Introduction

The pathophysiological mechanisms of irritable bowel syndrome (IBS) are complex and incompletely known. Studies investigating the role of colonic volumes and their relation with symptoms and measurements of gut physiology in IBS are sparse.

Aims & Methods

The aim of this study was to explore the associations between colonic volume and symptoms and measurements of gut physiology in IBS and healthy individuals. We included 18 IBS patients (4 IBS-diarrhea, 5 IBS-constipation, 9 IBS-mixed or IBS-unspecified) and 19 healthy individuals. Total and segmental colonic volumes were determined by magnetic resonance imaging (MRI). The GSRS-IBS was used to measure gastrointestinal symptoms and a stool diary (Bristol Stool Form Scale) was completed 14 days before the MRI. Oro-anal transit time (radiopaque markers) and rectal sensitivity (rectal barostat, including pressure thresholds for first perception, defecation, and discomfort) were measured.

Results

The total colonic volume did not differ between IBS patients and healthy individuals (736 ml [528-903] vs 597 [498-939] (median [IQR]); p=0.44). In the IBS group, there were trends towards inverse associations between total colonic volume and the perceived severity of diarrhea (r_s= -0.43; p=0.08), as well as the volume of the descending colon and stool frequency (r_s= -0.48; p=0.07). Other GI symptoms and stool consistency were not associated with colonic volumes. When investigating the physiological parameters in IBS, the total colonic volume was positively associated with oro-anal transit time (r_s=0.54; p=0.02) and negatively associated with rectal pressure thresholds for sensations (first perception: r_s= -0.51; p=0.04, defecation: r_s= -0.44; p=0.09), Table 1. A similar pattern was seen when investigating individual colonic segments, with tendencies towards positive associations between segmental colonic volumes and oro-anal transit time, and negative associations with rectal sensory thresholds. The associations in healthy individuals between colonic volumes and oro-anal transit time and rectal sensitivity, respectively, were overall weaker (all p>0.05).

Conclusion

In this pilot study, we have shown that larger colonic volumes, measured with MRI, seem to be associated with slower oro-anal transit and rectal hypersensitivity in IBS. This suggests a potential role for measuring colonic volumes in IBS pathophysiology studies, but larger studies are needed to better appreciate subtype differences and their relevance for symptoms.

Introduction

Irritable bowel syndrome (IBS) is subtyped based on bowel habits. However, an alternative based on combined gastrointestinal (GI), non-GI somatic and psychological symptom profiles has been proposed ^1,2.

Aims & Methods

This study aimed to validate the novel more comprehensive way to subgroup IBS and investigate differences in symptoms and gut physiology in these groups. In total, 760 IBS patients (Rome III and IV) from six study cohorts were included. Subgroups were based on Gaussian mixture model analysis using 13 single-item GI symptom scores (GSRS-IBS), stool frequency and consistency (Bristol Stool Form Scale), 11 single-item non-GI somatic symptom scores (PHQ-12, excluding menstruation problems), and anxiety and depression scores (HADS). Differences between subgroups were investigated for fatigue (MFI), GI-specific anxiety (VSI), IBS-specific quality of life (IBS-QOL), and measurements of gut physiology, including oro-anal transit time (OATT) assessed by radiopaque markers, visceral sensitivity assessed by a rectal barostat procedure and lactulose nutrient challenge test (LNCT), and breath hydrogen and methane production during LNCT as markers for microbial fermentation.

Results

Six subgroups based on GI and non-GI symptom profiles were identified: diarrhea with low comorbidities (n=67), constipation with low comorbidities (n=120), overall mild severity (n=166), diarrhea with high comorbidities (n=231), constipation with high comorbidities (n=89), and mixed GI symptoms with high comorbidities (n=87). The groups with high comorbidities had higher levels of fatigue and GI-specific anxiety, and lower QOL compared to the low comorbidities groups, Table 1. OATT was longer in constipation with low comorbidities vs diarrhea with low comorbidities (1.7 [1.0-2.7] vs 0.9 [0.5-1.3] days (median [IQR]), p<0.01), but there was no difference in OATT comparing constipation with high comorbidities vs. diarrhea with high comorbidities. Visceral sensitivity and postprandial hydrogen and methane production did not differ between groups, but with a tendency of methane production to be highest in constipation with high comorbidities.

Conclusion

We have confirmed previously reported IBS subgroups based on combinations of GI and non-GI symptom profiles. Demonstrated associations with fatigue, GI-specific anxiety, and oro-anal transit time, suggest different pathophysiological mechanisms in these novel subgroups. Our results suggest that the presence or absence of non-GI symptoms could be important when planning IBS treatment strategies.

