Antibiotics: Evidence for Probiotics, Nutraceuticals, Herbal Therapies, and Diet in Small Intestinal Bacterial Overgrowth. A Narrative Review

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1. Introduction

Small intestinal bacterial overgrowth (SIBO) is a heterogeneous gastrointestinal disorder characterized by an abnormal increase in the number and/or composition of microorganisms within the small intestine, resulting in excessive fermentation and a broad spectrum of gastrointestinal manifestations. Abdominal bloating, distension, abdominal pain, diarrhea, altered bowel habits, flatulence, and nutritional abnormalities are among the most commonly reported manifestations. The clinical phenotype is influenced by the underlying disorder, intestinal transit, microbial composition, and the predominant gases generated during fermentation. [1,2]

SIBO should also be distinguished from intestinal methanogen overgrowth (IMO). Although the two conditions frequently coexist in the clinical literature, methane is produced predominantly by archaea rather than bacteria, and methane-positive patients may exhibit different clinical characteristics and therapeutic responses. This distinction has become increasingly important when interpreting studies that combine hydrogen- and methane-positive breath tests within a single therapeutic outcome. [1, 3] The pathophysiology of SIBO is multifactorial. Normal defenses against excessive microbial colonization of the small intestine include gastric acidity, pancreaticobiliary secretions, an intact ileocecal valve, intestinal immune mechanisms, and, particularly, coordinated small-bowel motility and the migrating motor complex. Structural abnormalities, impaired motility, systemic diseases, previous gastrointestinal surgery, medications, and other conditions that disturb these protective mechanisms may predispose to microbial overgrowth. Consequently, eradication of excessive microorganisms without correction of the underlying predisposing factor may be followed by recurrence. [1, 2] Antibiotics, particularly poorly absorbed agents such as rifaximin, remain the most extensively studied pharmacological approach to SIBO. Nevertheless, antibiotic therapy has several limitations, including incomplete response, recurrence after initially successful treatment, adverse effects, cost, and concerns regarding repeated antimicrobial exposure. These limitations have stimulated considerable interest in non-antibiotic and complementary approaches aimed not only at reducing microbial overgrowth but also at modifying the intestinal ecosystem, luminal fermentation, intestinal barrier function, and gastrointestinal motility. [1] Among these strategies, probiotics have accumulated the largest body of direct clinical evidence. Other approaches include berberine and botanical therapies, elemental diets, prebiotics and synbiotics, conventional dietary interventions, and increasingly popular fermented foods such as kefir and kombucha. Importantly, biological plausibility and widespread use should not be conflated with demonstrated therapeutic efficacy. [4-6] Accordingly, the objective of this narrative review was to critically evaluate the clinical evidence supporting non-antibiotic and adjunctive approaches to SIBO, with particular emphasis on probiotics, berberine and other nutraceuticals, herbal therapies, elemental and dietary interventions, prebiotics and synbiotics, and fermented foods. Particular attention was given to the hierarchy of available evidence and to the important distinction between objective resolution of SIBO and improvement in gastrointestinal symptoms.

2. Methods

This evidence-based narrative review was designed to critically examine non-antibiotic, complementary, and adjunctive interventions evaluated for the management of SIBO. Because the purpose was to integrate a heterogeneous literature encompassing evidence syntheses, randomized and non-randomized clinical trials, dietary interventions, and emerging microbiome-directed approaches rather than to perform a new quantitative synthesis, a narrative review framework was adopted.

Relevant literature was identified through searches of major biomedical databases and reference lists of key reviews and clinical studies. Priority was given to network meta-analyses, conventional meta-analyses, systematic reviews, randomized controlled trials, controlled clinical studies, and clinically informative prospective or retrospective studies. Recent evidence syntheses were additionally used to identify earlier primary studies.

Search concepts combined terms related to small intestinal bacterial overgrowth, SIBO, and intestinal methanogen overgrowth with probiotics, Saccharomyces boulardii, Bacillus clausii, Lactobacillus, Bifidobacterium, prebiotics, synbiotics, berberine, herbal therapy, botanical therapy, nutraceuticals, elemental diet, diet, low-FODMAP, fermented foods, kefir, and kombucha. Reference lists of relevant reviews and clinical trials were examined for additional studies.

Evidence was interpreted according to study design, with evidence syntheses followed by randomized controlled trials, controlled non-randomized studies, uncontrolled clinical studies, and indirect or mechanistic evidence. This hierarchy was used descriptively and was not intended as a formal certainty-of-evidence grading system.

