70.1% and 17.8%) vs both CD (48.7% and 9.4%, P=.03 and P=.01, respectively) and IBS/FD (50.8% and 6.7%, P=.01 and P<.001, respectively). On multiple logistic regression analysis, a coexistent atopic disease (OR 1.481), MFH (OR 3.882) and SRMI (OR 2.259) were associated with the NCWS diagnosis. NCWS subjects with atopy compared to those without more frequently had Ni-ACD (P<.001) and SRMI (P=.03), positive patch test (P<.001), SPT for foods (P=0.001) and both total and food-specific serum IgE (P=.02 and P=.002, respectively). On multiple logistic regression analysis, positivity to patch test (OR 2.955), SPT for foods (OR 5.799), and food-specific serum IgE (OR 3.101) were confirmed as differentiating the 2 subgroups.

Conclusion

NCWS subjects have a higher frequency of atopic disease, MFH and SRMI compared to both CD and IBS/FD ones. These conditions could be expression of an underlying hypersensitivity milieu characterizing NCWS and might be of support in the differential diagnosis between NCWS and functional gastrointestinal disorders, if inserted into a broader diagnostic panel.

References

1) Zevallos VF, Raker V, Tenzer S, Jimenez-Calvente C, Ashfaq-Khan M, Rüssel N, et al. Nutritional Wheat Amylase-Trypsin Inhibitors Promote Intestinal Inflammation via Activation of Myeloid Cells. Gastroenterology. 2017;152:1100-1113.e12.
2) Uhde M, Ajamian M, Caio G, De Giorgio R, Indart A, Green PH, et al. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut. 2016;65:1930–7.
3) Volta U, De Giorgio R, Caio G, Uhde M, Manfredini R, Alaedini A. Nonceliac Wheat Sensitivity. Gastroenterol Clin North Am. 2019;48:165–82.
4) Catassi C, Elli L, Bonaz B, Bouma G, Carroccio A, Castillejo G, et al. Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): The Salerno Experts’ Criteria. Nutrients. 2015;7:4966–77.
5) Carroccio A, Mansueto P, Iacono G, Soresi M, D’Alcamo A, Cavataio F, et al. Non-Celiac Wheat Sensitivity Diagnosed by Double-Blind Placebo-Controlled Challenge: Exploring a New Clinical Entity. American Journal of Gastroenterology. 2012;107:1898–906.

Disclosure

This study is funded by the European Union - Next Generation EU, Mission 4, Component 1 CUP B53D23031860001, Project Code: P2022Z9RZY_001.

Introduction

Patients (pts) with disorders of gut–brain interaction (DGBI) frequently present with overlapping non-gastrointestinal conditions such as fibromyalgia (FM), whose prevalence in irritable bowel syndrome (IBS) varies from 28–33% to 65%. The co-presence of FM complicates clinical management and worsens outcomes. The pathophysiology of IBS is now well established, involving dysfunction of the gut-brain axis and peripheral factors including microbiome alterations, mucosal barrier disruption, and immune activation. Recently, dysfunction of the gut-musculoskeletal axis was proposed for FM. Shared pathophysiology, involving altered intestinal permeability (IP), and multidisciplinary therapeutic strategies, including dietary interventions, have been proposed for both conditions.

Aims & Methods

To evaluate the effects of a low-FODMAP diet (LFD) on clinical symptoms and IP in pts with IBS, FM, or both, and to assess correlations with serum biomarkers.
This prospective study included 35 pts (88,6% female): 45.7% had IBS+FM, 28.6% IBS-only, and 25.7% FM-only. IP was assessed using serum zonulin (ZO) levels. Clinical evaluations included: SF-36 (quality of life, QoL) for all pts; IBS Symptom Severity Score (IBS-SSS) for IBS; and both Fibromyalgia Impact Questionnaire (FIQ) and Polysymptomatic Distress Scale (PDS) for FM. Assessments occurred at baseline (T0), after 1 month of LFD (T1), at 3 months (T2, reintroduction phase), and 6 months (T3, free diet/follow-up).

