Clinical Efficacy and Gut Microbiota Effects of High-Dose Single-Strain and Multi-Strain Bacillus Probiotics as Adjunctive Therapy to Bismuth Quadruple Therapy for Helicobacter Pylori Eradication: A Randomised, Double-Blind, Placebo-Controlled Trial

Helicobacter pylori (H. pylori) infection affects roughly half of the world's population, making it a very common digestive disease. In developing countries, infection rates are especially high, with 85-95% of the population potentially infected with H. pylori, making this disease a major public health concern. H. pylori mainly infects and lives in the mucous membrane of the stomach lining, enabling it to persist for long periods and lead to chronic infection. Its survival in the stomach's harsh acidity is primarily due to urease, an enzyme that breaks down urea into ammonia, neutralizing the stomach acid. In Vietnam, historically, clarithromycin-based triple therapy achieved eradication rates exceeding 90%. However, rising global antibiotic resistance has reduced its efficacy to below 70%, leading to its removal from first-line recommendations in regions with high resistance. As a result, bismuth-containing quadruple therapy, which includes a proton pump inhibitor (PPI), tetracycline, metronidazole, and bismuth, has become the standard first-line and rescue treatment for H. pylori eradication.

While this regimen is highly effective, yielding eradication rates between 90.4% and 99.3%, it frequently induces significant gastrointestinal adverse effects. Clinical data indicate that 54.1% to 67.0% of patients experience symptoms such as dizziness, nausea, vomiting, diarrhea, black stools, fatigue, and anorexia. Furthermore, the high-dose administration of tetracycline and metronidazole causes severe disruption of the normal gut microbiota (dysbiosis). This dysbiosis is characterized by a marked decrease in beneficial microbial populations, such as Bacteroidetes and Actinobacteria, alongside a concerning overgrowth of opportunistic pathogens, such as Proteobacteria. These severe side effects often lead to poor patient compliance, causing patients to reduce dosages or prematurely discontinue therapy. This lack of adherence, in turn, contributes to treatment failure and exacerbates the increasing global challenge of antibiotic resistance.

The use of spore-forming probiotic strains from the genus Bacillus in Helicobacter pylori eradication regimens has recently garnered considerable attention within the scientific community, yielding promising outcomes in randomized controlled trials (RCTs). Multicenter studies have demonstrated that supplementation with Bacillus clausii alongside antibiotic regimens significantly reduces the incidence of antibiotic-associated diarrhoea (AAD) and other gastrointestinal symptoms, including nausea and a bitter taste. This, in turn, enhances drug tolerance and treatment adherence among patients. Additionally, research on Bacillus subtilis and Bacillus coagulans offers substantial medical evidence concerning their direct and indirect mechanisms of action. In vitro studies indicate that B. subtilis may inhibit H. pylori growth through secretion of natural antimicrobial compounds, particularly amicoumacin A, while other Bacillus-derived bacteriocins and lipopeptides may contribute to broader antimicrobial activity. In contrast, B. coagulans has demonstrated efficacy in modulating local immune responses, reducing inflammatory cytokines, and preserving the integrity of the gastric mucosa against bacterial damage.

Although there is substantial evidence for the effectiveness of Bacillus species, data on their effectiveness in supportive treatment with bismuth-containing quadruple drug regimens remain limited, particularly studies evaluating the simultaneous effects on bacterial eradication, adverse effects, and changes in mucosal immune response and gut microbiota.

Therefore, this study was conducted with two main objectives: