Introduction

The pathophysiological mechanism involved in irritable bowel syndrome (IBS) is thought to be multifactorial, involving the gut-brain axis and the immune system. Despite this complexity, dietary restriction of fermentable oligo-, dis-, mono- saccharides, and polyols (FODMAPs) has become the first line of treatment, improving symptoms in up to 80% of patients (1). FODMAPs are poorly absorbed in the small intestine and serve as a substrate for the colonic microbiota, which has been proposed as a key mediator of FODMAP tolerance and symptom development. Considering that both the gut microbiota and the (in)tolerance to individual FODMAPs are highly personalised (2), there is a growing need to understand the host-microbiota interactions underlying individual responses to FODMAP restriction and intake. This personalised interplay may be key to more targeted dietary interventions for IBS.

Aims & Methods

We aimed to disentangle the role of the gut microbiota in FODMAP tolerance by exploring microbial dynamics upon restriction and reintroducing individual FODMAPs. To this end, we performed 16S rRNA gene sequencing of over 1,700 faecal samples from 463 IBS patients participating in two clinical trials: a) The DOMINO trial (3), where primary-care patients underwent a FODMAP-lowering diet and b) A cohort of 117 tertiary-care patients underwent a strict FODMAP-restriction followed by a blinded re-introduction of 6 FODMAPs powders (2). Response to the diet was defined as a reduction of at least 50 points on the IBS symptom severity scale. Linear and logistic mixed models were used to assess the relation between the microbiome, response to dietary intervention, host genetics and 32 blood and faecal parameters.

Results

Participants with dysbiotic microbiota at baseline were shown to be less likely to respond to the dietary restriction (p-value=0.01). These participants also showed higher levels of fecal calprotectin, secretory IgA and eosinophil-derived neurotoxin, suggesting immune activation in this subgroup of IBS patients (p-value<0.05). In both cohorts, limiting FODMAP intake was associated with decreased Bifidobacterium abundance (FDR<0.01). Moreover, a dose-dependent effect was observed as depletion was less severe in the FODMAP-lowering DOMINO diet. This effect was independent of response and IBS subtype. Furthermore, total bacterial biomass did not change during the restriction or the reintroduction period. However, we found 25 significant associations between individual FODMAPs and gut bacteria. The reintroduction of galacto-oligosaccharides and fructans restored the levels of Bifidobacterium, while polyols increased the abundance of Anaerostipes, regardless of participants’ tolerance (FDR<0.05). In addition, we observed distinct dynamics in the gut microbiota associated with the tolerance of specific FODMAPs, although they did not reach significance after multiple testing corrections at the current sample size. For example, participants intolerant to sorbitol showed an increase in Alistipes upon exposure to this compound (p-value<0.05, FDR>0.05).

Conclusion

Our results suggest that microbiota composition at baseline influences the clinical response to FODMAP restriction. A low-FODMAP diet does not induce drastic changes in the microbiome composition, although we confirmed the negative impact of dietary restriction on the abundance of Bifidobacterium. However, the less restrictive DOMINO diet results in a milder depletion, suggesting that moderate FODMAP reduction may better preserve beneficial microbiota while still offering symptom relief. Finally, we found evidence for a link between microbial dynamics and FODMAP tolerance, although this needs to be confirmed in larger cohorts.

References

(1) Staudacher HM, Whelan K The low FODMAP diet: recent advances in understanding its mechanisms and efficacy in IBS Gut 2017;66:1517-1527.
(2) Van den Houte K, Colomier E, Routhiaux K, Mariën Z, Schol J, Van den Bergh J, Vanderstappen J, Pauwels N, Joos A, Arts J, Caenepeel P, De Clerck F, Matthys C, Meulemans A, Jones M, Vanuytsel T, Carbone F, Tack J. Efficacy and Findings of a Blinded Randomized Reintroduction Phase for the Low FODMAP Diet in Irritable Bowel Syndrome. Gastroenterology. 2024
(3) Carbone F, Van den Houte K, Besard L DOMINO Study Collaborators, et al Diet or medication in primary care patients with IBS: the DOMINO study - a randomised trial supported by the Belgian Health Care Knowledge Centre (KCE Trials Programme) and the Rome Foundation Research Institute Gut 2022;71:2226-2232.