References

1. Black CJ, Ng CE, Goodoory VC, Ford AC. Novel Symptom Subgroups in Individuals With Irritable Bowel Syndrome Predict Disease Impact and Burden. Clin Gastroenterol Hepatol. 2024;22(2):386-396.e310.
2. Polster A, Van Oudenhove L, Jones M, Öhman L, Törnblom H, Simrén M. Mixture model analysis identifies irritable bowel syndrome subgroups characterised by specific profiles of gastrointestinal, extraintestinal somatic and psychological symptoms. Aliment Pharmacol Ther. 2017;46(5):529-539.

Introduction

Food is often reported as a trigger for symptoms in patients with irritable bowel syndrome (IBS). One of the proposed pathophysiological mechanisms is a local immune response to food antigens, triggered by a preceding infection¹.

Aims & Methods

This study aimed to investigate rectal mucosal reactions to food in patients with IBS. Therefore, patients with IBS and food-related symptoms were included. Allergies to the food items that were tested during the colonoscopic antigen provocation (COLAP) were excluded by an allergologist. The COLAP was started in the absence of macroscopic abnormalities during sigmoidoscopy. A 200 μL solution of each food antigen (wheat, gluten, soy, and milk; administered in a randomized order and blinded), a negative control (NaCl 0.9%), and a positive control (histamine) were injected in the rectal mucosa, with a positive reaction defined as mucosal edema 12 minutes after injection and judged based on a previously used semiquantitative scale ². The reaction was independently judged by two endoscopists, resulting in a positive or negative reaction when they agreed and doubtful when they did not.

Results

Data from ten patients were available for this interim analysis. Nine were female, with a median age of 45 [range 24-58] years, and a median IBS symptom severity score of 356 [range 197-416], i.e. in the moderate to severe range. Six patients had predominant constipation, one predominant diarrhea, and three mixed bowel habits. COLAP was positive in seven patients, with a positive reaction for one food antigen in three patients and for two food antigens in four patients. In the other three patients, the test was only doubtful for one of the food antigens (n=2), or negative for all (n=1). A positive reaction to gluten was observed in five patients, to soy in three, to wheat in two, and to milk in one (Table). The reaction to histamine was positive in eight patients, with no positive reaction after injection of the negative control in all.

Conclusion

A local intestinal reaction to food antigens was seen in a subset of patients with IBS. Further research will focus on underlying pathophysiological mechanisms and clinical relevance of these findings.

References

1. Aguilera-Lizarraga J, Florens MV, Viola MF, Jain P, Decraecker L, Appeltans I, et al. Local immune response to food antigens drives meal-induced abdominal pain. Nature. 2021;590(7844):151-6.
2. Bischoff SC, Mayer J, Wedemeyer J, Meier PN, Zeck-Kapp G, Wedi B, et al. Colonoscopic allergen provocation (COLAP): a new diagnostic approach for gastrointestinal food allergy. Gut. 1997;40(6):745-53.

Introduction

The pathophysiology of irritable bowel syndrome (IBS) includes alterations in gut-brain communication, gastrointestinal (GI) physiology and gut microbiota. The essential amino acid tryptophan (Trp) is metabolized in the gut to different classes of metabolites, including serotonin, kynurenine and indoles which have been implicated in the modulation of intestinal motility, immune function and pain sensation. Balanced Trp metabolism requires a complex host-microbiota interplay, which might be dysregulated in IBS. However, Trp metabolism is incompletely understood, and studies are needed to clarify its link with IBS and gastrointestinal physiology.

Aims & Methods

Aim: To profile fecal and circulating levels of Trp metabolites in IBS and explore relationships with oro-anal transit time (OATT) and symptoms.
Methods: We combined targeted and untargeted metabolomics to determine fecal and serum Trp metabolites in a cohort of healthy controls (HC; n=29) and IBS patients with predominant constipation (IBS-C; n=59), diarrhea (IBS-D; n=53) or mixed bowel habits (IBS-M; n=55). OATT was measured using radiopaque markers and participants completed questionnaires to assess GI symptom severity (GSRS-IBS), stool frequency and consistency (Bristol Stool Form Scale), non-GI somatic symptoms (PHQ-12), and symptoms of anxiety and depression (HAD). For correlation analyses, Spearman’s rho (r) was used.