Studies were evaluated according to population, diagnostic method, intervention, comparator, duration, objective breath-test outcomes, gastrointestinal symptom outcomes, adverse events, and major methodological limitations. Whenever possible, objective SIBO resolution or breath-test normalization was considered separately from symptomatic response, because improvement in bloating, abdominal pain, diarrhea, or other gastrointestinal symptoms does not necessarily indicate eradication of small-intestinal microbial overgrowth.

Studies enrolling methane-positive participants were interpreted cautiously because methane positivity may represent IMO rather than bacterial overgrowth. Results involving hydrogen- and methane-predominant populations were distinguished whenever sufficient information was available. For emerging interventions such as kefir, kombucha, and other fermented foods, the absence of controlled SIBO-specific trials was considered an evidence gap rather than evidence of ineffectiveness.

3. Results

3.1. Overall Landscape and Hierarchy of Evidence

The clinical literature evaluating non-antibiotic SIBO treatment was heterogeneous with respect to patient population, definition of SIBO, breath-test substrate and positivity threshold, treatment duration, comparator, and outcome definition. Earlier systematic evaluation of alternative therapies demonstrated a relatively small evidence base, principally involving probiotics, herbal preparations, and dietary therapy. More recent evidence syntheses have expanded this literature, particularly for probiotics and through network comparisons incorporating berberine and other interventions. [4] The overall hierarchy of evidence supporting non-antibiotic and adjunctive approaches to SIBO, ranging from evidence syntheses and controlled clinical studies to preliminary, indirect, and mechanistic evidence, is summarized in Figure 1.

Fig 1 The hierarchy of available evidence is summarized in Table

1. Probiotics currently represent the non-antibiotic

intervention with the broadest body of direct clinical evidence. Berberine has recently gained prominence through network-level comparisons and emerging direct comparative evidence. Specific probiotic preparations, particularly Saccharomyces boulardii, have additional controlled clinical evidence. Herbal combinations and elemental diets have generated clinically relevant signals, although their supporting study designs are less robust. Evidence for low-FODMAP diets, kefir, kombucha, and several other nutraceutical or fermented-food strategies remains largely indirect or insufficient for establishing SIBO eradication.

3.2. Probiotics: The Largest Body of Direct Non-

Antibiotic Evidence Probiotics have been studied more extensively than other non-antibiotic approaches, although the literature is characterized by considerable heterogeneity in species, strains, doses, duration, and study populations. The earlier meta-analysis by Zhong et al. reported a pooled SIBO decontamination rate of 62.8% (95% CI 51.5–72.8). In comparisons with non-probiotic controls, probiotics were associated with a higher decontamination rate (RR 1.61, 95% CI 1.19–2.17). Probiotic therapy was also associated with a reduction in hydrogen concentration (weighted mean difference −36.35 ppm, 95% CI −44.23 to −28.47) and a modest improvement in abdominal pain. [5] The more recent review by Niño et al. identified 18 clinical trials; 14 had control groups and nine were randomized, encompassing 496 probiotic-treated patients and 480 controls. Six trials compared probiotics with placebo (122 vs 104 participants), but only three were sufficiently comparable for quantitative pooling. The individual studies further illustrate why probiotics should not be regarded as a homogeneous therapeutic class. Trials involved Bacillus clausii, Saccharomyces boulardii, Lactobacillus species, Bifidobacterium species, and multispecies preparations, with markedly different populations and comparators. [6] For example, Scarpellini et al. reported improvement in 17/30 (56.6%) patients receiving B. clausii compared with 12/30 (40%) receiving metronidazole. Soifer et al. reported clinical improvement in 20/25 (82%) probiotic-treated patients compared with 13/25 (52%) receiving metronidazole. Conversely, other probiotic trials did not demonstrate significant benefit. In a placebo-controlled study in chronic liver disease, a multispecies probiotic produced SIBO resolution in 24% compared with 0% in the placebo group after four weeks. Taken together, probiotics have the largest clinical evidence base among non-antibiotic interventions, but efficacy observed with one formulation cannot automatically be extrapolated to another. [7, 8, 9]

