Introduction
Antibiotic-associated diarrhea (AAD) is a well-recognized consequence of antimicrobial therapy, disrupting the gut microbiome and leading to gastrointestinal complications. The new meta-analysis by Wanyama et al., published in the current issue of Gastroenterology Review, provides compelling evidence on the effectiveness of probiotics in mitigating AAD [1]. Their analysis included 15 trials with a total of 7,427 participants, with the overall study quality rated as moderate. Pooled results showed that probiotics lowered the incidence of AAD by 40% (RR = 0.60, 95% CI: 0.43–0.82), with consistent benefits across subgroups. Multistrain probiotics provided the strongest protection (RR = 0.40), outperforming dual-strain (RR = 0.90) and single-strain (RR = 0.60) formulations [1]. Our editorial explores the clinical implications of these findings and addresses a critical question: Should probiotics be routinely recommended alongside antibiotics?
The evidence for probiotics in antibiotic-associated diarrhea
The American Gastroenterological Association (AGA) has recently issued a positive recommendation for probiotic supplementation in preventing antibiotic-induced Clostridioides difficile-associated diarrhea (CDAD) [2]. However, despite this endorsement, the overall certainty of evidence across all critical outcomes remains classified as low.
In contrast, Colleen et al. in the recent American College of Gastroenterology (ACG) Clinical Guidelines recommend against probiotics for the prevention of CDAD in patients being treated with antibiotics, both in primary and secondary prevention [3]. This discrepancy between recommendation and evidence highlights the ongoing challenges in establishing probiotics as a standard therapeutic intervention in clinical practice. Systematic reviews and meta-analyses – those published previously as well as those appearing in this issue of Gastroenterology Review – have consistently shown that probiotics can reduce the incidence of AAD and CDAD [1, 4–6]. However, the described results may not always be applicable in selected clinical scenarios, especially of lower baseline of AAD risk. Dudzicz et al., although in a non-randomized, but observational and retrospective, single-center study, analyzing 5,341 patients hospitalized in a nephrology and transplantation ward in Poland, investigated the impact of Lactiplantibacillus plantarum 299v (LP299v) on the incidence and rates of CDAD over 3 years, comparing periods before, during, and after routine LP299v administration [7]. During the LP299v prophylaxis period, the CDAD incidence dropped significantly from 1.03% to 0.11% (p = 0.0003). In immunosuppressed patients, the reduction was even more pronounced, from 4.49% to 0.72%. No severe CDAD cases were observed during probiotic administration, and CDAD recurrences were milder. The authors highlighted the cost-effectiveness of this approach, with a very low prevention cost per patient. Their findings support the strategy of probiotics as adjuncts to antibiotics for reducing CDAD in high-risk hospitalized patients, supporting the need for further randomized clinical trials [7].
Probiotics and Helicobacter pylori eradication: a growing body of evidence
A recent meta-analysis by Mishra et al. provides compelling evidence that Lactobacillus spp. supplementation significantly improves Helicobacter pylori eradication rates, particularly when used as an adjunct to triple therapy [8]. Additionally, probiotic supplementation has been shown to reduce common gastrointestinal side effects associated with eradication therapy, including nausea, diarrhea, and abdominal pain. Deza et al. analyzed data of the European Registry on the Management of Helicobacter Pylori Infection (HpEUReg) from 36,699 treatments across Europe to assess the prescription patterns, effectiveness, and safety of probiotics used alongside H. pylori eradication therapy [9]. The authors reported higher eradication success across different therapy regimens (OR = 1.631 [95% CI: 1.456–1.828]) among patients who received probiotics as part of their treatment. Notably, probiotics were prescribed to only 22% of all patients undergoing eradication therapy. Lactiplantibacillus species improved effectiveness, especially in Eastern Europe. Bifidobacterium and Saccharomyces reduced the overall incidence and severity of adverse events [9]. This study supports the potential of probiotics to enhance both the effectiveness and safety of H. pylori eradication therapy. We have previously emphasized that probiotics must be evaluated based on strain-specific efficacy and well-defined indications. While probiotics are generally safe, their benefits are context-dependent, requiring careful selection based on clinical need and patient-specific factors [10].
Probiotics in severe acute pancreatitis: friend or foe?
