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Treatment options for irritable bowel syndrome

7th Sep, 2021

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Irritable bowel syndrome (IBS) is associated with significant healthcare and financial burden, as well as quality of life consequences. Patients and primary healthcare providers are often unsatisfied with available pharmacologic remedies and may seek complementary and alternative medicine (CAM) therapies, which may be beneficial for abdominal pain and overall response in IBS (1,2). There is a continued need for novel evidence-based practices for the optimal management of IBS, regardless of whether treatments are CAM or traditional Western medicine.

In general, treatment is targeted at addressing a patient’s predominant symptoms, be that abdominal pain, diarrhoea, constipation or bloating (3). The main strategies for treatment for patients with IBS are dietary, psychotherapy, pharmacotherapy, and microbial therapies (4).

Management of IBS should include an integrated care model in which behavioural interventions, dietary modification, and medications are considered equal partners. This approach offers the greatest likelihood for success in the management of patients with IBS (5).

Good communication is paramount, and clinicians should provide a clear explanation about the disorder, with a focus on exploring the patient’s own beliefs about IBS and a discussion of any concerns they may have. It should be emphasised that symptoms are often chronic and that treatment, while aiming to improve symptoms, may not relieve them completely (3).

Initial management should include simple lifestyle and dietary advice (see below). Exercise, stress reduction, adequate daily fluid intake, and improved sleep can all help improve IBS symptoms (6). The concept of self-help is important in empowering patients to take control of managing their condition. Antispasmodics and peppermint oil can be used first-line for the treatment of abdominal pain. If patients fail to respond, central neuromodulators can be used second-line; tricyclic antidepressants are preferred (3).

If medical treatment is unsuccessful, patients should be referred for psychological therapy if they are amenable to this.

Pharmacotherapy

In addition to effective older medications that are inexpensive and reliable, there are also newer treatments for IBS-D such as eluxadoline, and IBS-C with linaclotide, lubiprostone, plecanatide, which also can provide lasting relief (7).

Diet

Dietary therapies for IBS are of particular interest because up to 90% of IBS patients exclude certain foods such as wheat products, milk and its products, cabbage, onion, hot spices, and fried and smoked foodstuffs (8,9) to improve their GI symptoms (9,10,11). However, in most cases, a positive response to food triggers are largely related to the meal-related nature of IBS rather than a true food allergy (3).

Dietary approaches to ease IBS symptoms have mixed results; however, diets empower patients and make them feel more in control, which may alleviate anxiety and improve symptoms in a non-specific way, which is probably why they are so popular with patients. Although dietary therapies are rapidly becoming the first-line treatment of IBS, clinicians need to be aware of the negative effects of prescribing restrictive diets and red flag symptoms of maladaptive eating patterns (12). In addition, the diets of IBS patients tend to be low in calcium, magnesium, phosphorus, vitamin B₂, and vitamin A (8).

FODMAP

The fundamental basis for recommending a diet low in fermentable oligosaccharides, disaccharides, and monosaccharides and polyols (FODMAPs) is that bloating results from bacterial fermentation of intraluminal saccharides.

Among the available dietary interventions for IBS, the low FODMAP diet has the greatest evidence, albeit controversial, for efficacy and may be useful for overall symptom improvement (13,14,15).

The low FODMAP diet is a 3 step diet used to help manage the symptoms of medically diagnosed IBS (16). Patient and practitioner FODMAP resources can be found here.

The intake of a low FODMAP diet reportedly improves both symptoms and the quality of life in 50-76% of IBS patients (17).
There is significant evidence from meta-analyses for the short-term benefits of a low FODMAP diet on GI symptoms and quality of life in patients with IBS (18,19). However, studies are generally of low quality due to methodological heterogeneity and a high risk of bias, which commonly occurs in studies of dietary treatments (20). Studies were also short duration studies (never >6 weeks), lacked definitions to substantiate claims of improvement, and lacked assessment of reintroduction of the FODMAPs during follow-up periods, leading researchers to conclude that the symptomatic effects reported in trials were likely to be driven primarily by a placebo response (4).
Another meta-analysis found no statistically significant benefit of a low FODMAP diet compared with an alternative diet (13). Traditional dietary advice to eat small regular meals, avoid known trigger foods, and reduce alcohol and caffeine is as effective as a low FODMAP diet (21,22).
Existing diet, colonic microbiota and their metabolic products may help predict who will respond to a low FODMAP diet (23).
Current guidelines only weakly suggest a low FODMAP diet to treat IBS-C (13).

Concerns

A low FODMAP diet requires intensive meal-planning, is expensive and difficult to maintain over a long period, and can result in negative changes in the intestinal microbiota (22,24,25,26). Consuming a low FODMAP diet for a long time may result in deficiencies in vitamins, minerals, and naturally occurring antioxidants (24,26). Therefore, FODMAPs should be reintroduced to tolerance after a limited period of restriction, although randomised controlled trials (RCTs) to date have only examined the effect on symptoms during FODMAP elimination. Patients with IBS who choose to follow a low FODMAP diet should be aware of its 3 phases: restriction (4-8 weeks), reintroduction (6-10 weeks), and personalisation (ongoing) (5).

A selective approach rather than a comprehensive exclusion of all FODMAPs may be beneficial. The selective approach excludes (4):

Fructans - these are not digested in the human gut and are therefore potential causes of bloating in all humans.
Sugars (based on ethnicity) - for example, lactose, given that 65% of the human population has a reduced ability to digest lactose after infancy, albeit with wide regional and ethnic variations (27).

Modified NICE diet

The modified National Institute for Health and Care Excellence (NICE) diet has the same effect as a low FODMAP diet in around half (46-54%) of IBS patients, but it is easy to maintain and does not have the risks associated with a low-FODMAP diet (21,22). The modified NICE diet is the first diet recommended for IBS patients by the British Dietetic Association (BDA) (8,28,29,30,31). In the modified NICE diet, patients are advised to:

Consume regular meals and moderate portion sizes. Do not skip meals.
Drink plenty (up to 2 litres) of liquids a day, preferably water or caffeine-free drinks
Replace wheat products with spelt products
Reduce intake of fatty food, onions, cabbage, and beans
Limit consumption of fresh fruit to no more than three daily portions of 80 g each
Reduce consumption of “resistant starch” that is usually in pre-cooked or pre-packaged foods
Avoid carbonated beverages and sweeteners whose names end with “-ol”. For example, sorbitol, an artificial sweetener found in chewing gums, sugar-free drinks and some products, especially for diabetic subjects.
Moderate fibre intake, as it may be linked to the onset of symptoms. Reduce insoluble fibre (e.g., bran or bran-based cereals, wholemeal flour or derivatives) and increase soluble fibre, such as oat or psyllium husk fibres.

The BDA also recommends reducing the intake of coffee/tea (less than 3 cups per day), spicy foods, and alcohol (8,28). For IBS-D patients especially, it is important to control the consumption of fructose and sorbitol, alcohol and coffee (independently of caffeine content) (32).

Fibre

A systematic review and meta-analysis of 15 RCTs found a statistically significant effect in favour of dietary fibre compared with placebo in IBS (13). A subsequent review found fibre had no significant benefit compared with placebo (33), and fibre supplementation may also be associated with aggravation of symptoms for some patients with IBS (34).

Psyllium husks had a significant effect in treating IBS symptoms (13).
Insoluble fibres such as bran should be limited in IBS as they can exacerbate symptoms such as pain and bloating, and there is no evidence demonstrating efficacy in alleviating symptoms (6,13).
Prunes and prune fibre have demonstrated efficacy in alleviating constipation, with one meta-analysis demonstrating increased stool frequency and greater improvement in stool consistency compared with the administration of psyllium fibre in patients with IBS-C (35).
A total fibre intake of 20–30 g/day is recommended (6).

Lactose

While there is plenty of evidence that IBS patients commonly report milk intolerance, there is no conclusive evidence to suggest an objective link between IBS and any known malabsorption syndromes, including lactose malabsorption (36). Due to the similarity of clinical presentations of lactose intolerance and IBS and the high prevalence of both conditions in the general population, a hydrogen breath test should be performed in patients newly diagnosed with IBS to identify those who would be most likely to benefit from a lactose-free diet (36).

Gluten

There is little evidence to support a benefit of a gluten-free diet in IBS (18). However, because wheat contains fructan, a FODMAP, a gluten-free diet incorporates elements of a low FODMAP diet. Therefore, some patients might adapt a low FODMAP diet to one that instead avoids gluten (37).

