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Aliment Pharmacol Ther. 2021 Dec;54:S63-S74. doi: 10.1111/apt.16625.

Review Article: Current and future treatment approaches for IBS with diarrhoea (IBS-D) and IBS mixed pattern (IBS-M).

Alimentary pharmacology & therapeutics

Judy Nee, Anthony Lembo

Affiliations

  1. Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

PMID: 34927757 DOI: 10.1111/apt.16625

Abstract

BACKGROUND: Irritable bowel syndrome-diarrhoea (IBS-D) and IBS-mixed stool pattern (IBS-M) are disorders of gut-brain interaction characterised by abdominal pain associated with diarrhoea or both diarrhoea and constipation respectively. The pathophysiology of IBS-D/M is multifactorial and not completely understood; thus, treatment is aimed at multiple mechanisms such as altering gut microbiota, visceral hypersensitivity, intestinal permeability, gut-brain interaction and psychological strategies.

AIM: The goal of this article was to provide an up-to-date review of the current evidence for both non-pharmacological and pharmacological treatment options in IBS-D and IBS-M. Future treatments for IBS-D and IBS-M will also be discussed.

METHODS: Medline and Embase database searches (through April 30 2021) to identify clinical studies in subjects with IBS-D in which dietary modification, alternative treatments (probiotics, acupuncture, exercise) as well as FDA-approved medications were used.

RESULTS: Dietary modification is often the first line of therapy. Furthermore, lifestyle treatments include complementary alternative medications (CAM), probiotics and peppermint oil are useful adjuncts but have not specifically been described in IBS-D/M. Evidence strongly supports psychotherapy in the treatment of IBS. Beyond over-the counter anti-diarrhoeals, anti-spasmodics and anti-depressants, pharmacological treatment now includes treating for bile acid malabsorption and the FDA-approved medications rifaximin, eluxadoline and alosetron.

CONCLUSIONS: The treatment of IBS-D/M ideally involves a multidisciplinary approach of primary care, gastroenterologist and psychologist. Treatment often involves both non-pharmacological and pharmacological therapies. Future therapies may include faecal microbial transplant, Crofelemer and serotonin antagonists, but further studies are needed.

© 2021 John Wiley & Sons Ltd.

