Mechanisms underlying the laxative effect of lactulose: A randomized placebo-controlled trial showing increased small bowel water and motility unaltered by the 5-HT
MRI
diarrhea
lactulose
ondansetron
randomized trial
Journal
Neurogastroenterology and motility
ISSN: 1365-2982
Titre abrégé: Neurogastroenterol Motil
Pays: England
ID NLM: 9432572
Informations de publication
Date de publication:
05 Feb 2024
05 Feb 2024
Historique:
revised:
16
01
2024
received:
20
09
2023
accepted:
18
01
2024
medline:
6
2
2024
pubmed:
6
2
2024
entrez:
5
2
2024
Statut:
aheadofprint
Résumé
Lactulose is a laxative which accelerates transit and softens stool. Our aim was to investigate its mechanism of action and use this model of diarrhea to investigate the anti-diarrheal actions of ondansetron. A double-blind, randomized, placebo-controlled crossover study of the effect of ondansetron 8 mg in 16 healthy volunteers. Serial MRI scans were performed fasted and 6 h after a meal. Participants then received lactulose 13.6 g twice daily and study drug for a further 36 h. On Day 3, they had further serial MRI scans for 4 h. Measurements included small bowel water content (SBWC), colonic volume, colonic gas, small bowel motility, whole gut transit, and ascending colon relaxation time (T1AC), a measure of colonic water content. Lactulose increased area under the curve (AUC) of SBWC from 0 to 240 min, mean difference 14.2 L · min (95% CI 4.1, 24.3), p = 0.009, and substantially increased small bowel motility after 4 h (mean (95% CI) 523 (457-646) a.u. to 852 (771-1178) a.u., p = 0.007). There were no changes in T1AC after 36 h treatment. Ondansetron did not significantly alter SBWC, small bowel motility, transit, colonic volumes, colonic gas nor T1AC, with or without lactulose. Lactulose increases SBWC and stimulates small bowel motility; however, unexpectedly it did not significantly alter colonic water content, suggesting its laxative effect is not osmotic but due to stimulation of motility. Ondansetron's lack of effect on intestinal water suggests its anti-diarrheal effect is not due to inhibition of secretion but more likely altered colonic motility.
Sections du résumé
BACKGROUND
BACKGROUND
Lactulose is a laxative which accelerates transit and softens stool. Our aim was to investigate its mechanism of action and use this model of diarrhea to investigate the anti-diarrheal actions of ondansetron.
METHODS
METHODS
A double-blind, randomized, placebo-controlled crossover study of the effect of ondansetron 8 mg in 16 healthy volunteers. Serial MRI scans were performed fasted and 6 h after a meal. Participants then received lactulose 13.6 g twice daily and study drug for a further 36 h. On Day 3, they had further serial MRI scans for 4 h. Measurements included small bowel water content (SBWC), colonic volume, colonic gas, small bowel motility, whole gut transit, and ascending colon relaxation time (T1AC), a measure of colonic water content.
KEY RESULTS
RESULTS
Lactulose increased area under the curve (AUC) of SBWC from 0 to 240 min, mean difference 14.2 L · min (95% CI 4.1, 24.3), p = 0.009, and substantially increased small bowel motility after 4 h (mean (95% CI) 523 (457-646) a.u. to 852 (771-1178) a.u., p = 0.007). There were no changes in T1AC after 36 h treatment. Ondansetron did not significantly alter SBWC, small bowel motility, transit, colonic volumes, colonic gas nor T1AC, with or without lactulose.
CONCLUSION & INFERENCES
CONCLUSIONS
Lactulose increases SBWC and stimulates small bowel motility; however, unexpectedly it did not significantly alter colonic water content, suggesting its laxative effect is not osmotic but due to stimulation of motility. Ondansetron's lack of effect on intestinal water suggests its anti-diarrheal effect is not due to inhibition of secretion but more likely altered colonic motility.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e14754Subventions
Organisme : University of Nottingham
Informations de copyright
© 2024 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.
Références
Committee JF. British National Formulary. Pharmaceutical Press; 2012.