Two small RCTs of gluten rechallenge among patients whose IBS responded to gluten withdrawal found no statistically significant effect on IBS symptoms between the gluten challenge and the gluten-free diet (38,39). Further larger studies are required.

Polyphenols

Polyphenols, such as green tea polyphenol, curcumin, resveratrol and quercetin, interact with the microbiome, producing various metabolites that influence dysbiosis and gastrointestinal tract (GIT) barrier permeability. These gastro-protective effects of polyphenols may be beneficial in IBS prevention and management (40,41). However, clinical trials are needed to confirm the theoretical benefit of polyphenols in IBS.

Dietary and herbal supplements

The commonly studied dietary and herbal supplements for IBS management are shown in Table 1. There is limited data available for the use of berberine (42), melatonin (43) and Boswellia caterii (44). Traditionally, herbal antispasmodic, laxative, antidiarrheal and anxiolytic formulas are used to treat various IBS symptoms.

Table 1 Commonly studied dietary and herbal supplements


Aloe vera (45,46,47)	250 mg Aloe barbadensis Mill. Extract (AVH200) twice daily (47). Avoid in IBS-D patients due to laxative effect.
Aniseed oil (48)	200 mg three times daily, enteric-coated anise oil capsule
Ginger (49,50)	1 g per day
Glutamine (51)	5 g three times daily in IBS-D following an enteric infection
Curcumin (52,53,54,55)	The combination of Curcumin and Foeniculum vulgare oil demonstrated efficacy in rigorously designed clinical trials (54). Dosing: 42 mg curcumin and 25 mg fennel essential oil. First 30 days: 2 capsules twice daily before meals. Next 30 days: Reduce to 2 capsules per day before a meal.
Peppermint oil (56,57,58,59)	Peppermint essential oil is both efficacious and well-tolerated in the short-term management of IBS (60). 1–2 capsules (180 mg each) three times daily, 15–30 min before food for 1 month (57). Improves abdominal pain, discomfort, and bloating; impact on motility is more limited (61). Heartburn is the most commonly reported adverse event.
St John’s wort (62,63,64)	Iberogast® (STW 5) has been proven to reduce abdominal pain and global IBS symptoms (63,64).

Microbial manipulation

Potential approaches that manipulate intestinal microbes are prebiotics, probiotics, synbiotics, and faecal microbial transplant (FMT).

Pre and probiotics

Some probiotics may be beneficial in IBS; however, which combination, strain or species should be preferred in any individual patient remains unclear (65). The quality of evidence is low, with the majority of trials being small and at unclear risk of bias. Overall, it is reasonable to advise patients wishing to try probiotics to take a combination product for up to 12 weeks, but to discontinue treatment if symptoms do not improve (3).

Probiotics, specifically Bifidobacteria, may improve abdominal pain in patients with IBS; however, RCT results are conflicting and vary based on strain, dosage and delivery method used (66).
Flortec, a symbiotic containing Lactobacillus paracasei B21060 as well as prebiotics, xylooligosaccharides, glutamine, and arabinogalactan, improved pain and well-being in patients with IBS-D compared with a preparation of the same three prebiotics (67).
The probiotic longum NCC3001 reduces depression scores, improves quality of life, and alters brain activity by reducing flow in multiple brain areas, including the amygdala and frontolimbic regions that are associated with negative emotional stimuli in patients with IBS (68).
Co-supplementation with Vitamin D₃ and probiotics (L. acidophilus, CUL60, CUL21, B. bifidum CUL20 and B. animalis subsp. lactis CUL34) did not provide benefit to IBS patients (69).
Gelsectan is a combination prebiotic containing xyloglucan, pea protein and tannins from grape seed extract, and xylooligosaccharides may be beneficial in patients with IBS-D (70).
The intake of inulin has been linked to the regulation of bowel peristalsis and transit, stool consistency and frequency, therefore making it particularly suitable for patients with IBS-C (71).

There are various pathophysiologic mechanisms of action of probiotics, prebiotics, and synbiotics via multidisciplinary domains in mitigating IBS symptoms. These include (72):

Gastroenterology (microbiota modulation, alteration of gut barrier function, visceral hypersensitivity, and GI dysmotility)
Immunology (intestinal immunological modulation)
Neurology (microbiota-gut-brain axis communication and comorbidities)

Faecal microbial transplant

Studies of the potential effect of FMT in IBS have yielded inconclusive results.

