Efficacy and safety of spore-forming probiotics in the treatment of functional dyspepsia: a pilot randomised, double-blind, placebo-controlled trial

Summary

Background

Current treatments for functional dyspepsia have limited efficacy or present safety issues. We aimed to assess spore-forming probiotics in functional dyspepsia as monotherapy or add-on therapy to long-term treatment with proton-pump inhibitors.

Methods

In this single-centre, randomised, double-blind, placebo-controlled pilot trial that took place at University Hospitals Leuven (Leuven, Belgium), adult patients (≥18 years) with functional dyspepsia (as defined by Rome IV criteria, on proton-pump inhibitors or off proton-pump inhibitors) were randomly assigned (1:1) via computer-generated blocked lists, stratified by proton-pump inhibitor status, to receive 8 weeks of treatment with probiotics (Bacillus coagulans MY01 and Bacillus subtilis MY02, 2·5 × 10⁹ colony-forming units per capsule) or placebo consumed twice per day, followed by an open-label extension phase of 8 weeks. Individuals with a history of abdominal surgery, diabetes, coeliac or inflammatory bowel disease, active psychiatric conditions, and use of immunosuppressant drugs, antibiotics, or probiotics in the past 3 months were excluded. All patients and on-site study personnel were masked to treatment allocation in the first 8 weeks. Symptoms, immune activation, and faecal microbiota were assessed and recorded. The primary endpoint was a decrease of at least 0·7 in the postprandial distress syndrome (PDS) score of the Leuven Postprandial Distress Scale in patients with a baseline PDS score of 1 or greater (at least mild symptoms), assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT04030780.

Findings

Between June 3, 2019, and March 11, 2020, of 93 individuals assessed for eligibility, we included 68 patients with functional dyspepsia (51 [75%] women, mean age 40·1 years [SD 14·4], 34 [50%] on proton-pump inhibitors). We randomly assigned 32 participants to probiotics and 36 to placebo. The proportion of clinical responders was higher with probiotics (12 [48%] of 25) than placebo (six [20%] of 30; relative risk 1·95 [95% CI 1·07–4·11]; p=0·028). The number of patients with adverse events was similar with probiotics (five [16%] of 32) and placebo (12 [33%] of 36). Two serious adverse events occurring during the open-label phase (appendicitis and syncope in two separate patients) were assessed as unlikely to be related to the study product.

Interpretation

In this exploratory study, B coagulans MY01 and B subtilis MY02 were efficacious and safe in the treatment of functional dyspepsia. Participants had potentially beneficial immune and microbial changes, which could provide insights into possible underlying mechanisms as future predictors or treatment targets.

Funding

MY HEALTH.

Introduction

Functional dyspepsia is a common chronic gastrointestinal disorder defined by upper abdominal symptoms originating from the gastroduodenal region with no structural disease on routine investigations.¹ However, the presence of subtle pathology is not excluded by the Rome IV criteria and increasing evidence points to local duodenal and systemic changes in functional dyspepsia.2, 3 Impaired duodenal mucosal integrity and low-grade inflammation have been reported in patients with functional dyspepsia, correlating with gastric emptying and postprandial symptoms.4, 5 Moreover, systemic immune activation and increased small-bowel-homing T cells (CD4⁺α4β7⁺CCR9⁺) and the correlation with gastric emptying rate and symptom severity were reported.⁶ Different underlying mechanisms have been studied, including gastric dysfunction, hypersensitivity to duodenal luminal content, and central factors such as gut–brain signalling.2, 3 Despite the socioeconomic impact to the health service and patient and decreased quality of life, the pathophysiology of functional dyspepsia is incompletely understood and treatment options are limited in efficacy and number.3, 7

First-line therapy for functional dyspepsia is acid suppression with proton-pump inhibitors and although guidelines advise against dose escalation, inappropriate use of proton-pump inhibitors, even in the absence of clinical benefit, is frequently reported.² Long-term intake of proton-pump inhibitors can increase the risk of enteric infections (including Clostridioides difficile),⁸ and changes in faecal microbiota or dysbiosis have been reported.⁹ Probiotics are live microorganisms that exert a health benefit on the host.¹⁰ Previous studies suggested efficacy of probiotics for proton-pump inhibitor-related side-effects and uninvestigated dyspeptic symptoms, which could be caused by an altered small intestinal microbiome.11, 12, 13 An intestinal-like bacterial profile in the gastric fluid suggested the presence of small intestinal bacterial overgrowth in at least a subset of patients with functional dyspepsia.¹² Nevertheless, placebo-controlled studies investigating probiotics in functional dyspepsia are scarce.¹⁴ Gram-positive and spore-forming probiotic strains could be more efficacious than traditional probiotic supplements because of gastric-acid resistant endospores with improved storage conditions and survival in the intestine.15, 16 Despite beneficial effects of Bacillus coagulans and Bacillus subtilis strains on gut permeability and inflammation in in-vitro models,¹⁷ clinical trials on the effect of spore-forming probiotics are absent in human disorders with similar alterations, including functional dyspepsia.

Research in context

Evidence before this study

Functional dyspepsia is a common and costly gastrointestinal disorder and current treatments have limited efficacy or safety issues. Long-term treatment with proton-pump inhibitors can cause intestinal dysbiosis, and potential beneficial effects of probiotics have been suggested. We searched PubMed for articles published from database inception until June 1, 2021, using the search terms “functional dyspepsia”, and “probiotic”. Studies in animals and children were excluded. Of the five studies in adult patients identified, only one study included a placebo yoghurt as control for probiotic efficacy in uninvestigated dyspepsia. Besides the absence of rigorous and placebo-controlled probiotic trials, the efficacy and safety of spore-forming probiotics or gastric-acid-resistant endospores have not been assessed in patients with functional dyspepsia.

Added value of this study

The combination of Bacillus coagulans MY01 and Bacillus subtilis MY02 strains was effective and safe in patients with functional dyspepsia compared with placebo. Decreased Th17 signalling in blood and increased Faecalibacterium in stools were associated with clinical efficacy of probiotics. Beneficial probiotic effects in patients with functional dyspepsia on proton-pump inhibitors included a reduction in small intestinal bacterial overgrowth.

Implications of all the available evidence

Treatment with spore-forming probiotics can be considered as monotherapy or as add-on to proton-pump inhibitors in patients with functional dyspepsia with refractory symptoms. Changes in immune activation and intestinal microbiota are potential underlying mechanisms of spore-forming probiotics. This study underscores the potential role of microbiota in functional dyspepsia and provides effect sizes to design future trials. Further investigation is needed.

To bridge this gap, we aimed to assess the efficacy and safety of the combination of B coagulans MY01 and B subtilis MY02 strains in patients with functional dyspepsia. We hypothesised that functional dyspepsia symptoms, measured with a validated daily diary, would be improved by these spore-forming probiotics compared with placebo in patients with functional dyspepsia as add-on to proton-pump inhibitors or as monotherapy. In addition to a comprehensive clinical and safety evaluation, biological markers of immune activation and both relative and quantitative microbiota composition were studied to assess potential underlying mechanisms.