Effectiveness of Saccharomyces boulardii CNCM I-745 in Adult Indian Patients with Diarrhoea: A Real-world, Multicentre, Retrospective, Comparative Study

Diarrhoea is defined by the World Health Organization (WHO) as the passage of three or more loose or watery stools per day [1]. The etiological factors related to diarrhoea include infections from bacterial, viral or protozoal organisms, and other causes such as medications (antibiotics, non-steroidal anti-inflammatory drugs and chemotherapeutic agents) [2]. Based on the symptoms and duration, diarrhoea could be acute or chronic and infectious or non-infectious. Acute diarrhoea lasts less than 2 weeks and is commonly due to infections, while chronic lasts longer (> 2 weeks) and is generally non-infectious. According to the global burden of disease study on the burden of diarrhoea in India from 1990 to 2019, the mortality rate per 100,000 population for all ages was 45.46, under 5 years was 47.24; 5–14 years was 6.31, 15–49 years was 6.65, 50–69 years was 62.76, and > 70 years was 682.21 [3]. The prevalence of diarrhoea is highly heterogeneous across Indian states, and it ranged from 0.1 to 33.8% in the period between 2007 and 2008 and 0.6–29.1% in the period between 2015 and 2016 [4]. A recently published Indian study by Shrivastava et al. evaluated the prevalence of diarrhoea among older Indian adults between 2017 and 2018 [5]. About 15% of older adults reported to the physician with complaints of diarrhoeal episodes over the preceding 2 years. Every year, over 10 million patients suffer from diarrhoea in India, and over 1000 deaths are reported consequently [6]. Of these cases, 90% are attributed to unsafe drinking water, inadequate sanitation and poor hygiene [7]. The mainstay of managing diarrhoea involves maintenance of hydration by oral rehydration or intravenous fluids. Oral rehydration solution is intended to decrease the mortality and morbidity due to diarrhoea by restoring hydration and electrolyte balance [8].

Apart from rehydration strategies, probiotics are also used in the management of diarrhoea [9]. A retrospective, multicentre, electronic medical record (EMR) study by Ragavan et al. evaluated the effects of Saccharomyces boulardii against acute diarrhoea in children. A significant reduction in the frequency of stools and duration of diarrhoea was noted in the Saccharomyces boulardii group versus the control group [9]. Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host [10]. The seven core genera of microbial organisms most often used in probiotic products are Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, Escherichia, and Bacillus [11]. Yeast probiotics differ from bacterial probiotics in size, cell wall composition, antibiotic resistance and metabolic properties [12, 13]. Compared with bacterial probiotics, yeast cells are naturally resistant to antibiotics, as they are fungi, and there is no observed DNA exchange pertaining to antimicrobial resistance genes [14]. The only yeast genus that has been proven effective as probiotic in humans in double-blind studies is Saccharomyces [15]. Existing evidence strongly suggests that the efficacy of probiotics is both strain-specific and disease-specific [16]. The probiotic actions demonstrated by a particular strain of yeast are not extrapolatable to other strains. Saccharomyces boulardii (S. boulardii) CNCM I-745 is the first identified yeast strain that has been studied for use as a probiotic in human medicine. A study by Dinleyici et al. established that S. boulardii significantly diminished the duration of diarrhoea by about 24 h in the Western world, in both adults and children [17]. Multiple clinical studies have discussed the benefit of S. boulardii in the management of both adult and paediatric diarrhoea associated with various causes, whether it be antibiotics or Clostridium difficile (C. difficile) infection [18, 19]. A systematic review and meta-analysis by McFarland et al. noted that S. boulardii CNCM I-745 showed the strongest effect on decreasing the diarrhoea duration, as well as hospital stay in paediatric acute gastroenteritis cases [20]. There is a lack of Indian studies which have assessed the effectiveness of S. boulardii CNCM I-745 in adult diarrhoea, showing reduction in duration as well as the frequency of loose motions. We aimed to evaluate the effectiveness of S. boulardii CNCM I-745 in adult Indian patients with diarrhoea with the help of a retrospective, multicentre, comparative study. The study also evaluated the effectiveness of S. boulardii CNCM I-745 in comparison to non-probiotic treatment (control group) in adult diarrhoea patients. Diarrhoea is a major concern in India, with high morbidity and mortality related to it. In a study by Joseph et al.⁶ the monthly prevalence rate of diarrhoea in India was reported as 12%, which was more than the monthly prevalence rate of 5.1 % reported from the USA [21]. Unsatisfactory living conditions and poor sanitation as a consequence of the population explosion in the country are significantly associated with presence of diarrhoea in Indian households.⁶ If the diarrhoea is not controlled in time, malabsorption can affect the individual, leading to malnutrition and unintentional weight loss. Dehydration and severe renal damage from the dehydration are potential complications as well. Abnormalities in serum electrolytes can also be problematic and necessitate monitoring for replenishment requirements [22]. Hence, there is an urgent need for effective treatment modalities to control diarrhoeal episodes. Numerous clinical studies have noted the benefit of S. boulardii in the management of diarrhoea, but there remains a dearth in published real-world experience with the probiotic. Usually, the quality of the evidence produced in a randomized controlled clinical trial (RCT) holds greater credibility than that produced in the real world. However, the inference of results from an RCT can be restricted only to the kind of patients who were eligible for the RCT. In the real world, the clinician cannot exclude any patient from receiving treatment. Therefore, RCT results can have generalizability restrictions [23, 24]. Real-world and observational studies are important to understand whether the benefits and efficacy of S. boulardii CNCM I-745 seen in clinical trials are replicated in clinical practice. This real-world study, which was planned to evaluate the effectiveness of S. boulardii CNCM I-745 in adult patients with diarrhoea, can help in bridging the gap between the clinical trial results and real-world practice.