A systematic review and meta-analysis involving 267 patients showed no significant benefit of FMT whether administered by capsule, colonoscopy, or nasojejunal tube, with FMT almost equivalent to placebo (73).
There has been considerable interest in the results of a study using stool from a super-donor. The study compared placebo with 30-g and 60-g doses that were delivered via upper gastrointestinal endoscopy (74). While it appears that FMT from the super-donor was beneficial in the treatment of IBS compared with placebo, 75% of the treated patients still had moderate or severe IBS symptom severity after treatment. In addition, around 20% of the patients in the FMT group reported adverse effects of abdominal pain, cramping or tenderness, diarrhoea, or constipation compared with only 2% of patients in the placebo group.
It is important to recognise the risks of FMT, including the transmission of pathogenic bacteria (75).

Exercise

With respect to GI symptoms, exercise can accelerate GI transit (76), improve intestinal gas clearance in patients with bloating (77) and might increase gut microbial diversity, with the potential to positively impact symptoms via the gut-brain axis (78). It is, therefore, reasonable to assume that exercise will benefit patients with IBS.

Psychological interventions

Cognitive behavioural therapy and gut-directed hypnotherapy are the psychological therapies with the largest evidence base, with evidence of efficacy for up to 12 months follow-up (3,79,80). Other effective therapies include relaxation therapy, multicomponent psychological therapy, and dynamic psychotherapy (81).

Acupuncture

Acupuncture can also be considered as an adjunctive therapy for improvement of IBS symptoms and quality of life (82).

