Introduction

Irritable bowel syndrome (IBS) affects 15% of the population in the USA, and functional bowel disorders make up to 40% of the visits to the gastroenterologist [1, 2]. Rome IV characterizes IBS by recurrent abdominal pain weekly for at least 3 months associated with changes in bowel habits; symptoms must have started at least 6 months before establishing a diagnosis. The various subtypes of the disease include IBS-D (diarrhea predominant), IBS-C (constipation-predominant), or IBS-M (mixed diarrhea and constipation) [3]. Over the years, the complexity and heterogeneity of the mechanisms of IBS have led to a more forward-thinking approach to a disease state than a syndrome. The complexity in the pathophysiological pathways may contribute to the challenges in treating patients with IBS successfully using conventional medicine alone. Thirty percent to 50% of patients with IBS turn to complementary health approaches to manage their condition [4,5,6].

Complementary health approaches include an array of modalities and products with a history of use or origins outside of conventional Western medicine. Although the words complementary and alternative are often grouped, they are distinct. A National Institute of Health (NIH) 2012 survey revealed that the majority of persons use complementary medicine to augment conventional medicine and only less than 5% use complementary medicine as a replacement [7]. In December 2014, the NIH changed the agency name from the National Center for Complementary and Alternative Medicine (NCCAM) to the National Center for Complementary and Integrative Health (NCCIH) to better align with the organization’s strategic plan for public education and research.

The philosophy of complementary medicine is based on a holistic approach wherein all disease results from disturbances on physical, psychological, social, and spiritual levels. Complementary health modalities are used to restore balance and facilitate the body’s healing to improve troublesome symptoms.

A significant trend in the use of complementary health approaches is observed in female gender, higher BMI, non-Hispanic whites, adults with some college degree or higher, and patients with private insurance. Patients who are more symptomatic and experience an overall feeling of dissatisfaction with conventional therapy also turn towards complementary medicine [6,7,8]. The most commonly used complementary health therapies are non-vitamin, non-mineral dietary supplements. Ginger, peppermint, and probiotics or digestive enzymes were predominant in this category. Following herbs and supplements were mind-body therapies, which included gut-directed hypnosis, biofeedback, meditation, yoga, and tai chi, among other guided-imagery exercises (Table 1) [7].

Table 1 Complementary health modalities
Full size table

There are numerous challenges in study design and implementation with these modalities, particularly as it pertains to studies evaluating different diets or the incorporation of mind-body medicine to assess outcomes. IBS trials also show a strong placebo response, a recent meta-analysis finding an average placebo response rate of 37.5% [9]. Over the past 3–5 years, there has been a growing body of evidence in the form of randomized placebo-controlled trials and meta-analysis comparing the safety and efficacy of complementary health modalities therapies. This review intends to share the body of evidence for the most common modalities that are gaining wider use among our patients with functional bowel disorders, particularly IBS, an entity that can be difficult to manage and presents with significant economic health costs.

Microbiome-directed therapy

Currently, it is recognized that alterations in the gut microbiome and gut immune function are implicated, to some degree, in the development of IBS [10, 11••, 12]. Increasing research on the human microbiome highlighted the role of gut microbial dysbiosis in IBS. In the Swedish study by Tap et al., using the microbial signature for IBS, severity was associated with low microbial richness, reduced breath methane levels, and enrichment of Bacteroides enterotypes [11]. In a recent meta-analysis by Pittayanon et al., differences in stool microbiome in patients with IBS of different subtypes were compared to healthy cohorts. The study concluded that family Enterobacteriaceae (phylum Proteobacteria), family Lactobacillaceae, and genus Bacteroides are increased in patients with IBS compared with controls. In contrast, uncultured Clostridiales I, genus Faecalibacterium, and genus Bifidobacterium were decreased in patients with IBS [12]. Wang et al. in a more comprehensive analysis of 23 included studies with 1340 subjects across the globe reported their results of a data synthesis on the stool microbiome of IBS patients. They reported that individuals with diarrhea-predominant IBS (IBS-D) have increased fecal Enterobacter and are deficient in Lactobacillus and Bifidobacterium species when compared to healthy controls. In a subgroup analysis of Asian studies, Bacteroides was increased in stool of IBS-D subjects when compared to healthy controls [13].