References

  1. Palsson OS, Whitehead W, Törnblom H, Sperber AD, Simren M. Prevalence of Rome IV functional bowel disorders among adults in the United States, Canada, and the United Kingdom. Gastroenterology. 2020;158:1262-1273.e3. doi:10.1053/j.gastro.2019.12.021 - PubMed
  2. Mönnikes H. Quality of life in patients with irritable bowel syndrome. J Clin Gastroenterol. 2011;45:S98-101. doi:10.1097/MCG.0b013e31821fbf44 - PubMed
  3. Ballou S, McMahon C, Lee H-N, et al. Effects of irritable bowel syndrome on daily activities vary among subtypes based on results from the IBS in America survey. Clin Gastroenterol Hepatol. 2019;17:2471-2478.e3. doi:10.1016/j.cgh.2019.08.016 - PubMed
  4. Halpert A. Irritable bowel syndrome: patient-provider interaction and patient education. J Clin Med. 2018;7:E3. doi:10.3390/jcm7010003 - PubMed
  5. Bertram S, Kurland M, Lydick E, Locke GR, Yawn BP. The patient’s perspective of irritable bowel syndrome. J Fam Pract. 2001;50:521-525. - PubMed
  6. Basnayake C, Kamm MA, Stanley A, et al. Standard gastroenterologist versus multidisciplinary treatment for functional gastrointestinal disorders (MANTRA): an open-label, single-centre, randomised controlled trial. Lancet Gastroenterol Hepatol. 2020;5:890-899. doi:10.1016/S2468-1253(20)30215-6 - PubMed
  7. Böhn L, Störsrud S, Törnblom H, Bengtsson U, Simrén M. Self-reported food-related gastrointestinal symptoms in IBS are common and associated with more severe symptoms and reduced quality of life. Am J Gastroenterol. 2013;108:634-641. doi:10.1038/ajg.2013.105 - PubMed
  8. Simrén M, Månsson A, Langkilde AM, et al. Food-related gastrointestinal symptoms in the irritable bowel syndrome. Digestion. 2001;63:108-115. doi:10.1159/000051878 - PubMed
  9. Dainese R, Galliani EA, De Lazzari F, Di Leo V, Naccarato R. Discrepancies between reported food intolerance and sensitization test findings in irritable bowel syndrome patients. Am J Gastroenterol. 1999;94:1892-1897. doi:10.1111/j.1572-0241.1999.01226.x - PubMed
  10. Rangan V, Ballou S, Shin A, Camilleri M, Lembo A; Beth Israel Deaconess Medical Center GI Motility Working Group. Use of treatments for irritable bowel syndrome and patient satisfaction based on the IBS in America survey. Gastroenterology. 2020;158:786-788.e1. doi:10.1053/j.gastro.2019.10.036 - PubMed
  11. Pauls RN, Max JB. Symptoms and dietary practices of irritable bowel syndrome patients compared to controls: results of a USA national survey. Minerva Gastroenterol Dietol. 2019;65:1-10. doi:10.23736/S1121-421X.18.02518-7 - PubMed
  12. BDA. Irritable Bowel Syndrome Food Fact Sheet. https://www.bda.uk.com/resource/irritable-bowel-syndrome-diet.html. Accessed July 19, 2021 - PubMed
  13. Francis CY, Morris J, Whorwell PJ. The irritable bowel severity scoring system: a simple method of monitoring irritable bowel syndrome and its progress. Aliment Pharmacol Ther. 1997;11(2):395-402. - PubMed
  14. Böhn L, Störsrud S, Liljebo T, et al. Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: a randomized controlled trial. Gastroenterology. 2015;149:1399-1407.e2. doi:10.1053/j.gastro.2015.07.054 - PubMed
  15. Varjú P, Gede N, Szakács Z, et al. Lactose intolerance but not lactose maldigestion is more frequent in patients with irritable bowel syndrome than in healthy controls: a meta-analysis. Neurogastroenterol Motil. 2019;31:e13527. doi:10.1111/nmo.13527 - PubMed
  16. Yang J, Deng Y, Chu H, et al. Prevalence and presentation of lactose intolerance and effects on dairy product intake in healthy subjects and patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2013;11:262-268.e1. doi:10.1016/j.cgh.2012.11.034 - PubMed
