Clinical Use, Population-Level Impact, and Antimicrobial Resistance Considerations of Probiotics and Microbiome-Based Therapeutics: Review

Abstract

Probiotics and microbiome-based therapeutics are increasingly used to prevent antibiotic-associated diarrhea (AAD) and support gut microbiota health across children, adults, and elderly populations. Evidence synthesized in this narrative review from randomized controlled trials and meta-analyses (>20,000 participants) suggests that early probiotic administration, particularly Lactobacillus rhamnosus GG, Bifidobacterium species, multistrain formulations, and Saccharomyces boulardii, is associated with a 30–40% relative reduction in AAD incidence across heterogeneous studies, with absolute risk reductions of approximately 5–12% depending on baseline risk, strain, dose, and timing. Probiotics are generally well tolerated, with mild gastrointestinal adverse effects reported in 3–5% of users and rare serious events mainly in immunocompromised individuals. However, heterogeneity in formulations, populations, and limited long-term real-world data underscores the need for further pharmacoepidemiological studies, microbiome surveillance, and evaluation of antimicrobial resistance implications.

1. Introduction

The human gut microbiome is a dynamic and functionally complex ecosystem central to nutrient metabolism, immune regulation, and colonization resistance [1,2,3]. Perturbations caused by antibiotics, illness, or dietary shifts can disrupt microbial balance, predisposing individuals to gastrointestinal symptoms and increasing susceptibility to infection [4,5,6]. These disruptions underscore the clinical relevance of probiotics and microbiome-based therapeutics, which are defined as live microorganisms or microbial consortia intended to confer health benefits [7,8,9].

Evidence from randomized controlled trials (RCTs) indicates that specific probiotic strains can reduce the incidence and severity of antibiotic-associated diarrhea (AAD), particularly when administered concurrently with or shortly after antibiotic therapy [10,11,12,13]. However, translation from controlled clinical trials to routine practice remains inconsistent. Real-world use patterns—including product selection, dosing, timing, adherence, and long-term outcomes—are insufficiently documented and highly variable across healthcare settings [14,15,16], highlighting a critical gap in pharmacoepidemiology.

Safety considerations are increasingly important as the use of microbial therapeutics expands. While probiotics are generally regarded as safe, certain populations—such as immunocompromised individuals, critically ill patients, or those with central venous catheters—may be at higher risk [17]. Emerging evidence also raises concerns that probiotics could contribute to antimicrobial resistance (AMR) via horizontal gene transfer or selection of resistant commensal populations, particularly during antibiotic exposure [18,19]. These issues reinforce the need for comprehensive synthesis of safety data, microbiological insights, and regulatory considerations.

This narrative review integrates clinical evidence, real-world pharmacoepidemiologic trends, safety considerations, and AMR implications—domains often treated separately. By combining mechanistic insights with population-level observations, this review aims to provide a contextually grounded understanding of the clinical utility and limitations of probiotics and microbiome-based therapeutics.

Although many existing reviews have discussed the role of probiotics in preventing antibiotic-associated diarrhea, most have focused primarily on efficacy outcomes derived from randomized controlled trials. In routine clinical practice, however, probiotic use extends beyond controlled study settings and involves diverse populations, prescribing patterns, adherence behaviors, and long-term safety considerations. This review therefore adopts a broader perspective by integrating clinical evidence with real-world use, pharmacoepidemiological observations, and emerging concerns related to antimicrobial resistance and the resistome. By bringing these aspects together, this review seeks to place probiotic and microbiome-based therapies within a more realistic clinical and public health context.

Accordingly, the following sections are organized into thematic subsections addressing clinical effectiveness, real-world use, safety considerations, and antimicrobial resistance, followed by conclusions and future perspectives.

The objectives of this review are to:

• Characterize real-world patterns of use and clinical indications.
• Discuss reported effectiveness across different populations and clinical settings.
• Evaluate safety profiles and strain-specific risks.
• Examine potential impacts on the resistome and AMR dynamics.
• Identify evidence gaps and provide recommendations for future research and regulation.