Studies on post infection IBS and notably the development of small intestinal bacterial overgrowth have provided etiological insights into the pathogenesis of IBS [14•, 15, 16]. In a systematic review and meta-analysis of 25 studies with 3192 patients with IBS and 3320 controls, SIBO prevalence in patients with IBS was significantly increased compared with controls (OR = 3.7, 95% CI 2.3–6.0) [17]. In a cohort study of 104 included patients, herbal therapies were non-inferior to rifaximin for the induction of remission for SIBO. The odds ratio of having a negative lactulose breath test after taking herbal therapy as compared to rifaximin was 1.85 (CI = 0.77–4.41, p = 0.17) once adjusted for age, gender, SIBO risk factors, and IBS status [18].

Attempts to restore healthy gut microbiota through diet, prebiotics, probiotics, and antibiotics to alleviate IBS symptoms have been demonstrated [19]. Complementary health approaches that may lead to changes in the gut microbiome are continually explored in patients with IBS.

Diet: fiber, gluten elimination, and low FODMAPS

Fiber—psyllium (ispaghula)

Dietary fiber is a type of carbohydrate found in edible plant foods resistant to digestion and absorption in the small intestine. Psyllium contains 70% soluble fiber and can help improve stool viscosity, can lead to a laxation effect through stool bulking, and though poorly fermentable can increase the production of short-chain fatty acids (SCFA). SCFA, particularly butyrate, promotes changes in the intestinal microbiota and immune and neuroendocrine systems [20, 21]. A recent meta-analysis that included 14 randomized controlled trials showed that soluble fiber, such as psyllium or wheat dextrin, had a benefit for global improvement of IBS (number needed to treat NNT 7) compared to wheat bran [22]. Similarly, a European meta-analysis concluded that soluble fiber improved global assessment of symptoms (RR 1.49; 95% CI 1.09–2.03) and abdominal pain score (mean difference: − 1.84, 95% CI − 2.72 to − 0.97), whereas insoluble fiber did not show benefit [23]. Complex long-chain carbohydrates are recommended for patients with IBS-C and IBS-M. The fermentation process is slower, resulting in reduced abdominal distension and bloating.

Gluten elimination

Few studies have suggested that IBS patients improve on a gluten-free diet, as it reduces fructan intake, a short-chain carbohydrate, fructooligosaccharide [24]. However, a meta-analysis evaluating gluten elimination in patients with IBS found insufficient evidence to recommend this diet for IBS [25]. A systematic review and meta-analysis found an increased prevalence of celiac disease worldwide among individuals with IBS symptoms [26], therefore highlighting the importance of testing patients with IBS symptoms for celiac disease, notably before a gluten elimination challenge. However, sustained gluten elimination in all patients with IBS is not proven to be beneficial though clearly further studies are needed.

Low FODMAPS

Numerous studies have shown improvement in 50–75% of patients with IBS on the low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (LFD) diet [27,28,29,30]. The diet involves a global restriction of FODMAP intake for 4–6 weeks, followed by a gradual reintroduction of foods containing individual FODMAP to determine a patient’s tolerances. This information is then used to personalize and liberalize the low FODMAPS diet for each individual patient. The physiological effects of FODMAPS include osmotic activity increasing luminal fluid volume, fermentation resulting in increased hydrogen and methane gas production [31], increased lipopolysacccharides leading to changes in gut permeability, intestinal inflammation, and visceral hypersensitivity resulting in abdominal symptoms such as pain and bloating [32]. Their fermentation by bacteria in the colon produces excess gas. The LFD improves symptoms of diarrhea, abdominal pain, distention, and bloating.

Restriction of oligosaccharides for 3–4 weeks resulted in a 6-fold reduction in Bifidobacteria in patients with IBS compared to healthy controls, along with providing symptom relief [33, 34]. However, studies evaluating gut microbiota in patients on LFD have shown inconsistent results possible due to heterogeneity in study design and protocols [35].

