SIBO and Anti-Inflammatories Boswellia & Curcumin

Reference

Giacosa A, Riva A, Petrangolini G, et al. Beneficial effects on abdominal bloating with an innovative food‐grade formulation of Curcuma longa and Boswellia serrata extracts in subjects with irritable bowel syndrome and small bowel dysbiosis. Nutrients. 2022;14(3):416.

Study Objective

To determine if supplemental phytosomal Boswellia serrata and curcumin will improve bloating and other secondary symptoms related to irritable bowel syndrome (IBS) in IBS patients with suspected small intestinal bacterial overgrowth (SIBO) who are already following a low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet

Key Takeaway

Boswellia serrata and curcumin in a 500-mg liposomal form can significantly improve treatment response in IBS patients with suspected SIBO who are already following the low-FODMAP diet.

Design

Randomized controlled trial

Participants       

The study included 67 participants (51 females, 16 males), aged 18 to 70 years. Of those, 34 were assigned to the control group and 33 to the supplement group.

Inclusion criteria:

• Bloating reported as the main symptom
• Diagnosis of moderate IBS, according to Rome III criteria, as abdominal pain for at least 1 day per week in the last 3 months that is associated with 2 or more of the following:
1. related to defecation,
2. associated with a change in stool form, or
3. associated with a change in stool
• Subjects included were small bowel dysbiosis positive, defined by the increase of urinary indican values with normal skatole urinary concentration.

Exclusion criteria:

• Normal urinary indican values or increased urinary skatole values
• Subjects already on a low-FODMAP diet or other dietary restriction, such as a gluten-free diet or lactose-free diet, within the past 6 months
• Soy, nuts, or seafood allergies
• Insulin-dependent diabetes
• Known history of celiac disease or symptomatic diverticular disease
• Inflammatory bowel disease
• Microscopic colitis
• Prior small bowel or colonic surgery or cholecystectomy
• Use of antibiotics, excluding topical, in the past 3 months
• Bloody diarrhea or severe vomiting
• Medical history of severe renal disease (defined as serum creatinine >1.5 mg/dL)
• Liver disease (defined as altered values of liver function tests)

Interventions

For 30 days those in the intervention group received 500 mg of a liposomal Boswellia and curcumin supplement while also following the low-FODMAP diet. The control group followed the low-FODMAP diet only, and no placebo pill was used.

During the study, supplementation was not allowed, including short-acting spasmolytics (eg, butylscopolammonium bromide), short-acting analgesics (eg, paracetamol), or anxiolytics.

Study Parameters Assessed

• Subjective report of abdominal bloating/uncomfortable fullness (mild, moderate, severe) at baseline and again at day 30
• Subjective report of abdominal pain intensity (0–10 using visual analogue scale) at baseline and again at day 30
• Investigators assessed intestinal dysbiosis by evaluating urinary indican and skatole within 7 days prior to study inclusion and at the end of study. Urinary indican and skatole were considered normal at values lower than 10 mg/L and 10 μg/L, respectively
• A global assessment of efficacy (GAE) 4-point scale was reported by each subject at the end of study (1 for ineffective, 2 for moderately effective/slight improvement of complaints, 3 for effective/marked improvement in symptoms, and 4 for very effective/as good as no symptoms
• During baseline and at 30 days, investigators took vital signs and serum levels of the above markers. They also asked patients to report side effects related to the gastrointestinal system.

Primary Outcome

The primary endpoint was the decrease in intensity of abdominal bloating.

Secondary endpoints included:

• Change of urinary indican values
• Change in intensity of abdominal pain
• Number of subjects with complete bloating relief
• Global assessment of efficacy

Key Findings

For bloating (P<0.0001) and abdominal pain (P<0.0001), a key difference was seen in the Boswellia-curcumin phytosomal group as compared to the control.

Compared to the control group, there was a 40% decrease of the urinary indican levels compared to the control group (P<0.0001).

As far as global assessment of efficacy, 57.58% of subjects in the treatment arm rated the treatment as very effective/as good as no symptoms compared to 0% in the control.

Further, 36.6% of treatment-arm subjects rated the treatment as effective/marked improvement in symptoms compared to 14.71% in the control group; and 6.1% rated the treatment moderately effective/slight improvement of complaints, compared to 35.29% of subjects in the control arm.