Attar A, Lemann M, Ferguson A, et al. Comparison of a low dose polyethylene glycol electrolyte solution with lactulose for treatment of chronic constipation. Gut. 1999;44(2):226-230. doi:10.1136/gut.44.2.226
Saunders DR, Wiggins HS. Conservation of mannitol, lactulose, and raffinose by the human colon. Am J Phys. 1981;241(5):G397-G402. doi:10.1152/ajpgi.1981.241.5.G397
Spiller RC, Jones BJ, Silk DB. Jejunal water and electrolyte absorption from two proprietary enteral feeds in man: importance of sodium content. Gut. 1987;28(6):681-687.
Bond JH, Levitt MD. Quantitative measurement of lactose absorption. Gastroenterology. 1976;70(6):1058-1062.
Debongnie JC, Phillips SF. Capacity of the human colon to absorb fluid. Gastroenterology. 1978;74(4):698-703.
Florent C, Flourie B, Leblond A, Rautureau M, Bernier JJ, Rambaud JC. Influence of chronic lactulose ingestion on the colonic metabolism of lactulose in man (an in vivo study). J Clin Invest. 1985;75(2):608-613.
Undseth R, Berstad A, Klow NE, et al. Abnormal accumulation of intestinal fluid following ingestion of an unabsorbable carbohydrate in patients with irritable bowel syndrome: an MRI study. Neurogastroenterol Motil. 2014;26(12):1686-1693. doi:10.1111/nmo.12449
Barrow L, Steed KP, Spiller RC, et al. Scintigraphic demonstration of lactulose-induced accelerated proximal colon transit. Gastroenterology. 1992;103(4):1167-1173.
Washington N, Harris M, Mussellwhite A, Spiller RC. Moderation of lactulose-induced diarrhea by psyllium: effects on motility and fermentation. Am J Clin Nutr. 1998;67(2):317-321.
Garsed K, Chernova J, Hastings M, et al. A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut. 2014;63(10):1617-1625. doi:10.1136/gutjnl-2013-305989
Hansen MB, Witte AB. The role of serotonin in intestinal luminal sensing and secretion. Acta Physiol (Oxf). 2008;193(4):311-323.
Li Y, Wu XY, Zhu JX, Owyang C. Intestinal serotonin acts as paracrine substance to mediate pancreatic secretion stimulated by luminal factors. Am J Physiol Gastrointest Liver Physiol. 2001;281(4):G916-G923.
Coleman NS, Marciani L, Blackshaw E, et al. Effect of a novel 5-HT3 receptor agonist MKC-733 on upper gastrointestinal motility in humans. Aliment Pharmacol Ther. 2003;18(10):1039-1048.
von der Ohe MR, Camilleri M, Kvols LK. A 5HT3 antagonist corrects the postprandial colonic hypertonic response in carcinoid diarrhea. Gastroenterology. 1994;106(5):1184-1189.
Clemens CH, Samsom M, Van Berge Henegouwen GP, et al. Effect of alosetron on left colonic motility in non-constipated patients with irritable bowel syndrome and healthy volunteers. Aliment Pharmacol Ther. 2002;16(5):993-1002. doi:10.1046/j.1365-2036.2002.01252.x
Dinning PG, Wiklendt L, Maslen L, et al. Quantification of in vivo colonic motor patterns in healthy humans before and after a meal revealed by high-resolution fiber-optic manometry. Neurogastroenterol Motil. 2014;26(10):1443-1457. doi:10.1111/nmo.12408
Dinning PG, Wiklendt L, Maslen L, et al. Colonic motor abnormalities in slow transit constipation defined by high resolution, fibre-optic manometry. Neurogastroenterol Motil. 2015;27(3):379-388. doi:10.1111/nmo.12502
Chaddock G, Lam C, Hoad CL, et al. Novel MRI tests of orocecal transit time and whole gut transit time: studies in normal subjects. Neurogastroenterol Motil. 2014;26(2):205-214. doi:10.1111/nmo.12249
Hoad CL, Marciani L, Foley S, et al. Non-invasive quantification of small bowel water content by MRI: a validation study. Phys Med Biol. 2007;52(23):6909-6922.