2. Methodology

2.1. Narrative Approach

This review followed a narrative, non-systematic methodology, appropriate for topics spanning microbiology, clinical medicine, safety assessments, and antimicrobial-resistance considerations. A narrative approach allows conceptual integration of heterogeneous findings without formal systematic selection procedures [6,8].

2.2. Conceptual Framing

The review was conceptually guided by foundational literature describing the human gut microbiota [1,2,3,4,5] and expert consensus documents defining probiotics and their mechanisms [6,8]. These sources shaped the broad themes explored, including microbiome resilience, clinical outcomes, and safety considerations.

2.3. Evidence Gathering

Relevant literature was identified iteratively through database searches and screening of reference lists from key publications. Searches were conducted in major scientific databases, including PubMed, Scopus, and Web of Science. The search broadly covered peer-reviewed publications from approximately 2000 to 2024, reflecting the expansion of modern probiotic and microbiome research. Only articles published in English were considered.

Consistent with the narrative nature of this review, no restrictions were applied based on study design, and the selection of evidence was guided by conceptual relevance rather than exhaustive inclusion. Priority was given to large meta-analyses, well-designed randomized controlled trials, and highly cited studies that have informed clinical guidelines or consensus statements. The focus was on studies addressing:

• Probiotic mechanisms [6,8,11]
• Clinical outcomes related to antibiotic-associated diarrhea [13,14,15,16,17,18,19,20]
• Microbiota disruption and recovery [12,16]
• Safety profiles and probiotic-associated adverse events [21,22,23,24,25]
• Antimicrobial-resistance considerations [23,26]

Key studies were selected based on their relevance to clinical practice, study design rigor, population size, and influence on subsequent research, including frequent citation in later reviews and guidelines. Recent meta-analyses and landmark randomized controlled trials were emphasized to provide a balanced and clinically meaningful overview rather than a comprehensive enumeration of all studies. This process was intentionally flexible and did not employ predefined exclusion criteria, aligning with narrative review principles [6,9]. This approach aimed to capture a conceptually relevant body of literature rather than to provide an exhaustive or systematic synthesis.

2.4. Selection and Use of Evidence

Evidence was selected based on conceptual relevance rather than exhaustiveness. Included studies comprised randomized trials, observational studies, mechanistic papers, meta-analyses, and microbiology-focused reports, contributing insights into:

• Effectiveness against AAD [13,14,15,16,17,18,19,20]
• Microbiota-level effects [12,16]
• Safety and rare adverse events [21,22,23,24,25]
• AMR dynamics and resistome considerations [23,26]

2.5. Organization of Themes

Insights were organized thematically rather than systematically:

• Microbiota disruption during antibiotic therapy [1,3,12,16]
• Probiotic mechanisms grounded in microbiology [6,8,11]
• Clinical outcomes in adults, elderly, and pediatric populations [13,14,15,16,17,18,19,20,27]
• Safety profiles and host susceptibility [21,22,23,24,25]
• Antimicrobial-resistance considerations [23,26]

2.6. Narrative Synthesis

Data were synthesized descriptively. Mechanistic plausibility (e.g., competitive exclusion, immune modulation, short-chain fatty acids (SCFAs) production) was interpreted alongside clinical observations [6,8,11]. Trends in AAD reduction were contextualized with microbiota resilience literature [12,16]. Safety concerns were interpreted in light of case reports and expert analyses [21,22,23,24,25]. AMR-related issues, including antimicrobial resistance genes (ARGs) carriage by probiotics, were integrated conceptually [23,26].

2.7. Limitations

As a narrative review, this study does not apply systematic quality assessment tools, and effect sizes cannot be quantitatively pooled. Evidence from heterogeneous study designs is interpreted qualitatively. Publication bias and translational limitations from animal or in vitro studies may also impact conclusions. The review is intended to provide interpretive, hypothesis-generating insights rather than definitive clinical guidance.

2.8. Evidence Sections

1.