  17. Aguilera-Lizarraga J, Florens MV, Viola MF, et al. Local immune response to food antigens drives meal-induced abdominal pain. Nature. 2021;590:151-156. doi:10.1038/s41586-020-03118-2 - PubMed
  18. Black CJ, Ford AC. Best management of irritable bowel syndrome. Frontline Gastroenterol. 2021;12:303-315. doi:10.1136/flgastro-2019-101298 - PubMed
  19. Dionne J, Ford AC, Yuan Y, et al. A systematic review and meta-analysis evaluating the efficacy of a gluten-free diet and a low FODMAPs diet in treating symptoms of irritable bowel syndrome. Am J Gastroenterol. 2018;113:1290-1300. doi:10.1038/s41395-018-0195-4 - PubMed
  20. Vazquez-Roque MI, Camilleri M, Smyrk T, et al. A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function. Gastroenterology. 2013;144:903-911.e3. doi:10.1053/j.gastro.2013.01.049 - PubMed
  21. Aziz I, Trott N, Briggs R, North JR, Hadjivassiliou M, Sanders DS. Efficacy of a gluten-free diet in subjects with irritable bowel syndrome-diarrhea unaware of their HLA-DQ2/8 genotype. Clin Gastroenterol Hepatol. 2016;14:696-703.e1. doi:10.1016/j.cgh.2015.12.031 - PubMed
  22. Biesiekierski JR, Peters SL, Newnham ED, Rosella O, Muir JG, Gibson PR. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology. 2013;145(2):320-328.e1-3. doi:10.1053/j.gastro.2013.04.051 - PubMed
  23. Skodje GI, Sarna VK, Minelle IH, et al. Fructan, rather than gluten, induces symptoms in patients with self-reported non-celiac gluten sensitivity. Gastroenterology. 2018;154:529-539.e2. doi:10.1053/j.gastro.2017.10.040 - PubMed
  24. Henström M, Diekmann L, Bonfiglio F, et al. Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome. Gut. 2018;67:263-270. doi:10.1136/gutjnl-2016-312456 - PubMed
  25. Kim SB, Calmet FH, Garrido J, Garcia-Buitrago MT, Moshiree B. Sucrase-isomaltase deficiency as a potential masquerader in irritable bowel syndrome. Dig Dis Sci. 2020;65:534-540. doi:10.1007/s10620-019-05780-7 - PubMed
  26. Eswaran S, Chey WD, Jackson K, Pillai S, Chey SW, Han-Markey T. A diet low in fermentable oligo-, di-, and monosaccharides and polyols improves quality of life and reduces activity impairment in patients with irritable bowel syndrome and diarrhea. Clin Gastroenterol Hepatol. 2017;15:1890-1899.e3. doi:10.1016/j.cgh.2017.06.044 - PubMed
  27. Zahedi MJ, Behrouz V, Azimi M. Low fermentable oligo-di-mono-saccharides and polyols diet versus general dietary advice in patients with diarrhea-predominant irritable bowel syndrome: a randomized controlled trial. J Gastroenterol Hepatol. 2018;33:1192-1199. doi:10.1111/jgh.14051 - PubMed
  28. Rej A, Shaw CC, Buckle RL, et al. The low FODMAP diet for IBS; A multicentre UK study assessing long term follow up. Dig Liver Dis. 2021;S1590-8658(21)00247-4. doi:10.1016/j.dld.2021.05.004 - PubMed
  29. Zhang Y, Feng L, Wang X, et al. Low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diet compared with traditional dietary advice for diarrhea-predominant irritable bowel syndrome: a parallel-group, randomized controlled trial with analysis of clinical and microbiological factors associated with patient outcomes. Am J Clin Nutr. 2021;113:1531-1545. doi:10.1093/ajcn/nqab005 - PubMed
  30. Bennet SMP, Böhn L, Störsrud S, et al. Multivariate modelling of faecal bacterial profiles of patients with IBS predicts responsiveness to a diet low in FODMAPs. Gut. 2018;67:872-881. doi:10.1136/gutjnl-2016-313128 - PubMed