Analysis was performed from an Indian electronic software, owned and administered by HealthPlix. HealthPlix is an Indian-origin-based EMR platform that operates from outpatient clinics and captures longitudinal information including demographics, diagnoses, medications, investigations, procedures conducted, functional status and other data elements.

Ethics committee approval for the study was obtained on 8 August 2022 from the Suraksha Ethics Committee with the protocol number DRL-IND-GGI08-AAD/2022. Informed consent waiver was acquired, as this is a non-experimental, retrospective data analysis study. Patient confidentiality was maintained throughout the time, as the study was performed using anonymized data. The study was conducted in accordance with the applicable national regulatory laws and guidelines.

Of the total patients on EMR from January 2020 to January 2022, 129,633 patients had reported diarrhoea. Of these, 270 patients received S. boulardii CNCM I-745. After assessing the completeness of data, a comparative assessment was done between adult patients who received S. boulardii CNCM I-745 (test group) and other non-probiotic treatment modalities (control group). The age range of patients included in the test group was 19–86 years, which led to the assessment of S. boulardii CNCM I-745 effectiveness across all adult age groups. The majority of patients were females in both groups. Though the gender predilection of diarrhoea is not observed in scientific literature, some diseases such as irritable bowel syndrome (IBS) are found to be more common in women [25, 26]. Hence, some of the included patients may be suffering from irritable bowel syndrome, leading to female predilection in the current study.

The clinical guideline update by Szajewska et al. was published in 2020, on behalf of the Working Group of Probiotics and Prebiotics of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. This update made weak recommendations for S. boulardii usage in the management of children with acute gastroenteritis [27]. A systematic review and meta-analysis by McFarland et al. noted that S. boulardii CNCM I-745 had the strongest effect on reducing the duration of diarrhoea and hospital stay in paediatric acute gastroenteritis cases [20]. Our present study mentions the effect of S. boulardii CNCM I-745 in specifically adult population, a distinct objective from other similar studies which have assessed S. boulardii CNCM I-745 mainly in paediatric population only.

As per the World Gastroenterology Organization Global Guidelines for recommendation of probiotics in adults, there is evidence supporting the use of S. boulardii in the treatment of acute diarrhoea in adults, antibiotic-associated diarrhoea, prevention of C. difficile-associated diarrhoea (or prevention of recurrence) [28]. One of the key findings related to diarrhoea in the general population is intestinal dysbiosis. Intestinal dysbiosis can be defined as any alteration to the composition of resident commensal microbiota relative to the commensals found in healthy individuals [29]. Microscopic examinations have revealed a disruption of the protective mucus layer for different diarrheic dysbiotic situations such as inflammatory bowel disease (IBD; either Crohn’s disease or ulcerative colitis), IBS, human immunodeficiency virus (HIV) enteropathy and other intestinal conditions. This disruption leads to the attachment of bacteria directly to the exposed mucosa and elicits a polymicrobial infection [30‐32]. There are certain risk factors causing dysbiosis, such as malnutrition, old age, diabetes/metabolic syndrome and stress, which can destabilize the microbiota [33, 34].

Numerous clinical studies performed with lyophilized S. boulardii CNCM I-745 demonstrated efficacy and safety in a variety of gastrointestinal conditions associated with diarrhoea. In contrast to other probiotics, S. boulardii achieved broad clinical efficacy with significant positive outcomes in many different dysbiotic situations [35]. Some of the conditions where S. boulardii CNCN I-745 has strong evidence is in tackling antibiotic-associated diarrhoea, [36] preventing or reducing C. difficile-associated colitis or traveller’s diarrhoea, significantly shortening duration of infectious diarrhoea and reducing the incidence of tube-feeding-associated diarrhoea in enterally fed patients [17]. The review article by Micklefield et al. [36] mentioned that 14 studies evaluating the effectiveness of S. boulardii demonstrated its protective effect against diarrhoea, ranging between 43.7% and 87.3%. The meta-analysis by Szajewska et al. [18] used data from 21 studies, 15 of which were clinical studies done in adult population, with the objective of understanding the effectiveness of S. boulardii in preventing antibiotic-associated diarrhoea. In 15 randomized controlled studies with 3114 participants, S. boulardii decreased the incidence of diarrhoea from 17.4% and 8.2% (RR: 0.49, 95% CI 0.38–0.63).

S. boulardii and its protein are known to inhibit proinflammatory cytokine production by interfering with the nuclear factor κB and modifying the activity of mitogen-activated protein kinases extracellular signal-regulated kinase (ERK1/2). This prevents gastrointestinal inflammation by upregulating the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ). Additionally, it inhibits the growth of bacteria, and the adhesion of host cells releases a protease that breaks down C. difficile toxin A and its intestinal receptor, and increases the generation of antibodies that fight toxin A [37]. The current study has strengthened and reinforced the existing evidence, showing the effectiveness of S. boulardii.

There was significant improvement noted in adult patients of diarrhoea managed with S. boulardii CNCM I-745. The effect of S. boulardii CNCM I-745 probiotic in controlling diarrhoea was better than other anti-diarrhoeal and/or oral rehydration therapy in the real-world practice, irrespective of concomitant administration of antibiotics.