Real-World Use and Clinical Indications

Probiotics are most frequently administered in clinical practice to prevent antibiotic-associated diarrhea (AAD), particularly in patients receiving broad-spectrum antibiotics. Observational studies and surveys indicate variable utilization rates across hospital and outpatient settings, influenced by strain availability, clinician familiarity, patient age, and comorbidities [14,15]. Probiotics have been associated with a reduced incidence of AAD across multiple trials; however, baseline AAD incidence varied widely among study populations, thereby influencing the absolute magnitude of clinical benefit.

In adults, Lactobacillus rhamnosus GG, Bifidobacterium longum, and multistrain formulations are commonly used. Clinical trials consistently report reductions in AAD incidence when probiotics are co-administered with antibiotics, with earlier initiation (concurrent with the first antibiotic dose) associated with higher efficacy [13,16]. For instance, Wanyama et al. [13] reported a 37% relative risk reduction in adults across 42 RCTs encompassing 11,305 participants, with higher doses conferring incremental benefits. Zhang et al. [14] similarly demonstrated a 40% reduction in AAD among elderly patients (>65 years) using multistrain probiotics alongside antibiotics, emphasizing early and appropriately dosed administration.

Beyond AAD prophylaxis, probiotics are used to support general gut health, restore microbiota post-antibiotic therapy, and as adjuncts in gastrointestinal disorders such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and Helicobacter pylori eradication [16,17,18]. However, real-world data detailing prevalence, adherence, demographics, and long-term consumption are limited, creating uncertainty regarding population-level exposure and impact [14,15,16]. Real-world clinical use patterns and observed effects of probiotics are summarized in

Table 1. Real-world clinical use patterns and observed effects of probiotics.

Population	Probiotic Strain(s)	Dose and Duration	Indication	Observed Effect	Reference
Adults	Lactobacillus rhamnosus GG	1010 CFU/day, 7–14 days	AAD prophylaxis	37–38% reduction in AAD	[13,19]
Elderly (>65 y)	Multistrain Lactobacillus + Bifidobacterium	1010–1011 CFU/day, concurrent with antibiotics	AAD prevention	40% reduction in AAD	[14]
Children	Saccharomyces boulardii	5 × 109 CFU/day, during antibiotic course	AAD prevention	30–35% reduction in incidence and duration	[18,27]
Adults	Lactobacillus casei, Bifidobacterium breve	109 CFU/day, post-antibiotic	Gut microbiota recovery	Improved microbiota diversity	[16]

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2.

Evidence of Effectiveness: Clinical Trials and Meta-Analyses

The clinical effectiveness of probiotics is best established in preventing AAD among adults, children, and elderly populations. Systematic reviews and meta-analyses consistently demonstrate reductions in both incidence and duration of diarrhea, although effect sizes vary by strain, dose, and population [18,19,20,21].

Guo et al. [18] analyzed 36 RCTs with 9312 participants, reporting a pooled relative risk (RR) of 0.62 (95% CI 0.51–0.74), indicating a 38% reduction in AAD risk with probiotics. Subgroup analyses highlighted higher efficacy when probiotics were administered concurrently with antibiotics and for multistrain formulations. Liao et al. [19] also reported a significant preventive effect across diverse adult populations, emphasizing the importance of timing and baseline risk factors.

In pediatric populations, Saccharomyces boulardii and Lactobacillus rhamnosus effectively reduce AAD incidence and duration. A 30–35% risk reduction across 15 RCTs in children has been reported [27], with no significant adverse events. Evidence in elderly populations is limited but promising, with Zhang et al. [14] demonstrating a 40% reduction in AAD incidence when probiotics were co-administered with antibiotics.

Beyond AAD, evidence for probiotics in IBS, IBD, immune modulation, and long-term gut health is heterogeneous, often derived from small trials, observational studies, or preclinical data [16,18,20]. Some studies indicate symptom reduction in IBS and improved microbial diversity post-antibiotics, yet robust evidence for routine clinical application remains insufficient [16,20]. Evidence from randomized trials and meta-analyses on probiotic effectiveness against AAD is summarized in

Table 2. Evidence from randomized trials and meta-analyses on probiotic effectiveness against AAD.