Results

Levels of Trp did not differ significantly between HC and IBS subtypes. The Trp metabolite kynurenine, the microbially produced indole propionic acid (IPA) and the serotonin degradation metabolite 5-hydroxyindoleacetic acid (5-HIAA) were lower in IBS-C compared to HC and IBS-D. There were inverse correlations between OATT and both fecal (p<0.0001; r= -0.40) and circulating (p= 0.021; r= -0.17) Trp levels. Similarly, stool kynurenine and indoles were negatively correlated with OATT. Fecal but not circulating serotonin was positively correlated with OATT (p= 0.041; r= 0.14) while 5-HIAA showed a negative correlation (p<0.0001; r= -0.29), suggesting potential serotonin accumulation due to deficient degradation. In IBS patients, fecal Trp, 5-HIAA, IPA and kynurenine, correlated negatively with the proportion of hard stools (BSF1-2) and positively with the proportion of loose stools (BSF6-7). Finally, serotonin catabolites and IPA were negatively correlated with the severity of constipation and positively correlated with diarrhea. No statistically significant correlations were noted between these metabolites and abdominal pain, abdominal distension, early satiety, or postprandial fullness while bloating was positively correlated with circulating IPA (p= 0.018; r= 0.18). Additionally, we report a negative correlation between circulating serotonin with symptoms of depression and anxiety, which was not found for fecal serotonin. No significant correlations were noted with non-GI somatic symptoms.

Conclusion

Our results suggest that slower transit time may favour increased intestinal catabolism of Trp, directly or indirectly through its effects on the gut environment and the microbiota. In addition, we report an association of fecal Trp metabolites with bowel habits, in line with their relations to OATT. On the other hand, these same fecal metabolites did not correlate with other GI (i.e., pain and bloating) or non- GI symptoms. This study underscores the link between intestinal transit time and the regulation of host and microbial metabolites important for intestinal homeostasis.

Introduction

While the mechanistic background to functional bowel disorders, including irritable bowel syndrome (IBS) is insufficiently understood, there is growing evidence that cytokine imbalance and inflammation may contribute to IBS pathogenesis.

Aims & Methods

We undertook a comprehensive investigation of serum cytokine profiles in individuals with functional bowel disorders (IBS n=164, functional constipation n=6, functional diarrhea n=3) and healthy controls (n=31), mapping their associations with clinical symptoms (GSRS-IBS, HAD), the gut microbiome (whole-metagenome sequencing of fecal samples), colonic mucosal responses (bulk RNA sequencing of sigmoid biopsies), intestinal physiological parameters, and the serum metabolome (liquid chromatography-mass spectrometry). Serum levels of IFN-γ, IL-1β, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-α, IL-17A and CXCL10 were measured with Meso Scale Discovery (MSD) multiplex immunoassay kits.

Results

While cytokine levels did not differ significantly between persons with functional bowel disorders and healthy individuals, CXCL10 was reduced in participants with predominant diarrhea (IBS-D and functional diarrhea, p=0.01), whereas IL-12p70 was increased in predominant constipation (IBS-C and functional constipation, p=0.03), compared to healthy controls. Within both the full study cohort and participants with functional bowel disorders, IL-12p70 levels correlated with oroanal transit time (rho 0.20 and 0.19, p=0.007 and 0.01, respectively), and were inversely associated with fecal short-chain fatty acids (p=0.006, 0.01 and 0.03 for acetate, propionate and butyrate, respectively), as well as with the abundance of several butyrate-producing species. By contrast, IL-12p70 levels were positively associated with mucus-resident species (e.g., from the Akkermansia and Victivallis genera), with metabolites potentially derived from the degradation of mucosal carbohydrates, and with a distinct T helper 1 type response in colonic biopsies. Moreover, IL-12p70 levels correlated with anxiety (rho 0.17, p=0.03) in participants with functional bowel disorders.

Conclusion

Systemic cytokine profiles did not discriminate persons with functional bowel disorders from healthy individuals, but participants with predominant constipation and diarrhea exhibited distinct cytokine profiles. Alteration of systemic cytokines, notably IL-12p70, may result from disrupted mucosal barrier integrity and host-microbe homeostasis, and contribute to extraintestinal symptoms in a subset of individuals with functional bowel disorders.

Introduction

Patients with irritable bowel syndrome (IBS) frequently report bothersome abdominal bloating and/or distention.

Aims & Methods

We aimed to investigate the association of these symptoms to overall symptom characteristics and gut sensorimotor function.

We included patients with IBS (Rome II-IV criteria) from studies investigating the association between IBS symptoms and pathophysiologic mechanisms. Validated questionnaires were used to evaluate gastrointestinal (GI) (GSRS-IBS and IBS-SSS), extraintestinal (PHQ-12), and psychological symptoms (HAD). Significant symptoms of abdominal bloating and/or distention were defined as a GSRS-IBS score ≥4 (at least moderate) for any of these two symptoms. Abdominal bloating or distention as the most bothersome symptom was defined in those scoring GSRS-IBS questions on bloating or distention higher than all other GI symptoms. Visceral sensory function was measured by a rectal barostat test and oro-anal transit time (OATT) was measured by use of radiopaque markers. Local reference values were used to define visceral hypersensitivity or abnormal OATT.