1	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 Aug;19(8):1538-1553.e14.
2	Wu JCY. Complementary and alternative medicine modalities for the treatment of irritable bowel syndrome: facts or myths? Gastroenterol Hepatol (N Y). 2010 Nov;6(11):705–11.
3	Black CJ, Ford AC. Best management of irritable bowel syndrome. Frontline Gastroenterol. 2021;12(4):303–15.
4	Camilleri M. Diagnosis and Treatment of Irritable Bowel Syndrome: A Review. JAMA. 2021 Mar 2;325(9):865–77.
5	Chey WD, Keefer L, Whelan K, Gibson PR. Behavioral and Diet Therapies in Integrated Care for Patients With Irritable Bowel Syndrome. Gastroenterology. 2021 Jan;160(1):47–62.
6	Lacy BE, Mearin F, Chang L, Chey WD, Lembo AJ, Simren M, et al. Bowel Disorders. Gastroenterology. 2016 May 1;150(6):1393-1407.e5.
7	Alammar N, Stein E. Irritable Bowel Syndrome: What Treatments Really Work. Med Clin North Am. 2019 Jan;103(1):137–52.
8	Ostgaard H, Hausken T, Gundersen D, El-Salhy M. Diet and effects of diet management on quality of life and symptoms in patients with irritable bowel syndrome. Mol Med Rep. 2012 Jun;5(6):1382–90.
9	Simrén M, Månsson A, Langkilde AM, Svedlund J, Abrahamsson H, Bengtsson U, et al. Food-related gastrointestinal symptoms in the irritable bowel syndrome. Digestion. 2001;63(2):108–15.
10	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 May;108(5):634–41.
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 Mar;65(1):1–10.
12	Harer KN, Eswaran SL. Irritable Bowel Syndrome: Food as a Friend or Foe? Gastroenterol Clin North Am. 2021 Mar;50(1):183–99.
13	Ford AC, Moayyedi P, Chey WD, Harris LA, Lacy BE, Saito YA, et al. American College of Gastroenterology Monograph on Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2018 Jun;113(Suppl 2):1–18.
14	Manning LP, Yao CK, Biesiekierski JR. Therapy of IBS: Is a Low FODMAP Diet the Answer? Front Psychiatry. 2020;11:865.
15	van Lanen A-S, de Bree A, Greyling A. Efficacy of a low-FODMAP diet in adult irritable bowel syndrome: a systematic review and meta-analysis. Eur J Nutr. 2021 Feb 14.
16	Monash University. Starting the Low FODMAP Diet [Internet]. 2019 [cited 2021 Aug 18]. Available from: https://www.monashfodmap.com/ibs-central/i-have-ibs/starting-the-low-fodmap-diet/
17	El-Salhy M, Patcharatrakul T, Gonlachanvit S. The role of diet in the pathophysiology and management of irritable bowel syndrome. Indian J Gastroenterol. 2021 Apr;40(2):111–9.
18	Dionne J, Ford AC, Yuan Y, Chey WD, Lacy BE, Saito YA, 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 Sep;113(9):1290–300.
19	Schumann D, Klose P, Lauche R, Dobos G, Langhorst J, Cramer H. Low fermentable, oligo-, di-, mono-saccharides and polyol diet in the treatment of irritable bowel syndrome: A systematic review and meta-analysis. Nutrition. 2018 Jan;45:24–31.
20	Krogsgaard LR, Lyngesen M, Bytzer P. Systematic review: quality of trials on the symptomatic effects of the low FODMAP diet for irritable bowel syndrome. Aliment Pharmacol Ther. 2017 Jun;45(12):1506–13.
21	Böhn L, Störsrud S, Liljebo T, Collin L, Lindfors P, Törnblom H, et al. Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: a randomized controlled trial. Gastroenterology. 2015 Nov;149(6):1399-1407.e2.
22	Eswaran SL, Chey WD, Han-Markey T, Ball S, Jackson K. A Randomized Controlled Trial Comparing the Low FODMAP Diet vs. Modified NICE Guidelines in US Adults with IBS-D. Am J Gastroenterol. 2016 Dec;111(12):1824–32.
23	Spiller R. Impact of Diet on Symptoms of the Irritable Bowel Syndrome. Nutrients. 2021 Feb 9;13(2):575.
24	Catassi G, Lionetti E, Gatti S, Catassi C. The Low FODMAP Diet: Many Question Marks for a Catchy Acronym. Nutrients. 2017 Mar 16;9(3):E292.
25	Halmos EP, Christophersen CT, Bird AR, Shepherd SJ, Gibson PR, Muir JG. Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut. 2015 Jan;64(1):93–100.
26	Staudacher HM, Whelan K. The low FODMAP diet: recent advances in understanding its mechanisms and efficacy in IBS. Gut. 2017 Aug;66(8):1517–27.
