Faecal and Urine Metabolites, But Not Gut Microbiota, may Predict Response to Low FODMAP Diet in Irritable Bowel Syndrome

Bridgette Wilson; Tokuwa Kanno; Rachael Slater; Megan Rossi; Peter M. Irving; Miranda C. Lomer; Chris Probert; A. James Mason; Kevin Whelan

Disclosures

Aliment Pharmacol Ther. 2023;58(4):404-416.

Abstract and Introduction

Abstract

Background: The low FODMAP diet (LFD) leads to clinical response in 50%–80% of patients with irritable bowel syndrome (IBS). It is unclear why only some patients respond.

Aims: To determine if differences in baseline faecal microbiota or faecal and urine metabolite profiles may separate clinical responders to the diet from non-responders allowing predictive algorithms to be proposed.

Methods: We recruited adults fulfilling Rome III criteria for IBS to a blinded randomised controlled trial. Patients were randomised to sham diet with a placebo supplement (control) or LFD supplemented with either placebo (LFD) or 1.8 g/d B-galactooligosaccharide (LFD/B-GOS), for 4 weeks. Clinical response was defined as adequate symptom relief at 4 weeks after the intervention (global symptom question). Differences between responders and non-responders in faecal microbiota (FISH, 16S rRNA sequencing) and faecal (gas–liquid chromatography, gas-chromatography mass-spectrometry) and urine (^[1]H NMR) metabolites were analysed.

Results: At 4 weeks, clinical response differed across the 3groups with adequate symptom relief of 30% (7/23) in controls, 50% (11/22) in the LFD group and 67% (16/24) in the LFD/B-GOS group (p= 0.048). In the control and the LFD/B-GOS groups, microbiota and metabolites did not separate responders from non-responders. In the LFD group, higher baseline faecal propionate (sensitivity 91%, specificity 89%) and cyclohexanecarboxylic acid esters (sensitivity 80%, specificity 78%), and urine metabolite profile (

Abstract and Introduction
Methods
Results
Discussion
Conclusion
References

Table 1. Baseline demographics of responders and non-responders to sham dietary advice (control) low FODMAP dietary advice (LFD) or low FODMAP dietary advice plus B-GOS prebiotic (LFD/B-GOS).
	Control			Low FODMAP diet (LFD)			Low FODMAP plus B-GOS (LFD/B-GOS)
	Responders (n = 7)	Non-responders (n = 16)	p-value*	Responders (n = 11)	Non-responders (n = 11)	p-value*	Responders (n = 16)	Non-responders (n = 8)	p-value*
Female, n (%)	3 (43)	9 (56)	0.667	7 (63.6)	6 (54.5)	0.665	9 (56.3)	4 (25.0)	0.772
Age, years, mean (SD)	26.7 (4.8)	31.7 (10.9)	0.262	40 (11)	37 (8)	0.530	32 (8)	35 (8)	0.363
BMI, kg/m², mean (SD)	23.6 (1.9)	24.2 (4.7)	0.735	26.5 (3.8)	25.9 (4.9)	0.751	24 (4.5)	23.4 (3.4)	0.764
White British, n (%)	4 (57)	10 (63)	1.000	4 (36.4)	6 (54.5)	0.392	11 (68.8)	7 (43.8)	0.317
IBS-D, n (%)	5 (71)	10 (63)	1.000	7 (63.6)	8 (72.7)	0.647	10 (62.5)	5 (31.3)	1.000
Hypermobile, n (%)	4 (57)	5 (31)	0.363	2 (18.2)	3 (27.3)	0.611	4 (25.0)	0 (0.0)	0.121
Medication, n (%)	4 (57)	8 (50)	1.000	6 (54.5)	8 (72.7)	0.375	9 (56.3)	5 (31.3)	0.770
Analgesia	1 (14)	2 (12.5)	1.000	0 (0.0)	2 (18.2)	0.138	2 (12.5)	1 (6.3)	1.000
Anti-diarrhoea	0 (0)	1 (6)	1.000	0 (0.0)	2 (18.2)	0.138	1 (6.3)	2 (12.5)	0.190
Anti-spasmodic	0 (0)	1 (6)	1.000	0 (0.0)	1 (9.1)	0.306	2 (12.5)	1 (6.3)	1.000

*p-values are the result of t test for continuous data and χ ² test for categorical data.