Data on the long-term use of an LFD diet are limited, and prolonged full dietary FODMAP restriction is not recommended. Some disadvantages of this particular diet are its complexity and high expense [36, 37]. The collaboration with a GI dietician is essential to identify which patients will benefit most from the diet, ensure compliance, and avoid over restriction, which may lead to nutritional deficiency, orthorexia, and avoidant restrictive food intake disorder.

Prebiotics, probiotics, and fecal microbial transplantation

Prebiotics are high-fiber foods that can positively modulate gut microbiota composition. In particular, inulin and oligofructose are shown to have a bifidogenic effect. However, to date, there are insufficient clinical trials using prebiotics and symbiotics to support the efficacy and use in patients with IBS [38, 39].

Probiotics are live microorganisms that promote health benefits through alterations or interactions with the intestinal microbiome. Probiotics containing Bifidobacterium lactis have been shown to accelerate whole gut transit and improve symptoms in patients with IBS-C [40]. In a recent randomized, double-blind placebo-controlled study in 443 adult patients with IBS, the daily use on one capsule of non-viable B. bifidum for 8 weeks revealed a significant improvement in overall IBS symptoms during treatment: 34% of 221 patients in the B. bifidum HI-MIMBb75 group compared with 19% of 222 in the placebo group (risk ratio 1·7, 95% CI 1·3–2·4; p = 0.0007) [41]. In recent years, several systematic reviews and meta-analysis, although limited by significant heterogenicity, have shown safety and significant benefit of using probiotics in increasing stool frequency and consistency in patients with IBS-C [42]. Similar results were noted in the most recent meta-analysis of 59 studies, including 6761 patients with IBS by Li et al. with a relative risk 1.52 (95% CI 1.32–1.76) in the improvement of symptoms in patients on probiotics versus placebo [43]. However, to date, there is insufficient data to determine which species, multi-strain versus single strain, dose, and duration of therapy have significant efficacy on IBS and subtypes. In 2018, the American College of Gastroenterology Monograph on Management of IBS suggested that probiotics taken as a group may improve global symptoms as well as bloating and flatulence in IBS patients, albeit the recommendation was weak as the quality of evidence low [29]. In the recently published AGA clinical practice guidelines, the recommendation is for the use of probiotics for IBS only in the context of clinical trials until further studies bridge the knowledge gap [44].

Fecal microbiota transplantation (FMT)

FMT provides a method to restore the abnormal gut microbiome. There has been inconsistent data and the absence of large-scale, long-term endpoints of randomized controlled trials to determine the effect on FMT on IBS symptoms [45,46,47]. In a recent randomized double-blind, placebo-controlled of 165 patients, reduction in IBS symptoms at 3 months occurred in 23.6%, 76.9% (p < 0.0001), and 89.1% (p < 0.0001) of the patients who received placebo, 30 g FMT, and 60 g FMT, respectively. The findings are promising and may provide further insights into the pathophysiology and the role of the gut microbiota in IBS; however, additional studies with larger populations and subtypes of IBS are needed [48].

Biologic-based therapy

Peppermint oil (PO)

Mentha piperita L. Menthacarin is the primary component of the PO responsible for its medicinal properties. It has several mechanisms of action, including intestinal smooth muscle relaxation, modulation of transient receptor potential (TRP) channel-mediated visceral nociception, 5-hydroxytryptamine antagonism, antimicrobial and antifungal effects, and κ-opioid receptor agonism.

In a meta-analysis by Alammar et al., 835 patients concluded that the risk ratio (RR) from seven RCTs for the effect of PO (n = 253) versus placebo (n = 254) on global symptoms was 2.39 (95% confidence interval (CI) 1.93–2.97, I2 = 0%, z = 7.93, p < 0.00001). The number needed to treat with the PO to prevent one patient from having persistent symptoms was three for global symptoms and four for abdominal pain [49]. A similar result was noted in the meta-analysis by Hawrelak et al. and revealed improved global IBS symptoms in PO treatment group compared with placebo groups after removal of trials with heterogeneity bias (RR = 2.14, 95% CI 1.71 to 2.66, p < 0.00001) [50].