27	Storhaug CL, Fosse SK, Fadnes LT. Country, regional, and global estimates for lactose malabsorption in adults: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2017 Oct;2(10):738–46.
28	El-Salhy M, Ostgaard H, Gundersen D, Hatlebakk JG, Hausken T. The role of diet in the pathogenesis and management of irritable bowel syndrome (Review). Int J Mol Med. 2012 May;29(5):723–31.
29	McKenzie YA, Bowyer RK, Leach H, Gulia P, Horobin J, O’Sullivan NA, et al. British Dietetic Association systematic review and evidence-based practice guidelines for the dietary management of irritable bowel syndrome in adults (2016 update). J Hum Nutr Diet. 2016 Oct;29(5):549–75.
30	McKenzie YA, Thompson J, Gulia P, Lomer MCE, (IBS Dietetic Guideline Review Group on behalf of Gastroenterology Specialist Group of the British Dietetic Association). British Dietetic Association systematic review of systematic reviews and evidence-based practice guidelines for the use of probiotics in the management of irritable bowel syndrome in adults (2016 update). J Hum Nutr Diet. 2016 Oct;29(5):576–92.
31	National Institute for Health and Care Excellence. Irritable bowel syndrome in adults: diagnosis and management [Internet]. NICE; 2017 [cited 2021 Aug 21]. Available from: https://www.nice.org.uk/guidance/cg61
32	Dapoigny M, Stockbrügger RW, Azpiroz F, Collins S, Coremans G, Müller-Lissner S, et al. Role of alimentation in irritable bowel syndrome. Digestion. 2003;67(4):225–33.
33	Black CJ, Yuan Y, Selinger CP, Camilleri M, Quigley EMM, Moayyedi P, 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 Feb;5(2):117–31.
34	Bijkerk CJ, de Wit NJ, Muris JWM, Whorwell PJ, Knottnerus JA, Hoes AW. Soluble or insoluble fibre in irritable bowel syndrome in primary care? Randomised placebo controlled trial. BMJ. 2009 Aug 27;339:b3154.
35	Lever E, Cole J, Scott SM, Emery PW, Whelan K. Systematic review: the effect of prunes on gastrointestinal function. Aliment Pharmacol Ther. 2014 Oct;40(7):750–8.
36	Cancarevic I, Rehman M, Iskander B, Lalani S, Malik BH. Is There a Correlation Between Irritable Bowel Syndrome and Lactose Intolerance? Cureus. 2020 Jan 20;12(1):e6710.
37	O’Keeffe LM, Kearney PM, McCarthy FP, Khashan AS, Greene RA, North RA, et al. Prevalence and predictors of alcohol use during pregnancy: findings from international multicentre cohort studies. BMJ Open. 2015 May 29;5(7).
38	Biesiekierski JR, Newnham ED, Irving PM, Barrett JS, Haines M, Doecke JD, et al. Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol. 2011 Mar;106(3):508–14.
39	Shahbazkhani B, Sadeghi A, Malekzadeh R, Khatavi F, Etemadi M, Kalantri E, et al. Non-Celiac Gluten Sensitivity Has Narrowed the Spectrum of Irritable Bowel Syndrome: A Double-Blind Randomized Placebo-Controlled Trial. Nutrients. 2015 Jun 5;7(6):4542–54.
40	Chiu H-F, Venkatakrishnan K, Golovinskaia O, Wang C-K. Gastroprotective Effects of Polyphenols against Various Gastro-Intestinal Disorders: A Mini-Review with Special Focus on Clinical Evidence. Molecules. 2021 Apr 6;26(7):2090.
41	Hagan M, Hayee BH, Rodriguez-Mateos A. (Poly)phenols in Inflammatory Bowel Disease and Irritable Bowel Syndrome: A Review. Molecules. 2021 Mar 25;26(7):1843.
42	Chen C, Tao C, Liu Z, Lu M, Pan Q, Zheng L, et al. A Randomized Clinical Trial of Berberine Hydrochloride in Patients with Diarrhea-Predominant Irritable Bowel Syndrome. Phytother Res. 2015 Nov;29(11):1822–7.
43	Saha L, Malhotra S, Rana S, Bhasin D, Pandhi P. A preliminary study of melatonin in irritable bowel syndrome. J Clin Gastroenterol. 2007 Jan;41(1):29–32.
44	Kazemian A, Toghiani A, Shafiei K, Afshar H, Rafiei R, Memari M, et al. Evaluating the efficacy of mixture of Boswellia carterii, Zingiber officinale, and Achillea millefolium on severity of symptoms, anxiety, and depression in irritable bowel syndrome patients. J Res Med Sci. 2017;22:120.
45	Davis K, Philpott S, Kumar D, Mendall M. Randomised double-blind placebo-controlled trial of aloe vera for irritable bowel syndrome. Int J Clin Pract. 2006 Sep;60(9):1080–6.