Khalaf A, Hoad CL, Menys A, et al. MRI assessment of the postprandial gastrointestinal motility and peptide response in healthy humans. Neurogastroenterol Motil. 2018;30(1). doi:10.1111/nmo.13182
Hamy V, Dikaios N, Punwani S, et al. Respiratory motion correction in dynamic MRI using robust data decomposition registration - application to DCE-MRI. Med Image Anal. 2014;18(2):301-313. doi:10.1016/j.media.2013.10.016
Odille F, Menys A, Ahmed A, Punwani S, Taylor SA, Atkinson D. Quantitative assessment of small bowel motility by nonrigid registration of dynamic MR images. Magn Reson Med. 2012;68(3):783-793. doi:10.1002/mrm.23298
Sadik R, Abrahamsson H, Stotzer PO. Gender differences in gut transit shown with a newly developed radiological procedure. Scand J Gastroenterol. 2003;38(1):36-42. doi:10.1080/00365520310000410
Pritchard SE, Marciani L, Garsed KC, et al. Fasting and postprandial volumes of the undisturbed colon: normal values and changes in diarrhea-predominant irritable bowel syndrome measured using serial MRI. Neurogastroenterol Motil. 2014;26(1):124-130. doi:10.1111/nmo.12243
Murray K, Wilkinson-Smith V, Hoad C, et al. Differential effects of FODMAPs (fermentable oligo-, di-, mono-saccharides and polyols) on small and large intestinal contents in healthy subjects shown by MRI. Am J Gastroenterol. 2014;109(1):110-119. doi:10.1038/ajg.2013.386
Bloembergen N, Purcell EM, Pound RV. Relaxation effects in nuclear magnetic resonance absorption. Phys Rev. 1948;73(7):679-712.
Barnaal D, Lowe I. Proton spin-lattice relaxation in hexagonal ice. J Chem Phys. 1968;48(10):4614-4618.
De Bazelaire CM, Duhamel GD, Rofsky NM, et al. MR imaging relaxation times of abdominal and pelvic tissues measured in vivo at 3.0 T: preliminary results. Radiology. 2004;230(3):652-659.
Wilkinson-Smith V, Dellschaft N, Ansell J, et al. Mechanisms underlying effects of kiwifruit on intestinal function shown by MRI in healthy volunteers. Aliment Pharmacol Ther. 2019;49(6):759-768. doi:10.1111/apt.15127
Major G, Pritchard S, Murray K, et al. Colon hypersensitivity to distension, rather than excessive gas production, produces carbohydrate-related symptoms in individuals with irritable bowel syndrome. Gastroenterology. 2017;152(1):124-133 e2. doi:10.1053/j.gastro.2016.09.062
Marciani L, Wright J, Foley S, et al. Effects of a 5-HT(3) antagonist, ondansetron, on fasting and postprandial small bowel water content assessed by magnetic resonance imaging. Aliment Pharmacol Ther. 2010;32(5):655-663. doi:10.1111/j.1365-2036.2010.04395.x
Kendall GP, Thompson DG, Day SJ. Motor responses of the small intestine to intraluminal distension in normal volunteers and a patient with visceral neuropathy. Gut. 1987;28(6):714-720.
Dinning PG, Arkwright JW, Costa M, et al. Temporal relationships between wall motion, intraluminal pressure, and flow in the isolated rabbit small intestine. Am J Physiol Gastrointest Liver Physiol. 2011;300(4):G577-G585.
Marciani L, Garsed KC, Hoad CL, et al. Stimulation of colonic motility by oral PEG electrolyte bowel preparation assessed by MRI: comparison of split vs single dose. Neurogastroenterol Motil. 2014;26(10):1426-1436. doi:10.1111/nmo.12403
Kamath PS, Phillips SF, Zinsmeister AR. Short-chain fatty acids stimulate ileal motility in humans. Gastroenterology. 1988;95(6):1496-1502.
Kellow JE, Borody TJ, Phillips SF, Haddad AC, Brown ML. Sulfapyridine appearance in plasma after salicylazosulfapyridine. Another simple measure of intestinal transit. Gastroenterology. 1986;91(2):396-400. 10.1016/0016-5085(86)90574-3.
