Gut-brain Mechanisms Of FODMAP-induced Symptom Generation In Irritable Bowel Syndrome

Background and aim:FODMAPs produce similar small bowel water and colonic gas in patients with irritable bowel syndrome（IBS）and healthy controls（HC）,despite IBS patients reporting increased gastrointestinal（GI）symptoms.To unravel the mechanisms underlying FODMAP-induced symptom reporting,we investigated gut and brain responses to fructans administration in IBS patients and HC.Methods:This randomized,double-blind,cross-over study consisted of three visits where fructans（40g/500m L saline）,glucose（40g/500m L saline）or saline（500m L）were infused intragastrically during 1h MRI brain scanning;abdominal MRI was performed before,1h,and 2h post-infusion.GI symptoms（bloating,pain,cramps,flatulence,nausea,and fullness）were repeatedly rated using 100mm visual analogue scale（VAS）,and questionnaires of emotional state were also collected at pre-defined timepoints using the positive and negative effect（PANAS）and profile of mood states（POMS）.Blood samples were taken at baseline and post-infusion during the brain MRI scan to measure ghrelin and blood glucose.Data were analyzed using linear mixed model.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）.No differences in emotional state were observed either between conditions or groups（all p>0.06）.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.Fructans indued a lesser decrease in octanoylated ghrelin compared to glucose in HC（p=0.006）,while fructans induced a greater decrease in octanoylated ghrelin compared to saline in IBS（p=0.048）.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.Ghrelin may account in part for the dysfunction of gut-brain axis in IBS.