  31. Wang B, Duan R, Duan L. Prevalence of sleep disorder in irritable bowel syndrome: a systematic review with meta-analysis. Saudi J Gastroenterol. 2018;24:141-150. doi:10.4103/sjg.SJG_603_17 - PubMed
  32. Ballou S, Alhassan E, Hon E, et al. Sleep disturbances are commonly reported among patients presenting to a gastroenterology clinic. Dig Dis Sci. 2018;63:2983-2991. doi:10.1007/s10620-018-5237-7 - PubMed
  33. Patel A, Hasak S, Cassell B, et al. Effects of disturbed sleep on gastrointestinal and somatic pain symptoms in irritable bowel syndrome. Aliment Pharmacol Ther. 2016;44:246-258. doi:10.1111/apt.13677 - PubMed
  34. Zhou C, Zhao E, Li Y, Jia Y, Li F. Exercise therapy of patients with irritable bowel syndrome: a systematic review of randomized controlled trials. Neurogastroenterol Motil. 2019;31:e13461. doi:10.1111/nmo.13461 - PubMed
  35. Johannesson E, Simrén M, Strid H, Bajor A, Sadik R. Physical activity improves symptoms in irritable bowel syndrome: a randomized controlled trial. Am J Gastroenterol. 2011;106:915-922. doi:10.1038/ajg.2010.480 - PubMed
  36. Ballou S, Keefer L. Psychological interventions for irritable bowel syndrome and inflammatory bowel diseases. Clin Transl Gastroenterol. 2017;8:e214. doi:10.1038/ctg.2016.69 - PubMed
  37. Drossman DA, Toner BB, Whitehead WE, et al. Cognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders. Gastroenterology. 2003;125:19-31. doi:10.1016/s0016-5085(03)00669-3 - PubMed
  38. Lackner JM, Jaccard J, Keefer L, et al. Improvement in gastrointestinal symptoms after cognitive behavior therapy for refractory irritable bowel syndrome. Gastroenterology. 2018;155:47-57. doi:10.1053/j.gastro.2018.03.063 - PubMed
  39. Li L, Xiong L, Zhang S, Yu Q, Chen M. Cognitive-behavioral therapy for irritable bowel syndrome: a meta-analysis. J Psychosom Res. 2014;77:1-12. doi:10.1016/j.jpsychores.2014.03.006 - PubMed
  40. Ford AC, Lacy BE, Harris LA, Quigley EMM, Moayyedi P. Effect of antidepressants and psychological therapies in irritable bowel syndrome: an updated systematic review and meta-analysis. Am J Gastroenterol. 2019;114:21-39. doi:10.1038/s41395-018-0222-5 - PubMed
  41. Hayee B, Forgacs I. Psychological approach to managing irritable bowel syndrome. BMJ. 2007;334:1105-1109. doi:10.1136/bmj.39199.679236.AE - PubMed
  42. White AR, Filshie J, Cummings TM; International Acupuncture Research Forum. Clinical trials of acupuncture: consensus recommendations for optimal treatment, sham controls and blinding. Complement Ther Med. 2001;9:237-245. doi:10.1054/ctim.2001.0489 - PubMed
  43. Manheimer E, Wieland LS, Cheng K, et al. Acupuncture for irritable bowel syndrome: systematic review and meta-analysis. Am J Gastroenterol. 2012;107:835-847; quiz 848. doi:10.1038/ajg.2012.66 - PubMed
  44. Guo J, Xing X, Wu J, et al. Acupuncture for adults with diarrhea-predominant irritable bowel syndrome or functional diarrhea: a systematic review and meta-analysis. Neural Plast. 2020;2020:1-16. doi:10.1155/2020/8892184 - PubMed
  45. Billings W, Mathur K, Craven HJ, Xu H, Shin A. Potential benefit with complementary and alternative medicine in irritable bowel syndrome: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2021;19(8):1538-1553.e14. doi:10.1016/j.cgh.2020.09.035 - PubMed
  46. Zhu J-J, Liu S, Su X-L, et al. Efficacy of Chinese herbal medicine for diarrhea-predominant irritable bowel syndrome: a meta-analysis of randomized, double-blind, placebo-controlled trials. Evid Based Complement Alternat Med. 2016;2016:1-15. doi:10.1155/2016/4071260 - PubMed