Table 2. Baseline and end of trial (4-week) energy, nutrient and FODMAP intake compared between responders and non-responders to sham dietary advice (control) low FODMAP dietary advice (LFD) or low FODMAP dietary advice plus B-GOS prebiotic (LFD/B-GOS).
Intakes per day, mean (SD)	Control			Low FODMAP diet (LFD)			Low FODMAP plus B-GOS (LFD/B-GOS)
Intakes per day, mean (SD)	Responder (n = 7)	Non-responder (n = 14)	p-value^a	Responder (n = 11)	Non-responder (n = 10)	p-value^a	Responder (n = 16)	Non-responder (n = 5)	p-value^a
Baseline
Energy (kcal)	1849 (526)	1985 (578)	0.607	2041 (501)	1827 (467)	0.326	1997 (476)	2379 (579)	0.152
Total protein (g)	82.6 (22.4)	90.1 (27.7)	0.545	84.4 (26.0)	75.9 (19.8)	0.412	81.1 (29.0)	95.7 (46.0)	0.403
Fat (g)	77.2 (31.7)	78.3 (24.2)	0.928	82.5 (18.6)	72.9 (18.2)	0.244	83.4 (21.3)	94.3 (22.3)	0.335
Carbohydrate (g)	172.3 (43.7)	202.6 (75.9)	0.343	212.5 (66.9)	188.6 (55.1)	0.385	208.4 (60.3)	252.3 (54.7)	0.164
NSP englyst (g)	12.2 (6.3)	13.0 (4.3)	0.741	15.7 (5.7)	15.0 (6.3)	0.769	13.2 (4.3)	17.5 (6.4)	0.93
Fibre AOAC (g)	16.6 (8.3)	19.2 (6.1)	0.417	21.4 (7.2)	19.2 (7.7)	0.491	18.5 (5.3)	26.1 (10.0)	0.035
Total FODMAPs^b	15.30 (3.75)	17.84 (5.38)	0.271	16.80 (7.21)	17.14 (5.35)	0.903	24.06 (14.24)	20.40 (9.16)	0.599
Fructans (g/d)	0.24 (0.36)	0.37 (0.44)	0.527	0.23 (0.26)	0.20 (0.18)	0.784	0.18 (0.25)	0.48 (0.64)	0.131
Oligos (g/d)	0.62 (0.31)	0.63 (0.37)	0.971	0.68 (0.29)	0.54 (0.31)	0.288	0.48 (0.22)	0.93 (0.39)	0.004
Lactose (g/d)	0.66 (0.64)	0.85 (0.54)	0.491	0.67 (0.64)	1.20 (1.30)	0.247	2.87 (3.03)	0.74 (0.71)	0.141
Sorbitol (g/d)	6.73 (4.88)	7.22 (3.71)	0.801	7.14 (4.04)	6.01 (4.90)	0.569	5.44 (4.25)	7.17 (2.98)	0.412
Mannitol (g/d)	0.33 (0.24)	0.36 (0.41)	0.893	0.48 (0.41)	1.03 (1.60)	0.292	0.55 (0.68)	0.77 (0.80)	0.558
GOS (g/d)	2.66 (1.82)	2.58 (1.17)	0.899	2.55 (1.04)	2.03 (1.09)	0.273	2.51 (0.98)	3.31 (1.54)	0.182
Excess fructose (g/d)	4.00 (1.13)	5.84 (2.83)	0.118	5.04 (2.77)	6.15 (2.62)	0.358	12.02 (10.75)	7.02 (4.92)	0.332
End of trial
Energy (kcal)	1689 (678)	1703 (472)	0.957	1538 (455)	1696 (672)	0.53	1743 (572)	1629 (336)	0.679
Total protein (g)	72.5 (43.3)	81.9 (23.6)	0.522	71.9 (25.3)	73.9 (29.3)	0.872	75.0 (23.5)	81.8 (34.0)	0.618
Fat (g)	72.0 (45.5)	68.9 (17.7)	0.823	66.8 (30.1)	69.1 (35.8)	0.875	73.3 (28.5)	71.4 (21.5)	0.889
Carbohydrate (g)	153.2 (40.2)	159.0 (44.6)	0.777	142.2 (44.6)	162.0 (59.4)	0.395	174.3 (77.3)	133.2 (24.0)	0.263
NSP englyst (g)	12.3 (8.4)	11.9 (3.9)	0.885	10.2 (5.0)	12.5 (5.7)	0.326	11.1 (3.9)	9.9 (4.4)	0.582
Fibre AOAC (g)	16.9 (11.2)	16.9 (6.1)	0.987	16.9 (8.6)	18.1 (8.8)	0.75	17.9 (7.6)	15.8 (8.2)	0.589
Total FODMAPs^b	12.03 (5.83)	15.13 (6.89)	0.321	6.46 (6.17)	10.84 (7.95)	0.173	10.99 (12.07)	9.23 (4.21)	0.755
Fructans (g/d)	0.07 (0.08)	0.26 (0.26)	0.082	0.05 (0.13)	0.01 (0.03)	0.454	0.03 (0.08)	0.07 (0.16)	0.461
Oligos (g/d)	0.45 (0.27)	0.63 (0.30)	0.193	0.09 (0.09)	0.08 (0.12)	0.824	0.15 (0.22)	0.05 (0.04)	0.339
Lactose (g/d)	0.22 (0.13)	0.87 (0.78)	0.044	0.07 (0.12)	0.23 (0.48)	0.286	1.13 (2.30)	0.01 (0.02)	0.298
Sorbitol (g/d)	6.82 (4.41)	5.32 (4.27)	0.461	3.20 (5.07)	4.50 (5.21)	0.57	2.72 (2.89)	7.43 (3.69)	0.008
Mannitol (g/d)	0.30 (0.56)	0.35 (0.49)	0.822	0.06 (0.14)	0.07 (0.09)	0.849	0.11 (0.18)	0.03 (0.03)	0.321
GOS (g/d)	1.59 (0.72)	2.42 (0.73)	0.023	0.34 (0.26)	0.57 (0.57)	0.236	0.46 (0.35)	0.22 (0.07)	0.148
Excess fructose (g/d)	2.58 (2.14)	5.28 (4.72)	0.17	2.67 (2.12)	5.38 (5.31)	0.134	6.39 (8.37)	1.42 (1.42)	0.21