3.3. Saccharomyces Boulardii

Among individual probiotic organisms, S. boulardii deserves particular attention because it has been evaluated as monotherapy and in combination with antibiotics. García-Collinot et al. conducted an open randomized pilot clinical trial in patients with systemic sclerosis and hydrogen-positive SIBO. Forty patients were randomized to metronidazole plus S. boulardii (n=13), metronidazole alone (n=13), or S. boulardii alone (n=14). [10]. After treatment, SIBO eradication was reported in 55% of patients receiving combination therapy, 33% receiving S. boulardii alone, and 25% receiving metronidazole alone. Reductions in expired hydrogen and improvements in gastrointestinal symptoms were also observed in the S. boulardii-containing groups. These results should nevertheless be interpreted cautiously: only 29 of the 40 randomized participants completed two months of follow-up. The study therefore provides a clinically interesting signal rather than definitive evidence of superiority. [10]

3.4. Berberine

More recent randomized pilot evidence in diarrhea-predominant irritable bowel syndrome (IBS) also supports continued investigation of S. boulardii CNCM I-745. Bustos Fernández et al. randomized patients to S. boulardii plus dietary advice or dietary advice alone; among 48 evaluable participants, hydrogen excretion decreased by 41% versus 29%, respectively, with greater symptom-score reduction in the probiotic group [15].

Berberine represents one of the most interesting emerging non-antibiotic interventions. A recent Bayesian network meta-analysis included 30 randomized controlled trials comprising 1,552 participants and 12 therapeutic interventions. Berberine achieved a favorable probabilistic ranking for SIBO eradication. [11] This finding is important but requires careful interpretation.

Network rankings integrate direct and indirect comparisons and can be influenced by the amount and quality of available evidence and the structure of the treatment network. Accordingly, berberine is best regarded as a promising emerging intervention for which additional direct comparative trials remain desirable.

3.5. Herbal and Botanical Therapies

Herbal combinations constitute another frequently discussed alternative to conventional antibiotic therapy. In the comparative study by Chedid et al., patients selected either rifaximin or one of two multi-ingredient botanical regimens (Dysbiocide plus FC Cidal or Candibactin-AR plus Candibactin-BR). Among patients with follow-up testing, 17/37 (46%) receiving herbal therapy achieved a negative lactulose breath test compared with 23/67 (34%) receiving rifaximin (P=0.24); the adjusted odds ratio was 1.85 (95% CI 0.77–4.41; P=0.17) [12].

Importantly, the herbal intervention evaluated by Chedid et al. [12] did not consist of a single botanical compound, but rather one of two multi-ingredient commercial regimens: Dysbiocide plus FC Cidal or Candibactin-AR plus Candibactin-BR, administered for four weeks. The formulations contained multiple botanicals with putative antimicrobial or microbiome-modulating properties. FC Cidal included Tinospora cordifolia, Equisetum arvense, pau d’arco, Thymus vulgaris, Artemisia dracunculus, Sida cordifolia, and Olea europaea, whereas Dysbiocide contained, among other ingredients, dill seed, Stemona sessilifolia, Artemisia absinthium, Pulsatilla chinensis, Brucea javanica, Picrasma excelsa, Acacia catechu, Hedyotis diffusa, and Achillea millefolium. The alternative regimen combined Candibactin-AR, containing thyme and oregano oils together with sage and lemon balm extracts, with Candibactin-BR, a berberine-rich preparation containing Coptis chinensis, Berberis aristata, berberine sulfate, Scutellaria baicalensis, Phellodendron chinense, ginger, Chinese licorice, and Chinese rhubarb. Because these were complex multi-ingredient formulations, the observed clinical response cannot be attributed to any individual botanical constituent.

Because treatment allocation was not randomized, these findings cannot establish equivalence between botanical therapy and rifaximin. Nevertheless, the observed response provides a meaningful signal supporting prospective randomized evaluation of standardized botanical preparations.

3.6. Elemental Diet

The elemental diet represents a different therapeutic concept because it profoundly modifies the luminal nutritional environment rather than primarily introducing beneficial microorganisms or directly suppressing selected microbial populations. In the study by Pimentel et al., approximately 80% of evaluable participants normalized their breath test after 14 days, increasing to approximately 85% after extension to 21 days. [13] The magnitude of this response is notable, but the absence of a randomized comparator, together with issues of adherence, tolerability, patient selection, and interpretation of lactulose breath testing, limits causal inference. The elemental diet therefore provides a strong preliminary efficacy signal rather than definitive comparative evidence.