Results

At baseline, QoL was significantly lower in the IBS+FM group compared to IBS-only, especially in physical functioning, social functioning, and general health domains (p<0.001). The IBS-only group showed global QoL improvement after 1 month on the LFD, with significant gains in general health (p=0.02) and emotional well-being (p=0.002). Improvements were sustained through T2, but did not increase further. In contrast, the IBS+FM group demonstrated delayed but significant improvements at T2 in physical functioning (p=0.01), energy/fatigue (p=0.02), and social functioning (p<0.001) domains. Similarly, IBS-SSS scores improved significantly at T1 in the IBS-only group (p<0.001) and remained low at T2 (p=0.006), while in the IBS+FM group, the improvement occurred later, reaching significance at T2 (p=0.02). For FM, FIQ and PDS scores improved significantly only at T3 in the IBS+FM group (p=0.03 and p=0.006, respectively), while no significant change occurred in the FM-only group. However, in this group of pts a non-significant reduction in FM symptom scores was observed at T1 and T2, but was followed by worsening symptoms during the free-diet follow-up at T3. Serum ZO levels at T0 were similar across all groups. Significant reductions were observed only in the FM-only and IBS+FM pts, both at T1 (p< 0.001 for both) and T2 (p=0.004, p=0.01, respectively), suggesting improved intestinal permeability. No significant ZO changes were instead observed in the IBS-only group.

Conclusion

The low-FODMAP diet improves gastrointestinal symptoms and quality of life in IBS patients, especially in general health and emotional well-being domains, with delayed but significant benefits also in those with FM. Reductions in zonulin levels in FM and IBS+FM groups suggest enhanced intestinal barrier function, though not directly tied to symptom relief. These findings support a role for central sensitization in FM and underscore the importance of a multidisciplinary approach for managing overlapping DGBI and FM.

Introduction

Non-invasive biomarkers that enable accurate diagnosis, patient stratification, and therapy monitoring in irritable bowel syndrome (IBS) are still lacking in clinical practice. Volatile organic compounds (VOCs) produced by the host metabolism, inflammatory processes, and the gut microbiota are present in exhaled breath and have recently gained attention as promising biomarker candidates. Prior research (Van Malderen et al. (2020)) demonstrated that breath VOC profiling could accurately distinguish IBS patients from healthy controls using multicapillary column/ion‑mobility spectrometry (MCC/IMS).

Aims & Methods

The present study aimed to assess the potential of high-resolution gas chromatography-quadrupole time‑of‑flight mass spectrometry (GC-QTOF-MS) profiling of breath VOCs to define distinct compound classes that enhance the mechanistic understanding of breath-based biomarkers in IBS. To this end, breath samples from 12 IBS patients and 11 healthy controls were collected, together with matched ambient air samples and were analyzed using GC-QTOF-MS. Breath samples were corrected by background subtraction and least‑absolute‑shrinkage‑and‑selection‑operator (LASSO) regression was applied with leave‑one‑out cross‑validation (LOOCV) to identify discriminative VOC signatures. The feature set was subsequently filtered to exclude sporadically detected VOCs and compounds of exogenous (non-host) origin. Finally, the remaining VOCs were mapped to putative pathways.

Results

IBS patients had a mean ± SD age of 36 ± 15.3 years, compared with 56 ± 15.4 for the healthy controls. The male-to-female ratio was 3:9 in the IBS cohort and 5:6 among the healthy controls. Within the IBS group, 7 patients had diarrhea-predominant IBS, 4 had constipation-predominant IBS, and 1 had mixed-type IBS. The LASSO regression model, validated with LOOCV, demonstrated high discriminative performance in differentiating IBS patients from healthy controls, with the corresponding model metrics in Table 1. Furthermore, the feature selection identified a panel of discriminative VOCs - predominantly alkanes, aldehydes, and ketones - that were up-regulated in the IBS breath profiles. These elevated compound classes could putatively be linked to mechanisms relevant to IBS pathophysiology, including altered microbial metabolism, increased oxidative stress, and low-grade inflammation.

Table 1: Model metrics

Conclusion

Volatomic breath profiling in IBS, shows great potential for discriminating IBS from healthy controls and for defining clinically relevant biomarkers composed of specific VOCs. Nonetheless, the limited sample size might risk model overfitting and introduces uncertainty in the estimates. Further research including larger, confounder-controlled cohorts is necessary, along with the targeted validation of the identified VOCs to further confirm their mechanistic role in IBS.

References

Van Malderen K, Hanning N, Lambrechts H, Haverhals T, Van Marcke S, Ceuleers H, De Man JG, De Winter BY, Lamote K, De Schepper HU. Volatile organic compound profiling as a potential biomarker in irritable bowel syndrome: A feasibility study. Front Med (Lausanne). 2022 Aug 4;9:960000. doi: 10.3389/fmed.2022.960000. PMID: 35991639; PMCID: PMC9388331.