Disclosure

JT has given Scientific advice to AlfaWassermann, Allergan, Christian Hansen, Danone, Grünenthal, Ironwood, Janssen, Kiowa Kirin, Menarini, Mylan, Neutec, Novartis, Noventure, Nutricia, Shionogi, Shire, Takeda, Theravance, Tramedico, Truvion, Tsumura, Zealand and Zeria pharmaceuticals, has received research support from Shire, Sofar and Tsumura, and has served on the Speaker bureau for Abbott, Allergan, AstraZeneca, Janssen, Kyowa Kirin, Menarini, Mylan, Novartis, Shire, Takeda, Truvion and Zeria. Funding was provided by a Methusalem grant from Leuven University to JT This study was supported by a research grant from the Belgian Health Care Knowledge Centre (KCE).

Introduction

Irritable Bowel Syndrome (IBS) is a prevalent and chronic gastrointestinal disorder that affects approximately 85 million Europeans. It predominantly impacts women and significantly impairs quality of life, presenting with recurrent abdominal pain and altered bowel habits in the absence of identifiable structural abnormalities. Beyond its gastrointestinal symptoms, IBS frequently co-occurs with mental and somatic conditions such as anxiety, depression, fibromyalgia (32.5%), and chronic fatigue syndrome (14%). Up to 60% of IBS patients experience mental comorbidities, highlighting the complex interplay between gut and brain—often referred to as dysregulation of the gut–brain axis. This dysregulation manifests in altered intestinal motility, increased gut permeability, visceral hypersensitivity, and significant shifts in gut microbiota composition.

Aims & Methods

We present the DISCOVERIE project (Development, dIagnostic and prevention of gender-related Somatic and mental COmorbitiEs in iRritable bowel syndrome In Europe), an international, multi-centre initiative aimed at characterizing IBS and its associated comorbidities, with a particular focus on sex- and gender-related differences. To this end, we generated a comprehensive multi-omics dataset from 743 individuals, including shotgun quantitative microbiome profiling and untargeted metabolomics. These molecular data were complemented by in-depth clinical phenotyping, capturing information on anxiety, depression, fibromyalgia, and chronic fatigue syndrome. Particular attention was given to age, sex/gender, lifestyle factors, and systemic inflammatory markers. Multivariate statistical models were applied, correcting for common microbiome confounders, to analyze the multi-omics layers and identify microbiome-related signatures and mechanistic links across IBS and its comorbid subgroups.

Results

Our microbiome analysis revealed that IBS subjects exhibit features of a dysbiotic bacterial community, characterized by an increased prevalence of the Bacteroides 2 enterotype (17–26% in IBS participants across comorbid groups vs. 17% in the general population and only 2% in the healthy control group; chi-squared test, FDR < 0.05), a reduced butyrate synthesis capacity, and increased levels of opportunistic taxa compared to non-IBS controls.
Interestingly, IBS individuals—regardless of comorbidities—showed enrichment of bacterial metabolic modules involved in the degradation of amino acids that serve as precursors for neurotransmitters. Specifically, we observed an increase in pathways associated with GABA degradation and a decrease in modules responsible for glutamate biosynthesis. This dysregulation of gut neurotransmitter metabolism may contribute to hallmark IBS symptoms.
Strikingly, pro-inflammatory IL-6 levels were strongly associated with specific bacterial genus (FDR < 0.05), as well as with a metabolic module responsible for the degradation of gamma-hydroxybutyric acid (GHB), a neurotransmitter and central nervous system depressant, suggesting a potential mechanistic link between low-grade inflammation and depressive symptoms in IBS.

Conclusion

The results from this large-scale, multi-center international study reveal a dysregulation of gut neurotransmitter metabolism that may contribute to IBS symptoms and associated comorbidities. These findings underscore a potential link between elevated IL-6 levels, microbial metabolism, and the gut–brain axis, offering new insights into the complex interplay between microbiota composition, host physiology, and IBS-related comorbidities.