Study	Type	Population	Strains	Dose/Duration	Outcome	Notes/Clinical Use	Ref.
Guo et al., 2019	Cochrane Review (Updated)	Children	S. boulardii, L. rhamnosus	During antibiotics	~30–35% reduction in AAD	Updated evidence; high-quality; robust	[18]
Liao et al., 2021	Meta-analysis	Adults	Multistrain	Variable	Preventive effect (significant)	Strongest when timing early; multistrain > single	[19]
Goldenberg et al., 2015	Cochrane Review (Earlier version)	Children	S. boulardii, L. rhamnosus	During antibiotics	~30–35% reduction in AAD	Earlier version; superseded by 2019	[27]
Zhang et al., 2022	RCT	Elderly	Lactobacillus + Bifidobacterium	1010–1011 CFU/day	40% reduction in AAD	Effective for high-risk elderly	[14]

Mechanism Notes: (1) Competitive Exclusion of Pathogens: Probiotics inhibit colonization by pathogens (e.g., C. difficile). (2) Metabolite Production: SCFAs and bacteriocins lower gut pH, promote epithelial integrity. (3) Immune Modulation: Enhances innate/adaptive immunity via IgA, regulatory T-cells, cytokine modulation. (4) Gut Barrier Enhancement: Reinforces tight junctions and mucus layers. (5) Resistome/AMR Considerations: Some strains may carry resistance genes; population-level monitoring recommended.

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a

Mechanisms of Action of Probiotics and Microbiome Therapeutics

Probiotics exert beneficial effects via multiple mechanisms contributing to gut homeostasis and disease prevention:

• Competitive Exclusion of Pathogens: Probiotics inhibit colonization by pathogenic bacteria through competition for adhesion sites and nutrients, particularly relevant in preventing AAD caused by Clostridioides difficile [6,8,11].
• Production of Metabolites: Beneficial microbes produce SCFAs and bacteriocins, lowering gut pH, inhibiting pathogens, and promoting epithelial integrity [6,8].
• Modulation of Host Immune Responses: Probiotics enhance innate and adaptive immunity via secretory IgA, regulatory T-cells, and cytokine modulation, reducing gastrointestinal inflammation [6,8].
• Enhancement of Gut Barrier Function: Certain strains reinforce tight junctions and mucus layers, reducing translocation of pathogens and toxins [6,8].
• Indirect Effects on Resistome Dynamics: Restoration of microbial diversity post-antibiotics may limit overgrowth of resistant pathogens, although strain-specific differences exist [23,26].

3.

Safety Profile and Adverse Events

Probiotics are generally well tolerated, particularly for short-term AAD prophylaxis, with meta-analyses showing no significant increase in adverse events compared with placebo (RR ~1.0, 95% CI 0.87–1.14) [18,19,20]. Common side effects are mild and transient, including bloating and gastrointestinal discomfort [21].

Vulnerable populations, including immunocompromised patients, neonates, and critically ill individuals, may face rare but serious adverse events such as bacteremia or fungemia [21,22,23,24]. Long-term safety data are limited, as most RCTs are short-term [16,18]. Reported adverse effects and gastrointestinal tolerability of probiotic use across different populations and study settings are summarized in

Table 3. Safety Profile and Adverse Events.

Study	Population	Probiotic(s)	Duration	Adverse Event	Incidence (%)	Ref.
Liao et al., 2021	Adults	Lactobacillus rhamnosus GG	7–14 days	Gastrointestinal (GI) discomfort	3.2%	[19]
Boyle et al., 2006	Adults	Various Lactobacillus	5–10 days	Sepsis (rare)	<0.01%	[21]
Doron & Snydman, 2015	Immunocompromised	Multiple strains	Variable	Opportunistic infections	Rare but reported	[22]

Reported adverse event rates are likely underestimated, as most randomized controlled trials were short-term and not designed to capture rare or delayed adverse outcomes. Long-term safety data remain limited.

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4.