Abbreviations: AOAC, association of official analytical chemists; NSP, non-starch polysaccharides.
^a p-values compare responders to non-responders in each group using a t test, p is significant if <0.05.
^bTotal FODMAPs are calculated as the sum of individual carbohydrates including excess fructose (not total fructose).

Table 3. Faecal short-chain fatty acid (mg/100 g dry weight) at baseline and week 4 comparing responders and non-responders to sham dietary advice (control) low FODMAP dietary advice (LFD) or low FODMAP dietary advice plus B-GOS prebiotic (LFD/B-GOS).
Mean (SD) SCFA values (mg/100 g)	Control			Low FODMAP diet (LFD)			Low FODMAP plus B-GOS (LFD/B-GOS)
Mean (SD) SCFA values (mg/100 g)	Responder (n = 5)	Non-responder (n = 13)	p-value*	Responder (n = 11)	Non-responder (n = 9)	p-value*	Responder (n = 16)	Non-responder (n = 5)	p-value*
Baseline
Acetate	1341.4 (854.0)	1298.3 (683.0)	0.882	1868.5 (827.8)	1342.6 (1134.4)	0.053	1934.9 (2219.7)	1563.6 (1122.0)	0.804
Propionate	421.6 (242.0)	480.9 (323.0)	0.882	771.3 (743.6)	381.1 (359.7)	0.009	790.6 (1174.9)	418.2 (183.2)	0.741
Butyrate	365.5 (236.6)	396.8 (303.4)	0.961	578.7 (315.6)	520.6 (624.4)	0.184	663.8 (811.6)	458.9 (490.5)	0.215
Valerate	37.6 (12.6)	60.6 (37.5)	0.218	65.6 (35.7)	40.4 (21.7)	0.102	121.6 (223.8)	35.7 (23.0)	0.058
Isobutyrate	45.4 (14.8)	46.5 (16.6)	0.657	51.4 (23.1)	31.9 (14.0)	0.063	73.5 (52.6)	26.8 (12.1)	0.008
Isovalerate	54.6 (11.4)	56.1 (19.9)	0.805	58.3 (24.5)	46.1 (18.8)	0.239	104.9 (117.7)	35.2 (18.8)	0.010
Total SCFA	2266.1 (1302.6)	2339.2 (1250.0)	0.961	3393.8 (1731.0)	2362.7 (2085.6)	0.053	3689.3 (4559.1)	2538.4 (1719.8)	0.869
End of trial	Responder (n = 7)	Non-responder (n = 13)	p*	Responder (n = 11)	Non-responder (n = 10)	p*	Responder (n = 15)	Non-responder (n = 5)	p*
Acetate	1734.9 (963.3)	1593.0 (716.6)	0.823	1306.5 (865.4)	1408.0 (1063.1)	0.888	1364.2 (718.3)	1144.5 (733.7)	0.407
Propionate	484.0 (296.2)	634.1 (420.9)	0.551	418.5 (294.1)	428.2 (334.2)	1.000	444.5 (230.2)	353.3 (331.2)	0.106
Butyrate	715.8 (576.4)	542.6 (356.0)	0.654	399.0 (280.7)	435.1 (319.3)	0.622	419.4 (246.2)	240.0 (145.2)	0.106
Valerate	44.5 (21.8)	80.2 (38.8)	0.030	50.8 (34.3)	50.2 (32.1)	1.000	63.6 (44.8)	38.7 (27.4)	0.239
Isobutyrate	33.0 (8.4)	58.6 (22.3)	0.006	57.8 (29.8)	38.9 (17.0)	0.105	60.3 (27.9)	32.2 (24.0)	0.040
Isovalerate	43.0 (12.3)	65.7 (21.6)	0.011	67.1 (33.7)	52.7 (19.7)	0.573	71.2 (31.1)	38.0 (20.0)	0.032
Total SCFA	3055.1 (1681.1)	2974.3 (1391.7)	0.881	2299.6 (1498.4)	2413.1 (1664.3)	0.944	2423.3 (1208.8)	1846.6 (1237.2)	0.106

