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

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.