Gut-brain Axis Dysfunction Underlies FODMAP-induced Symptom Generation in Irritable Bowel Syndrome

Jie Wu; Imke Masuy; Jessica R Biesiekierski; Heather E Fitzke; Chinar Parikh; Laurel Schofield; Hafsa Shaikh; Anisha Bhagwanani; Qasim Aziz; Stuart A Taylor; Jan Tack; Lukas Van Oudenhove

Disclosures

Aliment Pharmacol Ther. 2022;55(6):670-682.

Abstract and Introduction

Abstract

Background: FODMAPs produce similar small bowel water and colonic gas in patients with irritable bowel syndrome (IBS) and healthy controls (HCs), despite IBS patients reporting increased gastrointestinal (GI) symptoms.

Aim: To unravel the mechanisms underlying FODMAP-induced symptom reporting, we investigated gut and brain responses to fructan administration in IBS patients and HC.

Methods: This randomised, double-blind, cross-over study consisted of three visits where fructans (40 g/500 mL saline), glucose (40 g/500 mL saline) or saline (500 mL) were infused intragastrically during 1 h MR brain scanning; abdominal MRI was performed before, 1 h, and 2 h post-infusion. Symptoms were rated using validated scales.

Results: In IBS (n = 13), fructans induced more cramps, pain, flatulence and nausea compared to glucose (P = 0.03, 0.001, 0.009 and <0.001 respectively), contrary to HC (n = 13) (all P > 0.14), with between-group differences for cramps and nausea (P = 0.004 and 0.023). Fructans increased small bowel motility and ascending colonic gas and volume equally in IBS and HC (between-group P > 0.25). The difference in colonic gas between fructans and saline covaried with differences in bloating and cramps in IBS (P = 0.008 and 0.035 respectively). Pain-related brain regions responded differentially to fructans in IBS compared to HC, including the cerebellum, supramarginal gyrus, anterior and midcingulate cortex, insula and thalamus (p_{FWE-corrected} < 0.05); these brain responses covaried with symptom responses in IBS.

Conclusions: Fructans increase small bowel motility and colon gas and volume similarly in IBS patients and HC. Increased symptom responses to fructans in IBS covary with altered brain responses in pain-related regions, indicating that gut-brain axis dysregulation may drive FODMAP-induced symptom generation in IBS.

Introduction

Irritable bowel syndrome (IBS) is a prevalent disorder of gut-brain interaction (DGBI) with a high personal and socio-economic burden;^[1] treatment is challenging due to variability of symptoms and pathophysiology. Diet is increasingly considered as treatment,^[2] specifically a diet low in fermentable oligo-, di- and monosaccharides and polyols (FODMAPs) has shown to be an effective strategy to reduce IBS symptoms.^[3] FODMAPs are poorly absorbed short-chain carbohydrates including fructose (in excess of glucose), lactose, polyols, fructans and galacto-oligosaccharides. They are found in a wide variety of foods, and may trigger lower gastrointestinal (GI) symptoms by inducing luminal distention through their osmotic effects in the small intestine and via bacterial fermentation in the colon, resulting in increased gas production.^[4]

Recently, a magnetic resonance imaging (MRI) study demonstrated that increases in intestinal water and colonic gas after fructose and inulin were similar in IBS patients and healthy controls (HCs), despite higher GI symptom scores in the former.^[5] Hence, increased sensitivity to normal FODMAP-induced gas production and/or osmotic activity, rather than excessive gas production and water content, may contribute to FODMAP-induced symptoms in IBS. We demonstrated that IBS patients reported stronger increases in flatulence and cramps compared to HCs as early as 30 minutes after blinded intragastric fructan administration vs glucose. This suggests a potential role of the proximal GI tract in symptom generation in IBS, in addition to colonic hypersensitivity.^[6] However, caecal fermentation cannot be ruled out given nutrient delivery was without any nutrient meal and therefore the fructans may have transited the small bowel early. Moreover, together with increased FODMAP-induced non-GI (including psychological) symptoms in our mechanistic study^[6] and clinical trials,^[7,8] these findings suggest a role for aberrant central processing of visceral afferent signals in FODMAP-induced GI symptom generation in IBS.

The involvement of the brain-gut axis in IBS is increasingly being recognised and supported by research.^[9] It has been shown that the central processing of viscerosensory information in IBS patients differs from HC, with lowered perception thresholds to various stimuli in different parts of the GI tract^[10,11] accompanied by increased engagement of brain regions associated with emotional arousal and endogenous pain modulation in IBS compared to HC.^[12]

We aimed to investigate brain and gut responses to blinded intragastric administration of one specific FODMAP, fructans, vs glucose (positive control) and saline (negative control), and their association with symptom responses. Specifically, we compared activity in pain-responsive brain regions between IBS patients and HC, as well as small bowel motility, and colon gas and volume. We specifically focused on the ascending colon, as its impaired ability to accommodate post-prandial flow has been observed in IBS.^[13] Finally, we assessed the associations between symptom responses and these different gut-brain axis mechanisms. Based on our previous study^[6] as well as the abovementioned study,^[5] we hypothesised that IBS patients compared to HC would show increased symptom responses to fructans compared to both glucose and saline, as well as increased brain responses. Furthermore, we hypothesised gut responses (small bowel motility and colon gas and volume quantified using MRI) to fructans to be similar in IBS patients and HC.