Major G, Murray K, Singh G, et al. Demonstration of differences in colonic volumes, transit, chyme consistency, and response to psyllium between healthy and constipated subjects using magnetic resonance imaging. Neurogastroenterol Motil. 2018;30(9):e13400. doi:10.1111/nmo.13400
Binder HJ. Role of colonic short-chain fatty acid transport in diarrhea. Annu Rev Physiol. 2010;72:297-313. doi:10.1146/annurev-physiol-021909-135817
Christl SU, Murgatroyd PR, Gibson GR, Cummings JH. Production, metabolism, and excretion of hydrogen in the large intestine. Gastroenterology. 1992;102(4 Pt 1):1269-1277.
Bouhnik Y, Attar A, Joly FA, Riottot M, Dyard F, Flourié B. Lactulose ingestion increases faecal bifidobacterial counts: a randomised double-blind study in healthy humans. Eur J Clin Nutr. 2004;58(3):462-466.
Marciani L, Cox EF, Hoad CL, et al. Postprandial changes in small bowel water content in healthy subjects and patients with irritable bowel syndrome. Gastroenterology. 2010;138(2):469-477.e1.
Ritchie J. Mass peristalsis in the human colon after contact with oxyphenisatin. Gut. 1972;13(3):211-219. doi:10.1136/gut.13.3.211
Washington N, Ridley P, Thomas C, Spiller RC, Watts PJ, Wilson CG. Mebeverine decreases mass movements and stool frequency in lactulose-induced diarrhoea. Aliment Pharmacol Ther. 1998;12(6):583-588.
Donaldson GP, Lee SM, Mazmanian SK. Gut biogeography of the bacterial microbiota. Nat Rev Microbiol. 2016;14(1):20-32. doi:10.1038/nrmicro3552
Villmones HC, Halland A, Stenstad T, Ulvestad E, Weedon-Fekjaer H, Kommedal Ø. The cultivable microbiota of the human distal ileum. Clin Microbiol Infect. 2021;27(6):912.e7-912.e13. doi:10.1016/j.cmi.2020.08.021
Leonov GE, Varaeva YR, Livantsova EN, et al. The complicated relationship of short-chain fatty acids and oral microbiome: a narrative review. Biomedicine. 2023;11(10):2749.
Cherbut C. Motor effects of short-chain fatty acids and lactate in the gastrointestinal tract. Proc Nutr Soc. 2003;62(1):95-99. doi:10.1079/PNS2002213
Tazoe H, Otomo Y, Kaji I, et al. Roles of short-chain fatty acids receptors, GPR41 and GPR43 on colonic functions. J Physiol Pharmacol. 2008;59(Suppl 2):251-262.
Tazoe H, Otomo Y, Karaki S, et al. Expression of short-chain fatty acid receptor GPR41 in the human colon. Biomed Res. 2009;30(3):149-156.
Jouet P, Moussata D, Duboc H, et al. Effect of short-chain fatty acids and acidification on the phasic and tonic motor activity of the human colon. Neurogastroenterol Motil. 2013;25(12):943-949. doi:10.1111/nmo.12212
Fukumoto S, Tatewaki M, Yamada T, et al. Short-chain fatty acids stimulate colonic transit via intraluminal 5-HT release in rats. Am J Physiol Regul Integr Comp Physiol. 2003;284(5):R1269-R1276.
Grider JR, Piland BE. The peristaltic reflex induced by short-chain fatty acids is mediated by sequential release of 5-HT and neuronal CGRP but not BDNF. Am J Physiol Gastrointest Liver Physiol. 2007;292(1):G429-G437.
Lund ML, Egerod KL, Engelstoft MS, et al. Enterochromaffin 5-HT cells - a major target for GLP-1 and gut microbial metabolites. Mol Metab. 2018;11:70-83. doi:10.1016/j.molmet.2018.03.004
Hussein MO, Hoad CL, Wright J, et al. Fat emulsion intragastric stability and droplet size modulate gastrointestinal responses and subsequent food intake in young adults. J Nutr. 2015;145(6):1170-1177. doi:10.3945/jn.114.204339
Heitmann PT, Mohd Rosli R, Maslen L, et al. High-resolution impedance manometry characterizes the functional role of distal colonic motility in gas transit. Neurogastroenterol Motil. 2022;34(1):e14178. doi:10.1111/nmo.14178