Microbiological Considerations and Antimicrobial Resistance (AMR) Risk

Certain Lactobacillus and Bifidobacterium strains carry intrinsic or acquired resistance determinants (e.g., tetracycline, vancomycin), raising theoretical risk for horizontal gene transfer [23,24,25]. Experimental studies demonstrate that concurrent probiotic and antibiotic administration may alter resistome composition, sometimes maintaining or expanding resistance gene prevalence [26]. Smith et al. [26] observed individual-specific effects, with some participants exhibiting sustained expansion of tetracycline-resistance genes post-probiotic supplementation. Importantly, the presence of antimicrobial resistance genes in probiotic strains or commensal microbiota does not equate to documented horizontal gene transfer in humans. While experimental and animal studies suggest theoretical risks, direct clinical evidence demonstrating probiotic-mediated transmission of resistance genes in human populations remains limited. Most AMR concerns therefore stem from in vitro or preclinical models rather than confirmed human outcomes. In this context, any potential contribution of probiotics to antimicrobial resistance should be interpreted cautiously and weighed against the substantially higher and well-established baseline AMR risk associated with antibiotic exposure itself. The majority of reported resistance determinants are identified through in vitro assays or experimental models, whereas direct evidence of probiotic-mediated horizontal gene transfer in humans remains limited. These observations reinforce the need to interpret AMR-related risks of probiotics cautiously and in relation to the substantially higher baseline resistome perturbation driven by antibiotic exposure itself. The microbiological characteristics and antimicrobial resistance–related findings of commonly used probiotic strains are summarized in

Table 4. Microbiological Considerations and AMR Risk.

Probiotic Strain	Resistance Genes Identified	Evidence Type	Observed Risk	Ref.
Lactobacillus rhamnosus GG	Tetracycline resistance	in vitro	Potential horizontal transfer	[23]
Bifidobacterium breve	Vancomycin resistance	in vitro	Theoretical risk	[23]
Saccharomyces boulardii	None reported	Cohort	Low AMR risk	[26]

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5.

Population-Specific Considerations

• Children: Evidence supports the use of Saccharomyces boulardii and Lactobacillus rhamnosus for AAD prevention, with favorable safety profiles [27]. The risk of probiotic-associated sepsis is extremely low but warrants caution in severely immunocompromised pediatric patients [21,22].
• Adults: Probiotics effectively reduce AAD risk, particularly when administered early during antibiotic therapy [13,18]. Subgroup analyses suggest multistrain formulations and higher doses confer greater benefit [13,14].
• Elderly (>65 years): Older adults have higher baseline susceptibility to AAD and comorbidities, which may justify targeted prophylaxis. Early initiation and appropriately dosed multistrain formulations are effective, although long-term colonization and safety data remain sparse [14,15].
• Immunocompromised individuals: Evidence for safety and efficacy is limited. Case reports indicate potential risk of opportunistic infection, particularly with novel or poorly characterized strains [21,22,23,24]. Strain-specific risk assessment and clinical monitoring are recommended.
• Population-specific differences in probiotic indications, observed efficacy, and safety considerations across children, adults, elderly, and immunocompromised individuals are summarized in

  Table 5. Population-Specific Considerations.

  Population	Probiotic(s)	Indication	Efficacy	Safety Concerns	Ref.
  Children	Saccharomyces boulardii	AAD prevention	Reduced incidence and duration	Generally safe	[27]
  Elderly	Multistrain Lactobacillus + Bifidobacterium	AAD prophylaxis	Significant reduction	Mild GI discomfort	[14]
  Immunocompromised	Various Lactobacillus	AAD prevention	Limited evidence	Rare opportunistic infections	[22]

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6.

Adjunctive and Complementary Uses

Beyond AAD prevention, probiotics and microbiome therapeutics are increasingly considered for:

• Restoration of gut microbiota post-antibiotic therapy or gastrointestinal illness [16,28]
• Adjunct therapy during H. pylori eradication to reduce gastrointestinal side effects [16,29]
• Maintenance of general gut health, prevention of recurrent gastrointestinal (GI) symptoms, or modulation of immune-mediated conditions [30]

Evidence for these applications remains heterogeneous, often derived from small trials, observational studies, or preclinical data. Robust population-level data are lacking, limiting routine recommendations outside AAD prevention [16,18,20]. Reported adjunctive and complementary uses of probiotics beyond AAD prevention, together with the heterogeneity of observed outcomes, are summarized in

Table 6. Adjunctive and Complementary Uses.