  47. Leung WK, Wu JCY, Liang SM, et al. Treatment of diarrhea-predominant irritable bowel syndrome with traditional Chinese herbal medicine: a randomized placebo-controlled trial. Am J Gastroenterol. 2006;101(7):1574-1580. doi:10.1111/j.1572-0241.2006.00576.x - PubMed
  48. Ford AC, Quigley EMM, Lacy BE, et al. Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis. Am J Gastroenterol. 2014;109(10):1547-1561; quiz 1546, 1562. doi:10.1038/ajg.2014.202 - PubMed
  49. Lacy BE, Pimentel M, Brenner DM, et al. ACG clinical guideline: management of irritable bowel syndrome. Am J Gastroenterol. 2021;116(1):17-44. doi:10.14309/ajg.0000000000001036 - PubMed
  50. Su GL, Ko CW, Bercik P, et al. AGA clinical practice guidelines on the role of probiotics in the management of gastrointestinal disorders. Gastroenterology. 2020;159:697-705. doi:10.1053/j.gastro.2020.05.059 - PubMed
  51. Kim HJ, Camilleri M, Mckinzie S, et al. A randomized controlled trial of a probiotic, VSL#3, on gut transit and symptoms in diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2003;17:895-904. doi:10.1046/j.1365-2036.2003.01543.x - PubMed
  52. Michail S, Kenche H. Gut microbiota is not modified by Randomized, double-blind, placebo-controlled trial of VSL#3 in diarrhea-predominant irritable bowel syndrome. Probiotics Antimicrob Proteins. 2011;3:1-7. doi:10.1007/s12602-010-9059-y - PubMed
  53. Hod K, Sperber AD, Ron Y, et al. A double-blind, placebo-controlled study to assess the effect of a probiotic mixture on symptoms and inflammatory markers in women with diarrhea-predominant IBS. Neurogastroenterol Motil. 2017;29. doi:10.1111/nmo.13037 - PubMed
  54. Rezaie A, Heimanson Z, McCallum R, Pimentel M. Lactulose breath testing as a predictor of response to rifaximin in patients with irritable bowel syndrome with diarrhea. Am J Gastroenterol. 2019;114:1886-1893. doi:10.14309/ajg.0000000000000444 - PubMed
  55. Kaplan MA, Prior MJ, Ash RR, McKonly KI, Helzner EC, Nelson EB. Loperamide-simethicone vs loperamide alone, simethicone alone, and placebo in the treatment of acute diarrhea with gas-related abdominal discomfort. A randomized controlled trial. Arch Fam Med. 1999;8:243-248. doi:10.1001/archfami.8.3.243 - PubMed
  56. Hanauer SB, DuPont HL, Cooper KM, Laudadio C. Randomized, double-blind, placebo-controlled clinical trial of loperamide plus simethicone versus loperamide alone and simethicone alone in the treatment of acute diarrhea with gas-related abdominal discomfort. Curr Med Res Opin. 2007;23:1033-1043. doi:10.1185/030079907x182176 - PubMed
  57. Hovdenak N. Loperamide treatment of the irritable bowel syndrome. Scand J Gastroenterol Suppl. 1987;130:81-84. doi:10.3109/00365528709091004 - PubMed
  58. Efskind PS, Bernklev T, Vatn MH. A double-blind placebo-controlled trial with loperamide in irritable bowel syndrome. Scand J Gastroenterol. 1996;31:463-468. doi:10.3109/00365529609006766 - PubMed
  59. Lavö B, Stenstam M, Nielsen AL. Loperamide in treatment of irritable bowel syndrome-a double-blind placebo controlled study. Scand J Gastroenterol Suppl. 1987;130:77-80. doi:10.3109/00365528709091003 - PubMed
  60. Palmer KR, Corbett CL, Holdsworth CD. Double-blind cross-over study comparing loperamide, codeine and diphenoxylate in the treatment of chronic diarrhea. Gastroenterology. 1980;79:1272-1275. - PubMed
  61. Black CJ, Yuan Y, Selinger CP, et al. Efficacy of soluble fibre, antispasmodic drugs, and gut-brain neuromodulators in irritable bowel syndrome: a systematic review and network meta-analysis. Lancet Gastroenterol Hepatol. 2020;5:117-131. doi:10.1016/S2468-1253(19)30324-3 - PubMed