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Abstract and Introduction
Materials and Methods
Results
Discussion
References

Table 1. Demographical data of the study population
	HC (n = 13)	IBS (n = 13)	P value
Age years, mean (range)	31 (20–53)	28 (20–41)	0.42
Height cm, mean ± SD	167 ± 7	170 ± 6	0.33
Weight kg, mean ± SD	62.46 ± 7.3	69.12 ± 13.6	0.13
BMI kg/m², mean ± SD	22.31 ± 1.74	23.94 ± 4.23	0.20
PHQ12^a Mean ± SD	1.74 ± 1.01	9.18 ± 2.82	<0.001
PHQ9^b Mean ± SD	0.46 ± 0.88	4.38 ± 3.04	<0.001
GAD7^c Mean ± SD	0.08 ± 0.28	4.00 ± 2.86	<0.001

^aSomatic symptom severity subscale: 0–3 minimal, 4–7 low, 8–12 medium, 13–24 high.
^bDepression subscale: 0–4 none, 5–9 mild, 10–14 moderate, 15–19 moderately severe, 20–27 severe.
^cGeneralised anxiety subscale: 0–4 none, 5–9 mild, 10–14 moderate, >15 severe.

Table 2. Results of within-group planned contrast analyses
	P value
	Bloating	Fullness	Nausea	Cramps	Pain	Flatulence	Small bowel motility	Δ AC gas	Δ AC volume
HC
Fructans vs glucose	0.96	1.00	1.00	0.48	0.14	0.74	0.006	0.002	<0.001
Fructans vs saline	0.98	1.00	0.18	0.48	0.69	0.74	0.09	<0.001	<0.001
IBS
Fructans vs glucose	0.11	1.00	<0.001	0.03	0.001	0.009	<0.001	0.002	<0.001
Fructans vs saline	0.57	1.00	1.00	<0.001	0.08	0.24	0.006	0.002	0.001

Note: Significant P values are bold. All P values adjusted by stepdown Bonferroni correction for multiple comparisons.
Abbreviations: AC, Ascending Colon; HC, Healthy Control; IBS, Irritable Bowel Syndrome; Δ, change from baseline.

Table 3. Brain regions in which responses to fructans vs glucose and saline differ significantly over time between IBS patients and healthy controls
Region	Subregion	Side	Peak coordinates			F-value	Cluster volume	F-values within groups		Direction of response
Region	Subregion	Side	X	Y	Z	F-value	Cluster volume	HC	IBS	HC	IBS
Fructans vs glucose
Cerebellum	Crus 2	left	−44	−60	−48	8.19	24	3.61	4.84	↑	↓
Cerebellum	Vermis 3	right	6	−42	−16	6.27	41	7.09	/	↑	=
Supramarginal gyrus		left	−66	−36	30	7.38	75	3.77	3.77	↑	↓
Supramarginal gyrus		right	66	−20	20	5.70	48	2.31	3.55	↓	↑
Postcentral gyrus		left	−48	−24	26	9.45	206	2.46	7.92	↓	↑
		right	30	−30	60	6.35	82	2.43	4.05	↓	ns
		right	48	−20	32	4.04	43	/	4.06	=	↑
Cingulate cortex	Anterior	right	2	32	18	9.09	179	6.30	3.14	↑	↓
	Anterior	right	4	30	−4	6.74	27	1.77	5.60	↑	↓
	Middle	right	2	−14	40	5.58	116	7.27	/	↑	↓
Insula	Middle	left	−38	−2	−10	8.49	209	4.20	4.40	↑	↓
Insula	Anterior	right	38	16	−4	4.63	151	/	5.48	=	↑
Rolandic operculum		left	−42	−22	24	6.37	206	3.11	3.35	↓	↑
Putamen		right	22	14	2	7.28	51	7.17	1.35	↑	↓
Thalamus		left	−10	−14	14	7.06	318	2.69	4.98	↑	↓
Thalamus		right	6	−4	10	5.57	57	/	6.94	↑	↓
Fructans vs saline
Cerebellum	Crus 2	left	−44	−60	−48	5.03	318	2.09	3.19	↑	↓
Cerebellum	Cerebellum 9	right	8	−60	−42	19.48	24	13.35	6.87	↓	↑
Supramarginal gyrus		left	−66	−36	30	14.04	91	11.61	4.02	↑	↓
Supramarginal gyrus		right	52	−24	30	4.25	279	/	5.80	=	↑
Temporal gyrus	Superior	right	52	−20	12	5.22	279	1.71	3.79	↓	↑
Frontal gyrus	Superior	left	−22	46	24	4.40	51	/	4.22	=	↓
Frontal gyrus	Middle	right	42	48	8	3.22	22	/	4.64	=	↑
Cingulate cortex	Anterior	left	−12	8	34	3.48	38	3.45	/	↑	=
	Anterior	right	6	16	26	6.22	46	4.21	2.37	↑	↓
	Middle	left	0	−2	30	4.24	48	/	6.73	=	↓
Insula	Anterior	left	−32	24	4	6.73	137	4.20	3.05	↑	↓
	Anterior	right	36	10	6	3.57	58	/	3.61	↓	↑
	Middle	left	−36	−4	−10	4.88	83	1.35	3.92	↑	↓
	Middle	right	40	4	−8	3.31	43	4.26	/	↑	↑
Rolandic operculum		right	46	−14	10	3.79	279	/	2.31	↓	↑

Higher, lower or equal brain responses in fructans compared to glucose, fructans compared to saline and glucose compared to saline are indicated with ↑, ↓ and = respectively. No response is indicated by 'ns'.
Voxel-level threshold p_FWE-corrected < 0.05, cluster extent threshold k ≥ 20.
IBS, irritable bowel syndrome; HC, Healthy Control; FWE, family-wise error.