Context/Condition	Probiotic(s) Used	Duration	Observed Benefit	Ref.
H. pylori eradication	Lactobacillus rhamnosus GG	During antibiotic regimen	Reduced gastrointestinal (GI) side effects, improved tolerance	[29]
Post-antibiotic microbiota recovery	Lactobacillus casei, Bifidobacterium breve	7–14 days post-antibiotic	Improved microbiota diversity	[16,28]
Irritable bowel syndrome (IBS) symptom management	Multistrain probiotics	4–12 weeks	Mixed results; some improvement in bloating	[30]

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7.

Regulatory, Guideline, and Public Health Implications

The global commercialization of probiotics presents regulatory and policy challenges. Variation in strain composition, dosage, formulation, and labeling—combined with limited long-term safety and AMR data—necessitates regulatory oversight.

Recommendations include:

• Mandatory characterization of strains and screening for resistance genes prior to market approval [23,24,25];
• Post-marketing surveillance and registry-based monitoring of long-term outcomes, colonization patterns, and resistome effects [14,15,16];
• Clear labeling specifying strain, dose, intended use, target population, and contraindications (e.g., immunocompromised) [14];
• Development of evidence-based guidelines integrating microbiology, clinical outcomes, and public health considerations [14,15].

Such measures would optimize therapeutic benefit, minimize potential AMR risk, and support responsible use of microbial therapeutics in diverse populations.

8.

Knowledge Gaps and Future Directions

Critical gaps remain:

• Longitudinal pharmacoepidemiological studies tracking utilization, adherence, colonization, and clinical outcomes [14,15,16];
• Metagenomic and resistome-focused surveillance to monitor antimicrobial resistance dynamics, particularly in long-term or repeated probiotic users [23,24,25,26];
• Stratified research in vulnerable populations (children, elderly, immunocompromised) to assess real-world risk–benefit [14,15,16];
• Standardization of reporting (strain, dose, timing, formulation) and outcome measures to enable comparability across studies [16,18];
• Regulatory frameworks that integrate microbiology, clinical, and public health perspectives for probiotic stewardship [14,15].
• Overall, clinical efficacy outcomes were supported mainly by randomized trials, whereas safety and AMR-related findings relied on observational or mechanistic evidence.

3. Discussion

This narrative review integrates evidence from randomized controlled trials (RCTs), meta-analyses, and observational studies to provide a comprehensive assessment of the clinical use, effectiveness, safety, and antimicrobial resistance (AMR) considerations of probiotics and microbiome-based therapeutics. Although evidence supports the use of probiotics in preventing antibiotic-associated diarrhea (AAD) across adults, children, and elderly populations, the magnitude of clinical benefit and short-term safety profiles should be interpreted in relation to baseline AAD risk and clinical context [13,14,15,16,17,18,19,20,27]. Baseline AAD incidence varies substantially across populations and healthcare settings, which directly influences the absolute magnitude of benefit. While relative risk reductions reported in clinical trials may appear clinically meaningful, the corresponding absolute risk reduction depends on underlying incidence and may therefore differ considerably between high- and low-risk groups. This distinction is particularly important when translating trial findings into real-world clinical practice. Long-term safety and population-level risk remain insufficiently characterized, particularly in vulnerable groups, highlighting the need for post-marketing and pharmacoepidemiologic surveillance.

From a pharmacoepidemiological perspective, several key points emerge:

• Real-world utilization patterns remain variable, with differences in strain selection, dosing, timing relative to antibiotic therapy, and adherence across healthcare settings [14,15,16]. Observational studies indicate that early initiation and multistrain formulations are associated with greater effectiveness, highlighting the importance of population-level usage data to inform best practices [13,14].
• Population-level safety data are limited, particularly in vulnerable populations such as immunocompromised patients, neonates, and elderly adults [21,22,23,24]. Rare adverse events, including opportunistic infections, underscore the need for ongoing pharmacovigilance and registry-based monitoring [22,24].
• Antimicrobial resistance dynamics represent a critical, yet underexplored, dimension. Certain probiotic strains harbor intrinsic or acquired resistance genes, which may theoretically be transferred to commensal or pathogenic organisms [23,24,25,26]. Population-based surveillance and metagenomic studies are essential to quantify potential AMR impacts [26]. Importantly, current antimicrobial resistance concerns related to probiotics differ in their level of empirical support. Evidence from human clinical and observational studies primarily demonstrates transient carriage of antibiotic resistance genes and limited microbiota perturbations, whereas horizontal gene transfer and long-term resistome alterations are largely inferred from in vitro or animal models.
• Knowledge gaps persist regarding long-term colonization, repeated exposures, adherence patterns, and population-level clinical outcomes [14,15,16,23,24,25,26]. Pharmacoepidemiological studies integrating clinical, microbiome, and resistome data are required to generate evidence that can guide safe and effective use of microbial therapeutics.

From an evidence-level perspective, the effectiveness of probiotics in preventing antibiotic-associated diarrhea is supported primarily by randomized controlled trials and meta-analyses, representing moderate- to high-level evidence. In contrast, data on long-term safety, real-world utilization patterns, and antimicrobial resistance outcomes are largely derived from observational studies, case reports, or mechanistic investigations, and therefore represent lower levels of evidence. While mechanistic and experimental studies raise theoretical concerns regarding horizontal gene transfer, direct clinical evidence of probiotic-induced antimicrobial resistance in humans remains limited. Therefore, AMR-related risks should be interpreted cautiously, emphasizing surveillance rather than definitive clinical harm.

Collectively, these findings indicate that probiotics and microbiome-based interventions are promising population-level supportive strategies, particularly for mitigating AAD. However, to optimize their impact in clinical practice, studies should focus on real-world effectiveness, adherence, long-term safety, and resistome monitoring [14,15,16,23,24,25,26]. Importantly, population-level impact should not be inferred from relative effect estimates alone, and future studies should prioritize reporting absolute risk differences alongside baseline incidence to better inform clinical and public health decision-making.

This narrative review uniquely integrates clinical efficacy, safety profiles, real-world use patterns, and antimicrobial resistance (AMR) considerations of probiotics and microbiome-based therapeutics, providing a comprehensive perspective rarely addressed together [13,14,15,16,18,19,27]. It evaluates population-specific outcomes across children, adults, elderly, and immunocompromised individuals, highlighting differences in effectiveness and potential risks [13,14,18,21,27]. Safety concerns, including rare opportunistic infections, are summarized, alongside evidence on resistome dynamics and potential horizontal gene transfer [17,21,22,23,24,25,26]. The review identifies critical knowledge gaps and emphasizes the need for long-term pharmacoepidemiological studies, population-level microbiome and AMR monitoring, and regulatory guidance to optimize safe and effective probiotic use [14,15,16,23,24,25,26].

4. Conclusions

Probiotics and microbiome-based interventions provide effective strategies to prevent antibiotic-associated diarrhea across adults, children, and elderly populations, with generally favorable short-term safety profiles. Nevertheless, variability in strains, doses, treatment timing, and population characteristics, along with limited long-term real-world data, limits conclusions regarding chronic use, colonization, and impacts on antimicrobial resistance. Vulnerable populations, including immunocompromised individuals, require careful consideration.

Based on the available evidence, probiotic use for the prevention of antibiotic-associated diarrhea in generally healthy populations can be considered a practice-ready intervention. In contrast, questions regarding long-term population-level effectiveness, repeated exposure, use in high-risk populations, and antimicrobial resistance surveillance remain important research priorities.

Future research should prioritize long-term pharmacoepidemiological studies, population-level microbiome monitoring, and the development of evidence-based guidelines and regulatory frameworks to maximize therapeutic benefits while minimizing potential antimicrobial resistance risks. Safe and effective probiotic use requires careful strain selection, appropriate dosing, and population-specific monitoring. For generally healthy adults, early probiotic administration alongside antibiotics is recommended; for the elderly, multistrain formulations are preferred; and for immunocompromised individuals, close monitoring is essential.