Finally, 50% of subjects in the control arm, compared to 0% in the treatment arm, rated the treatment ineffective.

Transparency

No conflicts of interest declared.

Practice implications

Chronic inflammation is often overlooked in irritable bowel syndrome (IBS) and small intestinal bacterial overgrowth (SIBO). For the most part, inflammation has not been recognized as underlying pathophysiology in IBS, which has been hypothesized to be a brain-gut disorder with altered microbiota, visceral hypersensitivity, and motility disruption. Not surprisingly, therapeutic strategies have been aimed at these causes.

So I was eager to see if long-used natural anti-inflammatory compounds Boswellia serrata and curcumin would result in improved outcomes in the IBS patient with SIBO who suffers from the common complaints of abdominal pain and bloating.

Inflammation has been demonstrated in patients with functional digestive disorders. We are now able to see inflammation in the intestinal epithelial region/mucosal regions in IBS and SIBO patients using confocal laser endomicroscopy. Recently, duodenal fluid in the SIBO patients has been shown to have significantly higher levels of pro-inflammatory cytokines, including interleukin-1b (IL-1b), IL-6, and tumor necrosis factor (TNF) alpha, suggesting a pro-inflammatory environment.

Add to this that in SIBO patients, the presence of Klebsiella pneumoniae in duodenal fluid was associated with pro-inflammatory IL-6 levels, while the presence of Methanobrevibacter smithii was associated with pro-inflammatory IL-1b levels.¹ A systematic review of the literature found that small-intestinal-barrier defects, and their associated inflammation, occurs in almost all IBS patients, especially pediatric IBS patients.²

Proof of immune dysregulation is not limited to proinflammatory cytokines. IBS patients have been shown to suffer from altered immune signaling of mast cells by resident dysbiotic microbes. In these patients, toll-like receptors (TLRs) are upregulated on mast cells in the lamina propria where they interface with microbes and T helper 2 (T_H2) cells. Mast cells release histamine, serotonin, and proteases and are largely linked to pain and inflammation associated with IBS, as they are proposed to interact with histamine H1 receptors and transient receptor potential vanilloid 1 (TRPV1) on visceral afferent nerves. This immune stimulation is intertwined with the production of proinflammatory cytokines (TNF-alpha, IL-5, IL-10, and IL-13). ^3,4

In the paper currently under review, the primary endpoint was to reduce bloating by adding the curcumin-Boswellia phytosomal (CBP) compound to IBS patients with suspected SIBO who were already on a low-FODMAP diet. Bloating is a major concern in IBS with 66% to 90% of IBS patients reporting bloating. Women generally report higher rates of bloating than men, and IBS patients with constipation (IBS-C) have higher rates than those with diarrhea. In general, 75% of patients with bloating (no formal IBS diagnosis) characterize their symptoms as moderate to severe in nature, while 50% report that bloating causes a reduction in daily activities.⁵

Bloating is largely attributed to excessive gaseous waste formation from fibers in the small intestine and/or large intestine due to undigested carbohydrates and imbalances in the gut flora. These imbalances are continually being studied. For example, there is decreased presence of Ruminococcaceae and Eubacteriaceae families among IBS patients without bloating compared to IBS patients with bloating and healthy control subjects.⁵

It also seems plausible that bloating is secondary chronic dysbiosis that develops due to a chronically inflamed and oxidatively stressed intestine. However, this is classic case of “which came first, the chicken or the egg.” Did the dysbiosis create the inflamed intestine? Or did the inflamed intestine create the dysbiotic gut?

Finally, 50% of subjects in the control arm, compared to 0% in the treatment arm, rated the treatment ineffective."

Bloating and pain are conventionally treated by reducing food triggers (ie, the low-FODMAP diet, low-residue diet) and employing combinations of probiotics, antibiotics, secretagogues, antispasmodics, surfactants, and/or neuromodulators.

The study used 2 compounds that may be addressing an underappreciated aspect of the therapeutic strategy for IBS. Both Boswellia and curcumin are presumed to reduce oxidative stress and inflammation and, thereby, stabilize the gut microenvironment.

In cell studies of inflammatory bowel disease (IBD), terpenoids from Boswellia serrata were shown to preserve intestinal epithelial barrier from oxidative and inflammatory damage.⁶ Additionally, in previous in vitro and in vivo studies, Boswellia serrata extract demonstrated the ability to directly inhibit intestinal motility with the mechanism involving L-type Ca²⁺ channels, thus preventing experimental diarrhea in animal models without slowing the rate of transit.⁷ So, in addition to being anti-inflammatory, perhaps Boswellia also acts as an antispasmodic.