A recently published Dutch RCT by Weerts et al. with 190 patients with IBS meeting Rome IV criteria randomly assigned to groups given 182 mg small intestinal release PO, 182 mg ileocolonic release PO, or placebo three times a day for 8 weeks revealed conflicting outcomes. The primary endpoint of abdominal pain response did not differ significantly between the PO and placebo groups. There was no benefit in the ileocolonic release group. There was some improvement in the small intestinal PO group when compared to the placebo group in terms of secondary outcomes of abdominal pain (p = .016), discomfort (p = .020), and IBS severity (p = .020) [51]. The differences noted may be attributed to the formulations used and the modest sample size.

Overall, there is sufficient clinical evidence to support the use of small intestinal release PO to reduce symptoms in patients with IBS. Adverse effects of high-dose PO include gastroesophageal reflux disease by decreasing lower esophageal sphincter pressure. Drug interactions for medications metabolized through cytochrome P450 have also been noted. The safety of peppermint oil with pregnancy has not been demonstrated.

STW 5

STW 5 consists of a liquid formulation of nine herbs used in clinical practice for the treatment of functional dyspepsia. It includes extracts from bitter candytuft, angelica root, milk thistle fruit, celandine herb, caraway fruit, licorice root, peppermint herb, balm leaf, and chamomile flower. These active ingredients are thought to act synergistically to ease functional gastrointestinal symptoms [52].

There is only one randomized, double-blind, multicenter placebo-controlled clinical trial on the efficacy and safety of STW 5 in patients with IBS. A total of 208 patients were randomized to receive STW 5 in 2 different formulations or placebo over 4 weeks. It was found that STW 5 and STW 5-II significantly reduced total abdominal pain (p = 0.0009) and IBS symptoms (p = 0.001) compared with the placebo group [53]. In clinical practice, the benefit is seen in some patients with IBS; however, more RCTs are needed to determine dose requirements, duration, and efficacy in IBS subtypes.

Berberine

Berberine is an alkaloid obtained by extraction from Berberis spp. It is effective in limiting diarrhea due to its multi-factorial properties, including its antimicrobial, gut eubiotic and antisecretory actions, and its ability to slow gut motility [54]. The alkaloid is often a component of a multi-herbal herbal mixture, so its effects in isolation are difficult to know. It has been used as a component of a multi-herb antimicrobial formulation for the treatment of small intestinal bacterial overgrowth [18].

In a study by Chen et al., 132 patients were randomized to receive berberine hydrochloride 400 mg daily in two divided doses or placebo, delivered twice daily or placebo for 8 weeks followed by a 4-week washout period. The effects of berberine hydrochloride on IBS-D were significant in the berberine group with a reduction in the frequency of diarrhea (p = 0.032), abdominal pain (p < 0.01), and urgent need for defecation (p < 0.01) compared the placebo group [55]. The exact mechanism of berberine on the gut microbiome is not clear and more studies are encouraged.

Curcumin

Turmeric is a spice from a plant of the ginger family, Zingiberaceae, and its active component is curcumin. It has antioxidant and anti-inflammatory properties with the ability to modulate gut microbiota.

In a meta-analysis by Ng et al., of 5 RCT including 326 patients, curcumin was shown to have a beneficial albeit not statistically significant effect on IBS symptoms. There was significant heterogenicity in doses of curcumin and duration of treatment [56].

A smaller non-randomized control trial has suggested some improvement in the quality of life and reduced IBS symptoms on a combined regimen of curcumin and fennel oil [57].

In conclusion, while curcumin appears to have potential clinical benefits, further studies are needed to assess IBS efficacy.

Aloe vera

Aloe vera (AV) is a plant frequently used in Ayurvedic, homeopathic, and allopathic treatments. The plant is famed for its medicinal healing properties in prevention or healing injury of epithelial tissues, and its potent laxative effect. Studies suggest that it also possesses several pharmacological actions including antioxidant, anti-inflammatory, analgesic, anti-proliferative, and anti-diabetic properties.