Abbreviations: B-GOS, β-galactooligosaccharide; LFD, low FODMAP diet.
*p is significant if <0.05. Kruskal-Wallis test was used for non-normally distributed data set.

Authors and Disclosures

Bridgette Wilson^1,2, Tokuwa Kanno³, Rachael Slater⁴, Megan Rossi¹, Peter M. Irving^5,6, Miranda C. Lomer^1,2, Chris Probert⁴, A. James Mason³ and Kevin Whelan¹

¹Department of Nutritional Sciences, King's College London, London, UK
²Department of Nutrition and Dietetics, Guys and St Thomas' NHS Foundation Trust, London, UK
³King's College London, Institute of Pharmaceutical Science, London, UK
⁴University of Liverpool, Institute of Systems, Molecular and Integrative Biology, Liverpool, UK
⁵Department of Gastroenterology, Guys and St Thomas' NHS Foundation Trust, London, UK
⁶School of Immunology and Microbial Sciences, King's College London, London, UK

Correspondence
Kevin Whelan, Department of Nutritional Sciences, King's College London, London, UK. Email: kevin.whelan@kcl.ac.uk

Author Contributions
Bridgette Wilson: Conceptualization (equal); data curation (lead); formal analysis (lead); funding acquisition (equal); investigation (lead); methodology (lead); project administration (lead); writing – original draft (lead). Tokuwa Kanno: Formal analysis (equal); writing – review and editing (supporting). Rachael Slater: Formal analysis (equal); writing – review and editing (supporting). Megan Rossi: Conceptualization (equal); methodology (supporting); writing – review and editing (supporting). Peter Irving: Conceptualization (equal); writing – review and editing (supporting). Miranda C E Lomer: Conceptualization (equal); writing – review and editing (supporting). Chris Probert: Formal analysis (supporting); writing – review and editing (supporting). A.James Mason: Formal analysis (supporting); writing – review and editing (supporting). Kevin Whelan: Conceptualization (equal); formal analysis (equal); funding acquisition (equal); methodology (equal); supervision (lead); visualization (equal); writing – review and editing (lead). All authors reviewed and approved the final version of the manuscript.

Conflict of Interest Statement
BW was supported by a doctoral research grant from Clasado Biosciences Ltd and is the coinventor of volatile organic compounds in the diagnosis and dietary management of IBS. TK is an employee and shareholder of Johnson and Johnson. MR has received funding from the Almond Board of California, Danone and the International Nut and Dried Fruit Council, and is the coinventor of volatile organic compounds in the diagnosis and dietary management of IBS. PMI was a co-applicant of a research grant from Clasado Biosciences Ltd. MCL was co-applicant of a research grant from Clasado Biosciences Ltd. KW has served as a consultant for Danone, has received research funding from Clasado Biosciences, Almond Board of California, Danone and the International Nut and Dried Fruit Council, and is the coinventor of volatile organic compounds in the diagnosis and dietary management of IBS. CP is the coinventor of volatile organic compounds in the diagnosis and dietary management of IBS. AJM and RS have nothing to disclose.