Curcumin has been shown to have anti-inflammatory properties specifically by suppressing cytokine production (interferon-γ, interleukins, and TNF) and inhibiting the inducible nitric oxide synthase, as well as nuclear factor kappa B (NF-κB).⁸ Curcumin has also been shown in Western-diet-fed mice to increase the gut-barrier protective enzyme intestinal alkaline phosphatase (IAP). Interestingly, IAP regulates bicarbonate secretion, dephosphorylates lipopolysaccharide (LPS), and regulates gut microbes, and it has been proposed as a target for regulating intestinal barrier integrity.⁹

Both curcumin and Boswellia serrata have been shown to activate nuclear factor erythroid 2–related factor 2 (NRF2), binding to the antioxidant response element (ARE). The ARE is a key pathway in antioxidant production, inducing the expression of powerful redox enzymes such as glutathione and superoxide dismutase.¹⁰

It has been shown at least in the large intestine of rodents that gut-lining inflammation promotes dysbiosis as the oxygen gradient is changed, leading to expansion of facultative anaerobes like the overgrowth of Enterobacteriaceae.¹¹ Whether this same scenario takes place in the human small intestine of IBS patients with SIBO is unknown. Yet, in confirmed SIBO patients, it has been shown, using duodenal aspirates and polymerase chain reaction (PCR), that there is decreased alpha diversity and increased presence of pro-inflammatory Gammaproteobacteria.¹² Facultative anaerobe expansion, which is triggered by an oxidatively stressed environment in the SIBO, is certainly plausible.

If this is true, treating inflammation of the oxidatively stressed gut seems more achievable and sustainable than treating small intestinal dysbiosis with repeated rounds of herbal or conventional antimicrobials.

It is worth mentioning that in IBS patients, first-line IBD therapies such as mesalamine have not been promising.¹³ One 2012 study, however, did show benefit in a subset of IBS patients with mesalamine at 1,500 mg per day.¹⁴ Of note, mast cell stabilizers such as ketotifen and cromolyn sodium are being used in trials and have shown some promise in helping IBS patients.^15,16

Limitations

The study used peculiar and uncommon measurements of dysbiosis. Instead of using the more commonly used lactulose hydrogen breath test, the study used urinary indican to screen for small intestinal dysbiosis and urinary skatole to screen for large intestinal dysbiosis. Very few recent studies use these as markers in the IBS patient, and to the best of my knowledge, no commercially available labs offer the analyte of urinary skatole.

Indolic compounds (indoles), such as indican and skatole, are putrefactive metabolites produced by gut bacteria from the dietary amino acids tyrosine and tryptophan, respectively, whereas most SIBO studies focus on abnormal fermentation of carbohydrates.¹⁷

Another limitation of the study is that the investigators had limited knowledge of the participants’ adherence and compliance with the low-FODMAP diet. As with all restricted diets, outcomes are linked to the degree of compliance and the quality of the nutrition. As ridiculous as it sounds, theoretically one could follow a low-FODMAP diet by eating potato chips and chicken breast every day for 3 meals per day.

Moreover, the study wasn’t blinded, so recipients were likely receiving a pill that looked like and possibly tasted like the familiar-tasting spice turmeric. This could have added to a placebo response or influenced subjective sense of improvement.

Finally, the study used advanced phytosomal preparations of Boswellia and curcumin. These preparations have superior absorption to nonphytosomal preparations of similar compounds, and this likely influenced the results.

Regardless, there is no denying the subjective and quantitative improvements in bloating, pain, dysbiosis, and global digestive symptoms reported in the trial. It seems reasonable and safe to include liposomal preparations of Boswellia serrata and curcumin for patients with IBS and associated SIBO. What is overlooked but needs to be explored further is the impact of reduced inflammation on brain-gut interactions and how that may result in overall improvement in this patient subset.

I have long been interested in stabilizing the inflammatory environment as a top priority in IBS and SIBO patients, and this study reinforced the importance of this strategy as a primary foundational approach. Also, it is important to continue to address the impact of inflammation-balancing approaches on the brain-gut interactions in IBS.