Several studies evaluated the use of AV in patients with IBS and found no significant benefit in symptoms than placebo groups [58,59,60]. In a more recent meta-analysis by Hong et al., three RCTs with a total of 151 patients with IBS, a statistically significant difference in IBS symptoms score for patients taking AV compared to those on placebo (standardized mean difference, 0.41; 95% CI, 0.07–0.75; p = 0.020). Using intention-to-treat analysis, the AV patients showed significantly better response rates of IBS symptoms than placebo (pooled risk ratio, 1.69; 95% CI, 1.05–2.73; p = 0.030). No adverse events related to AV were found [61]. There may be a role for the uses of Aloe vera in the treatment for IBS-C, but additional randomized control trials are needed to determine dose, frequency, and duration.

Additional biologic-based nutraceuticals that have shown some potential benefit in reducing IBS symptoms include geraniol and glutamine. Geraniol (Ge-OH) is a naturally occurring acyclic monoterpene component of essential oils extracted from lemongrass, rose, and other aromatic plants. Several studies on the biological activities of Ge-OH have shown it to be a highly active antimicrobial compound with antioxidant and anti-inflammatory properties [62]. Glutamine, a nonessential amino acid, known for its role in the intestinal barrier and immune function of the gastrointestinal tract, may have some potential benefit by reducing intestinal permeability in patients with postinfectious IBS. In a randomized controlled study by Zhou et al., 54 IBS D subjects received glutamine (5 g in three divided doses) and 52 placebo subjects for 8 weeks. Reduction in Irritable Bowel Syndrome Severity Scoring System (IBS-SS) was noted in 43 (79.6%) in the glutamine group and 3 (5.8%) in the placebo group (a 14-fold difference). Glutamine also reduced all secondary endpoint means: IBS-SS score at 8 weeks (301 vs 181, p < 0.0001), daily bowel movement frequency (5.4 vs 2.9 ± 1.0, p < 0.0001), Bristol Stool Scale (6.5 vs 3.9, p < 0.0001), and intestinal permeability (0.11 vs 0.05; p < 0.0001) [63]. Larger studies are needed to determine the therapeutic doses and sustained efficacy for use of glutamine in post infection IBS. Supplements such as ginger and CBD oil have been studied in smaller trials which have not shown any significant benefit in relieving IBS symptoms. Traditional Chinese herbal medicine (CHM) such as Tong-Xie-Yao-Fang (TXYF) has shown high rate of relief of diarrhea and abdominal in small RCT. Recent meta-analysis of RCT using an array of CHM has demonstrated superior global symptom improvement when compared with placebo [64]. However, the heterogeneity, potential for interactions, and adverse effects are not negligible. More research is necessary to determine mechanistic roles of the individual herbs as dose titrations remain unclear [65].

Conclusion

Increasing understanding of the complex multisystemic pathophysiologic pathway of IBS suggests that treatment may warrant a multidisciplinary approach, to include complementary health modalities. There is strong evidence to support the benefits of diet, cognitive behavioral therapy, gut-directed hypnotherapy, herbal medicine acupuncture, and mindfulness-based therapies for the treatment of IBS [66,67,68]. Strategies to alter the gut microbiome using diet, probiotics, and biologic-based nutraceuticals have shown moderate to significant improvement with IBS global symptoms. Future studies are necessary to understand the ever-evolving etiologies and customize these treatment options for IBS subpopulations using precision medicine platforms that provide genetic, gut microbiome, and metabolomic data to refine dietary and other aforementioned interventions. Furthermore, defining treatment duration, standardizing dosage, and assessing for potential adverse effects or interactions with conventional drugs are essential.

Overall, patients with IBS contribute to high proportion of gastroenterology visits. The symptoms are chronic and recurring with significant impact on patients’ quality of life and healthcare costs. Expanding our treatment armamentarium beyond conventional medicine provides a more comprehensive therapeutic approach to managing IBS. Several surveys of providers demonstrate a bias against complementary approaches despite the evidence, and IBS patients are reluctant to disclose the use of complementary health modalities. Patients also report that they take complementary therapies for additional control of their disease and that they derive benefit from them. As clinicians, we should take the totality of evidence in context and partner with our patients with the goal of improving outcomes and patient satisfaction as IBS patients benefit by improved provider relationship. In 1996 the astronomer and science educator Carl Sagan included a saying in his book “The Demon-Haunted World: Science as a Candle in the Dark,” which provides insight for the IBS provider: “Keeping an open mind is a virtue—but, not so open that your brains fall out” [69].