  62. Slattery SA, Niaz O, Aziz Q, Ford AC, Farmer AD. Systematic review with meta-analysis: the prevalence of bile acid malabsorption in the irritable bowel syndrome with diarrhoea. Aliment Pharmacol Ther. 2015;42:3-11. doi:10.1111/apt.13227 - PubMed
  63. Camilleri M. Bile Acid diarrhea: prevalence, pathogenesis, and therapy. Gut Liv. 2015;9:332-339. doi:10.5009/gnl14397 - PubMed
  64. Wilcox C, Turner J, Green J. Systematic review: the management of chronic diarrhoea due to bile acid malabsorption. Aliment Pharmacol Ther. 2014;39:923-939. doi:10.1111/apt.12684 - PubMed
  65. Bajor A, Törnblom H, Rudling M, Ung K-A, Simrén M. Increased colonic bile acid exposure: a relevant factor for symptoms and treatment in IBS. Gut. 2015;64:84-92. doi:10.1136/gutjnl-2013-305965 - PubMed
  66. Camilleri M, Acosta A, Busciglio I, et al. Effect of colesevelam on faecal bile acids and bowel functions in diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2015;41:438-448. doi:10.1111/apt.13065 - PubMed
  67. Ford AC, Quigley EMM, Lacy BE, et al. Effect of antidepressants and psychological therapies, including hypnotherapy, in irritable bowel syndrome: systematic review and meta-analysis. Am J Gastroenterol. 2014;109:1350-1365; quiz 1366. doi:10.1038/ajg.2014.148 - PubMed
  68. Chey WD, Shah ED, DuPont HL. Mechanism of action and therapeutic benefit of rifaximin in patients with irritable bowel syndrome: a narrative review. Therap Adv Gastroenterol. 2020;13:1756284819897531. doi:10.1177/1756284819897531 - PubMed
  69. Lactulose Breath Testing as a Predictor of Response to Rifaximin in Patients With Irritable Bowel Syndrome With Diarrhea - PubMed. Accessed July 19, 2021. https://pubmed.ncbi.nlm.nih.gov/31688023/. Accessed July 19, 2021 - PubMed
  70. Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011;364:22-32. doi:10.1056/NEJMoa1004409 - PubMed
  71. Lembo A, Pimentel M, Rao SS, et al. Repeat treatment with rifaximin is safe and effective in patients with diarrhea-predominant irritable bowel syndrome. Gastroenterology. 2016;151:1113-1121. doi:10.1053/j.gastro.2016.08.003 - PubMed
  72. Schoenfeld P, Pimentel M, Chang L, et al. Safety and tolerability of rifaximin for the treatment of irritable bowel syndrome without constipation: a pooled analysis of randomised, double-blind, placebo-controlled trials. Aliment Pharmacol Ther. 2014;39:1161-1168. doi:10.1111/apt.12735 - PubMed
  73. Lembo AJ, Lacy BE, Zuckerman MJ, et al. Eluxadoline for irritable bowel syndrome with diarrhea. N Engl J Med. 2016;374:242-253. doi:10.1056/NEJMoa1505180 - PubMed
  74. Brenner DM, Sayuk GS, Gutman CR, et al. Efficacy and safety of eluxadoline in patients with irritable bowel syndrome with diarrhea who report inadequate symptom control with loperamide: RELIEF phase 4 study. Am J Gastroenterol. 2019;114:1502-1511. doi:10.14309/ajg.0000000000000327 - PubMed
  75. Lacy BE, Chey WD, Cash BD, Lembo AJ, Dove LS, Covington PS. Eluxadoline efficacy in IBS-D patients who report prior loperamide use. Am J Gastroenterol. 2017;112:924-932. doi:10.1038/ajg.2017.72 - PubMed
  76. Tong K, Nicandro JP, Shringarpure R, Chuang E, Chang L. A 9-year evaluation of temporal trends in alosetron postmarketing safety under the risk management program. Therap Adv Gastroenterol. 2013;6:344-357. doi:10.1177/1756283X13491798 - PubMed