The role of probiotics in severe acute pancreatitis (SAP) remains controversial, with conflicting evidence regarding their safety and efficacy. A landmark study published by Besselink et al. in The Lancet raised serious concerns about probiotic use in SAP patients [9]. This randomized, double-blind, placebo-controlled trial found that probiotic prophylaxis did not reduce infectious complications but was associated with increased mortality (16% vs. 6%) and a higher risk of bowel ischemia (p = 0.004), a complication absent in the placebo group. As a result, the authors advised against probiotic administration in this population [11]. However, more recent systematic reviews and meta-analyses have questioned these findings [12]. A meta-analysis by Gao et al. found that probiotics did not significantly impact mortality or organ failure risk in SAP patients but shortened hospital stays by an average of 5.49 days (p = 0.010) [10]. Similarly, a systematic review by Malik et al. analyzing seven clinical trials concluded that probiotics did not reduce the risk of multi-organ failure, sepsis, or mortality in SAP patients [13]. These results suggest that while probiotics may not provide substantial benefits, they also do not necessarily increase mortality in SAP as previously reported. Importantly, SAP patients often require intensive antibiotic treatment due to high risks of infected pancreatic necrosis, sepsis, and multi-organ failure. The use of probiotics in this setting remains questionable, as their interaction with the disrupted gut barrier and systemic inflammation in SAP is not fully understood. However, recent evidence suggests that alternative strategies for gut microbiota modulation may be of benefit. A retrospective study investigating the effects of rifaximin in patients with moderately severe acute pancreatitis (MSAP) and SAP yielded promising results. The study, which included 373 patients, reported a significant reduction in hospital stay for those receiving rifaximin (14 vs. 24 days, p = 0.001) and fewer cases of infected pancreatic necrosis (1 vs. 7, p = 0.0487), though mortality rates did not differ significantly between groups [14]. These findings indicate that gut decontamination with rifaximin could be a potential therapeutic approach for SAP, complementing or serving as an alternative to probiotics. Given these concerns and conflicting study results, probiotic use in SAP should remain under careful clinical evaluation, and further large-scale randomized trials are needed to clarify their potential risks and benefits.
The challenge of heterogeneous study designs
The broader field of probiotic research remains fragmented. As already highlighted, inconsistencies in study design, strain selection, and outcome measurement have hindered the establishment of clear clinical guidelines [15]. AAD prevention studies often yield mixed results, reflecting both the complexity of microbiome interactions and the variability in probiotic formulations. Concerns about the safety and efficacy of probiotics have been raised, emphasizing that mechanistic reasoning alone is insufficient to draw clinical conclusions [10]. Recent analyses of probiotic trials further emphasize the diversity in study designs and the challenges it poses for clinical interpretation. A global review of probiotic trials registered at ClinicalTrials.gov revealed substantial heterogeneity in trial methodologies, including differences in sample sizes, study duration, probiotic strains, and administration protocols. The median number of participants in probiotic trials is relatively low, limiting statistical power and generalizability. Additionally, study registration practices vary widely, with only 32% of trials registered before patient recruitment and 78% before study completion, raising concerns about reporting transparency [16]. This heterogeneity complicates the ability to draw firm conclusions regarding probiotic efficacy across different conditions, particularly in gastrointestinal and immune-related diseases. While mechanistic reasoning offers valuable insights, it is insufficient to establish clinical recommendations without well-conducted randomized controlled trials (RCTs) and rigorous long-term safety evaluations.
Moving forward: the need for precision in probiotic research
The future of probiotics as adjuncts to antibiotics, especially in gastroenterology, depends on rigorous, mechanistically sound research. As noted in previous analyses, well-designed, mechanistic studies using defined microbial consortia are essential – especially as the role of probiotics in microbiota preservation and recovery following antibiotic therapy remains uncertain. As recently outlined by Szajewska et al., several challenges persist: i) lack of consensus on what constitutes a ‘normal’ microbiota; 2) non-standardized and evolving microbiome measurement methods; 3) significant inter-individual microbiota variation [17]. Similarly, Porcari et al. in their International Consensus Statement on Microbiome Testing in Clinical Practice, underscore that microbiome testing is still in its infancy, with no standardized framework or proven clinical value for most commercially available tests [18]. This lack of standardization further complicates the assessment of probiotics’ role in modulating gut microbiota. Future research should focus on: i) defining strain-specific probiotic effects with clear mechanistic underpinnings; 2) establishing standardized microbiome assessment and quality control methodologies; 3) conducting long-term safety and efficacy studies; 4) developing regulatory frameworks to guide clinical implementation. While the enthusiasm for probiotics remains high, their indiscriminate use without sufficient evidence risks undermining their true potential. The challenge lies in distinguishing clinically meaningful interventions from commercial hype, ensuring that probiotics fulfill their promise in gastroenterology without falling victim to overgeneralization.
Conclusions
The evolving landscape of probiotic research necessitates a cautious yet progressive approach. While probiotics are effective in selected gastrointestinal indications (e.g. irritable bowel syndrome; IBS) [19], and show promise particularly in AAD, CDAD prevention and Helicobacter pylori eradication, significant gaps in the evidence persist. A concerted effort among researchers, clinicians, and regulatory bodies is required to establish probiotics as a reliable therapeutic tool in gastroenterology. In light of these findings, it is imperative that we move beyond broad generalizations and embrace a precision-based approach, ensuring that probiotics are leveraged effectively and safely in clinical practice.