46	Hutchings HA, Wareham K, Baxter JN, Atherton P, Kingham JGC, Duane P, et al. A Randomised, Cross-Over, Placebo-Controlled Study of Aloe vera in Patients with Irritable Bowel Syndrome: Effects on Patient Quality of Life. ISRN Gastroenterol. 2011;2011:206103.
47	Størsrud S, Pontén I, Simrén M. A Pilot Study of the Effect of Aloe barbadensis Mill. Extract (AVH200®) in Patients with Irritable Bowel Syndrome: a Randomized, Double-Blind, Placebo-Controlled Study. J Gastrointestin Liver Dis. 2015 Sep;24(3):275–80.
48	Mosaffa-Jahromi M, Lankarani KB, Pasalar M, Afsharypuor S, Tamaddon A-M. Efficacy and safety of enteric coated capsules of anise oil to treat irritable bowel syndrome. J Ethnopharmacol. 2016 Dec 24;194:937–46.
49	Al-Jassim ZG. Using Brewer’s yeast and Ginger in the management of Constipation-Predominant Irritable bowel syndrome (IBS-C): A randomized double-blind placebo-controlled trial. Asian Journal of Pharmaceutical and Clinical Research. 2019 Mar 7;12(3):372–6.
50	van Tilburg MAL, Palsson OS, Ringel Y, Whitehead WE. Is ginger effective for the treatment of irritable bowel syndrome? A double blind randomized controlled pilot trial. Complement Ther Med. 2014 Feb;22(1):17–20.
51	Zhou Q, Verne ML, Fields JZ, Lefante JJ, Basra S, Salameh H, et al. Randomised placebo-controlled trial of dietary glutamine supplements for postinfectious irritable bowel syndrome. Gut. 2019 Jun;68(6):996–1002.
52	Alt F, Chong P-W, Teng E, Uebelhack R. Evaluation of Benefit and Tolerability of IQP-CL-101 (Xanthofen) in the Symptomatic Improvement of Irritable Bowel Syndrome: A Double-Blinded, Randomised, Placebo-Controlled Clinical Trial. Phytother Res. 2017 Jul;31(7):1056–62.
53	Brinkhaus B, Hentschel C, Von Keudell C, Schindler G, Lindner M, Stützer H, et al. Herbal medicine with curcuma and fumitory in the treatment of irritable bowel syndrome: a randomized, placebo-controlled, double-blind clinical trial. Scand J Gastroenterol. 2005 Aug;40(8):936–43.
54	Di Ciaula A, Portincasa P, Maes N, Albert A. Efficacy of bio-optimized extracts of turmeric and essential fennel oil on the quality of life in patients with irritable bowel syndrome. Ann Gastroenterol. 2018;31(6):685–91.
55	Portincasa P, Bonfrate L, Scribano MLL, Kohn A, Caporaso N, Festi D, et al. Curcumin and Fennel Essential Oil Improve Symptoms and Quality of Life in Patients with Irritable Bowel Syndrome. J Gastrointestin Liver Dis. 2016 Jun;25(2):151–7.
56	Alam MS, Roy PK, Miah AR, Mollick SH, Khan MR, Mahmud MC, et al. Efficacy of Peppermint oil in diarrhea predominant IBS - a double blind randomized placebo - controlled study. Mymensingh Med J. 2013 Jan;22(1):27–30.
57	Cash BD, Epstein MS, Shah SM. A Novel Delivery System of Peppermint Oil Is an Effective Therapy for Irritable Bowel Syndrome Symptoms. Dig Dis Sci. 2016 Feb;61(2):560–71.
58	Merat S, Khalili S, Mostajabi P, Ghorbani A, Ansari R, Malekzadeh R. The effect of enteric-coated, delayed-release peppermint oil on irritable bowel syndrome. Dig Dis Sci. 2010 May;55(5):1385–90.
59	Weerts ZZRM, Masclee AAM, Witteman BJM, Clemens CHM, Winkens B, Brouwers JRBJ, et al. Efficacy and Safety of Peppermint Oil in a Randomized, Double-Blind Trial of Patients With Irritable Bowel Syndrome. Gastroenterology. 2020 Jan;158(1):123–36.
60	Hawrelak JA, Wohlmuth H, Pattinson M, Myers SP, Goldenberg JZ, Harnett J, et al. Western herbal medicines in the treatment of irritable bowel syndrome: A systematic review and meta-analysis. Complement Ther Med. 2020 Jan;48:102233.
61	Chey WD. SYMPOSIUM REPORT: An Evidence-Based Approach to IBS and CIC: Applying New Advances to Daily Practice: A Review of an Adjunct Clinical Symposium of the American College of Gastroenterology Meeting October 16, 2016 Las Vegas, Nevada. Gastroenterol Hepatol (N Y). 2017 Feb;13(2 Suppl 1):1–16.
62	Saito YA, Rey E, Almazar-Elder AE, Harmsen WS, Zinsmeister AR, Locke GR, et al. A randomized, double-blind, placebo-controlled trial of St John’s wort for treating irritable bowel syndrome. Am J Gastroenterol. 2010 Jan;105(1):170–7.
63	Ottillinger B, Storr M, Malfertheiner P, Allescher H-D. STW 5 (Iberogast®)—a safe and effective standard in the treatment of functional gastrointestinal disorders. Wien Med Wochenschr. 2013 Feb;163(3–4):65–72.