  77. Krause R, Ameen V, Gordon SH, et al. A randomized, double-blind, placebo-controlled study to assess efficacy and safety of 0.5 mg and 1 mg alosetron in women with severe diarrhea-predominant IBS. Am J Gastroenterol. 2007;102:1709-1719. doi:10.1111/j.1572-0241.2007.01282.x - PubMed
  78. Black CJ, Burr NE, Camilleri M, et al. Efficacy of pharmacological therapies in patients with IBS with diarrhoea or mixed stool pattern: systematic review and network meta-analysis. Gut. 2020;69:74-82. doi:10.1136/gutjnl-2018-318160 - PubMed
  79. Garsed K, Chernova J, Hastings M, et al. A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut. 2014;63:1617-1625. doi:10.1136/gutjnl-2013-305989 - PubMed
  80. Plasse TF, Barton G, Davidson E, et al. Bimodal release ondansetron improves stool consistency and symptomatology in diarrhea-predominant irritable bowel syndrome: a randomized, double-blind, trial. Am J Gastroenterol. 2020;115:1466-1473. doi:10.14309/ajg.0000000000000727 - PubMed
  81. Matsueda K, Harasawa S, Hongo M, Hiwatashi N, Sasaki D. A randomized, double-blind, placebo-controlled clinical trial of the effectiveness of the novel serotonin type 3 receptor antagonist ramosetron in both male and female Japanese patients with diarrhea-predominant irritable bowel syndrome. Scand J Gastroenterol. 2008;43(10):1202-1211. doi:10.1080/00365520802240255 - PubMed
  82. Matsueda K, Harasawa S, Hongo M, Hiwatashi N, Sasaki D. A phase II trial of the novel serotonin type 3 receptor antagonist ramosetron in Japanese male and female patients with diarrhea-predominant irritable bowel syndrome. Digestion. 2008;77:225-235. doi:10.1159/000150632 - PubMed
  83. Fukudo S, Ida M, Akiho H, Nakashima Y, Matsueda K. Effect of ramosetron on stool consistency in male patients with irritable bowel syndrome with diarrhea. Clin Gastroenterol Hepatol. 2014;12:953-959.e4. doi:10.1016/j.cgh.2013.11.024 - PubMed
  84. Fukudo S, Kinoshita Y, Okumura T, et al. Ramosetron reduces symptoms of irritable bowel syndrome with diarrhea and improves quality of life in women. Gastroenterology. 2016;150:358-366.e8. doi:10.1053/j.gastro.2015.10.047 - PubMed
  85. DiCesare D, DuPont HL, Mathewson JJ, et al. A double blind, randomized, placebo-controlled study of SP-303 (Provir) in the symptomatic treatment of acute diarrhea among travelers to Jamaica and Mexico. Am J Gastroenterol. 2002;97:2585-2588. doi:10.1111/j.1572-0241.2002.06027.x - PubMed
  86. Lembo AJ, Rosenbaum DP, Chey W, Drossman DA. Safety and efficacy of Crofelemer in patients with diarrhea predominant irritable bowel syndrome (d-IBS). 2007;132(4). https://scholar.google.com/scholar_lookup?journal=Gastroenterology&title=Safety+and+efficacy+of+crofelemer+in+patients+with+diarrhea-predominant+irritable+bowel+syndrome+(D-IBS)&author=A+Lembo&author=D+Rosenbaum&author=W+Chey&volume=132&publication_year=2007&pages=A141&. Accessed July 19, 2021 - PubMed
  87. Xu D, Chen VL, Steiner CA, et al. Efficacy of fecal microbiota transplantation in irritable bowel syndrome: a systematic review and meta-analysis. Am J Gastroenterol. 2019;114:1043-1050. doi:10.14309/ajg.0000000000000198 - PubMed
  88. El-Salhy M, Hatlebakk JG, Gilja OH, Bråthen Kristoffersen A, Hausken T. Efficacy of faecal microbiota transplantation for patients with irritable bowel syndrome in a randomised, double-blind, placebo-controlled study. Gut. 2020;69:859-867. doi:10.1136/gutjnl-2019-319630 - PubMed
  89. DeFilipp Z, Bloom PP, Torres Soto M, et al. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant. N Engl J Med. 2019;381:2043-2050. doi:10.1056/NEJMoa1910437 - PubMed

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