Results

We included 1100 patients with IBS; median age 35 (IQR 27-47) years and 794 (72%) females. IBS subtype distribution was IBS-C 30%, IBS-D 38%, and IBS-nonCnonD 32%.
Questions on abdominal bloating, abdominal distention, and passing gas had the highest median score, 5 (moderately severe), of all GSRS-IBS items (IQR 4-6 for bloating and passing gas, IQR 3-6 for distention). Significant abdominal bloating and/or distention was reported by 91.6% and 81.2% respectively, with a female predominance (74% and 78% respectively) and were equally distributed across IBS-subtypes (p=0.09). Having significant symptoms of abdominal bloating or distention was associated with more extraintestinal symptoms (PHQ-12) and more severe IBS symptoms (IBS-SSS) (p<0.001 for both). In addition, significant abdominal bloating was also associated with increased psychological symptoms (HAD), while significant distention was not (p<0.05 and p=0,22 respectively). There was no association between having significant abdominal bloating/distention and abnormal OATT or visceral hypersensitivity (Table 1).
Abdominal distention was more common as the most bothersome symptom compared to abdominal bloating (13% vs. 5%), both with a female predominance (76% and 79% respectively). The severity of IBS, extraintestinal, and psychological symptoms were similar in patients with and without abdominal bloating or distention as the most bothersome GI symptom (p=0.09, 0.45, and 0.76 for bloating and p=0.21, 0.13, and 0.69 for distention). However, abdominal bloating as the most bothersome GI symptom was associated with delayed OATT and visceral hypersensitivity. No such difference was noted comparing those with and without abdominal distention as the most bothersome GI symptom. Table 1.

Conclusion

The presence of significant bloating or distention in IBS is common and associated to more severe IBS as well as increased symptom burden, regardless of it being the most bothersome symptom or not, while the presence of bothersome abdominal bloating is associated to a deviant gut sensorimotor function. Our results suggest that bloating and distention play an important role in both disease burden and in further understanding pathophysiological mechanisms in IBS.

Disclosure

No conflicts of interest to declare

Introduction

Although urgency and sensation of incomplete evacuation are common symptoms in IBS, their relationship with other symptoms and gut physiology is still unclear.

Aims & Methods

We included IBS patients (Rome II-IV criteria) who participated in pathophysiology and treatment studies. The severity of urgency and sensation of incomplete emptying was graded using individual items of the Gastrointestinal (GI) Symptom Rating Scale-IBS (GSRS-IBS) and dichotomized into low (no to mild symptoms) and high symptom severity (moderate to severe symptoms). We investigated the association between these symptoms and the severity of other GI symptoms (GSRS-IBS), psychological distress (HADS), oro-anal transit time (OATT; radiopaque markers), rectal sensitivity (balloon distensions), and overlapping disorders of gut-brain interactions (DGBI) diagnosed using ROME questionnaire.

Results

We included 1084 patients with IBS (74% females, mean age 38±13 years; 33% IBS-C, 31% IBS-D, 14% IBS-M, and 22% IBS-U). High severity of urgency (55%) and sensation of incomplete evacuation (67%) were both highly prevalent. Among IBS subtypes, high severity of urgency was most prevalent in IBS-D and IBS-M (67 and 68% respectively) and sensation of incomplete emptying in IBS-C and IBS-M (73 and 75%). High severity of urgency was associated with more severe GI symptoms overall, except for constipation and hard stools, where the opposite pattern was seen (Table 1). The largest effect sizes among the GI symptoms were seen for diarrhea and loose stools. In addition, IBS patients with high severity of urgency demonstrated faster transit, rectal hypersensitivity and more severe psychological distress. For sensation of incomplete evacuation, the opposite pattern compared with urgency was seen for diarrheal and constipation symptoms, and with the largest effect sizes for constipation and hard stools. The sensation of incomplete evacuation was associated with slower OATT and more severe psychological distress, but not with rectal sensitivity. With increasing number of overlapping DGBI, there was a gradual increase in the severity of urgency (η²=0.026; p=0.003) and sensation of incomplete evacuation (η²=0.043; p<0.001).
Table 1. Characteristics of IBS patients with high vs low severity of urgency and sensation of incomplete evacuation, respectively.

Conclusion

Urgency and sensation of incomplete evacuation are common in IBS and predominantly associated with bowel habits. These symptoms are associated with transit, rectal hypersensitivity, overlapping DGBI and psychological distress supporting the relevance of gut-brain interactions in the pathophysiology of IBS symptoms.