64	Simmen U, Kelber O, Okpanyi SN, Jaeggi R, Bueter B, Weiser D. Binding of STW 5 (Iberogast) and its components to intestinal 5-HT, muscarinic M3, and opioid receptors. Phytomedicine. 2006;13 Suppl 5:51–5.
65	Ford AC, Harris LA, Lacy BE, Quigley EMM, Moayyedi P. Systematic review with meta-analysis: the efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable bowel syndrome. Aliment Pharmacol Ther. 2018 Nov;48(10):1044–60.
66	Pratt C, Campbell MD. The Effect of Bifidobacterium on Reducing Symptomatic Abdominal Pain in Patients with Irritable Bowel Syndrome: A Systematic Review. Probiotics Antimicrob Proteins. 2020 Sep;12(3):834–9.
67	Andriulli A, Neri M, Loguercio C, Terreni N, Merla A, Cardarella MP, et al. Clinical trial on the efficacy of a new symbiotic formulation, Flortec, in patients with irritable bowel syndrome: a multicenter, randomized study. J Clin Gastroenterol. 2008 Sep;42 Suppl 3 Pt 2:S218-223.
68	Pinto-Sanchez MI, Hall GB, Ghajar K, Nardelli A, Bolino C, Lau JT, et al. Probiotic Bifidobacterium longum NCC3001 Reduces Depression Scores and Alters Brain Activity: A Pilot Study in Patients With Irritable Bowel Syndrome. Gastroenterology. 2017 Aug;153(2):448-459.e8.
69	Tazzyman S, Richards N, Trueman AR, Evans AL, Grant VA, Garaiova I, et al. Vitamin D associates with improved quality of life in participants with irritable bowel syndrome: outcomes from a pilot trial. BMJ Open Gastroenterol. 2015;2(1):e000052.
70	Trifan A, Burta O, Tiuca N, Petrisor DC, Lenghel A, Santos J. Efficacy and safety of Gelsectan for diarrhoea-predominant irritable bowel syndrome: A randomised, crossover clinical trial. United European Gastroenterol J. 2019 Oct;7(8):1093–101.
71	Bărboi O-B, Ciortescu I, Chirilă I, Anton C, Drug V. Effect of inulin in the treatment of irritable bowel syndrome with constipation (Review). Exp Ther Med. 2020 Dec;20(6):185.
72	Simon E, Călinoiu LF, Mitrea L, Vodnar DC. Probiotics, Prebiotics, and Synbiotics: Implications and Beneficial Effects against Irritable Bowel Syndrome. Nutrients. 2021 Jun 20;13(6):2112.
73	Ianiro G, Eusebi LH, Black CJ, Gasbarrini A, Cammarota G, Ford AC. Systematic review with meta-analysis: efficacy of faecal microbiota transplantation for the treatment of irritable bowel syndrome. Aliment Pharmacol Ther. 2019 Aug;50(3):240–8.
74	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 May;69(5):859–67.
75	US Food and Drug Administration. Fecal Microbiota for Transplantation: Safety Alert - Risk of Serious Adverse Events Likely Due to Transmission of Pathogenic Organisms [Internet]. FDA. 2020 [cited 2021 Aug 21]. Available from: https://www.fda.gov/safety/medical-product-safety-information/fecal-microbiota-transplantation-safety-alert-risk-serious-adverse-events-likely-due-transmission
76	Strid H, Simrén M, Störsrud S, Stotzer P-O, Sadik R. Effect of heavy exercise on gastrointestinal transit in endurance athletes. Scand J Gastroenterol. 2011 Jun;46(6):673–7.
77	Villoria A, Serra J, Azpiroz F, Malagelada J-R. Physical activity and intestinal gas clearance in patients with bloating. Am J Gastroenterol. 2006 Nov;101(11):2552–7.
78	Dalton A, Mermier C, Zuhl M. Exercise influence on the microbiome-gut-brain axis. Gut Microbes. 2019;10(5):555–68.
79	Black CJ, Thakur ER, Houghton LA, Quigley EMM, Moayyedi P, Ford AC. Efficacy of psychological therapies for irritable bowel syndrome: systematic review and network meta-analysis. Gut. 2020 Aug;69(8):1441–51.
80	Krouwel M, Farley A, Greenfield S, Ismail T, Jolly K. Systematic review, meta-analysis with subgroup analysis of hypnotherapy for irritable bowel syndrome, effect of intervention characteristics. Complement Ther Med. 2021 Mar;57:102672.
81	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 Jan;114(1):21–39.
82	Zheng H, Chen R, Zhao X, Li G, Liang Y, Zhang H, et al. Comparison between the Effects of Acupuncture Relative to Other Controls on Irritable Bowel Syndrome: A Meta-Analysis. Pain Res Manag. 2019 Nov 11;2019:2871505.