3.7. Prebiotics, Synbiotics, And Adjunctive Microbiome-

Directed Therapy Evidence for prebiotics and synbiotics is substantially less developed than that for probiotics. Much of the available literature evaluates these agents following or concurrently with antibiotic treatment rather than as independent therapies. Rosania et al., for example, compared sequential rifaximin followed by Lactobacillus casei with rifaximin followed by short-chain fructooligosaccharides. Symptomatic improvement favored the probiotic sequence numerically (83.3% vs 66.6%), but the difference was not statistically significant (P=0.57). Such studies are clinically relevant but are best classified as adjunctive microbiome-directed strategies. [14, 14,16]

3.8. Dietary Interventions and Low-Fodmap Approaches

Dietary modification is widely used in patients with SIBO because fermentable carbohydrates can influence luminal fermentation, gas production, bloating, and abdominal discomfort. Nevertheless, evidence supporting symptom management should be distinguished from evidence demonstrating eradication of SIBO. Low-FODMAP strategies may reduce rapidly fermentable substrates and improve symptoms in selected patients, but direct controlled evidence demonstrating sustained normalization of SIBO through a low-FODMAP diet alone remains insufficient. Thus, these approaches are better viewed primarily as symptom- and substrate-modifying strategies.

3.9. Kefir, Kombucha, and Fermented Foods

Kefir and kombucha warrant inclusion because they are increasingly used as food-based approaches to microbiome modulation. Both contain complex microbial communities and fermentation-derived metabolites and therefore have biological plausibility. However, their composition may vary considerably according to starter culture, substrate, fermentation conditions, storage, and commercial processing. [4] Adequately controlled SIBO-specific clinical trials demonstrating eradication with kefir or kombucha have not been identified. Their position at the lower end of the evidence hierarchy should therefore not be interpreted as evidence that they are ineffective. Rather, it reflects an absence of direct clinical investigation. Efficacy demonstrated for a standardized probiotic strain cannot automatically be extrapolated to kefir, kombucha, or fermented foods as a class.

3.10. Integration of The Evidence

The available evidence reveals a mismatch between the popularity of several non-antibiotic SIBO therapies and the strength of their clinical evaluation. Probiotics have the broadest direct clinical literature, but effects appear formulation-specific. Berberine has emerged prominently from network-level evidence, while herbal combinations and elemental diets show clinically relevant signals supported by less robust direct study designs. Low-FODMAP diets and fermented foods occupy a different evidentiary position: their biological rationale and potential symptomatic effects are clinically relevant, but evidence of SIBO eradication is presently insufficient.

Collectively, these findings support a central distinction: improvement in gastrointestinal symptoms, modification of fermentation, alteration of the microbiome, and objective eradication of SIBO are related but non-equivalent therapeutic outcomes.

4. Discussion

The growing interest in non-antibiotic approaches to SIBO reflects both the limitations of conventional antimicrobial therapy and an evolving understanding of SIBO as more than a simple infectious disorder. Although excessive microbial colonization is central to its definition, the development and recurrence of SIBO frequently result from disturbances in intestinal motility, anatomy, luminal environment, host defenses, and microbial ecology. From this perspective, repeated antimicrobial eradication alone may not adequately address the mechanisms responsible for persistence or recurrence.

Among non-antibiotic strategies, probiotics have the most extensive direct clinical literature. This is biologically plausible because probiotics may influence the intestinal ecosystem through competitive exclusion, production of antimicrobial compounds, modification of luminal conditions, enhancement of epithelial barrier function, and modulation of mucosal immune responses. However, “probiotic” encompasses highly heterogeneous interventions. Saccharomyces boulardii, Bacillus clausii, Lactobacillus species, Bifidobacterium species, and multispecies preparations cannot reasonably be assumed to have identical biological or clinical effects. Future studies should therefore identify organisms at the strain level and standardize doses and treatment duration.

Saccharomyces boulardii is particularly interesting because it is a yeast rather than a bacterial probiotic and may be administered alongside antibacterial agents. The García-Collinot trial raises the possibility that microbiome-directed therapies may complement rather than necessarily replace antibiotics. Nevertheless, its small size, open-label design, systemic-sclerosis-specific population, and attrition preclude broad conclusions. [10] Berberine and botanical therapies represent another promising direction. Their proposed activity extends beyond direct antimicrobial effects and may include modulation of microbial composition, intestinal barrier function, inflammation, and host–microbial signaling. The favorable position of berberine in recent network analyses is noteworthy, but network ranking should not be equated with repeated direct demonstrations of superiority. Similarly, the Chedid study provides a useful signal for herbal combinations, but its non-randomized design does not establish equivalence with rifaximin. Standardization is also essential because “herbal therapy” is not a single reproducible pharmacological intervention. [11, 12] The elemental diet provides a different conceptual model. By altering nutrient delivery and reducing substrate available for microbial fermentation, it may change the luminal environment sufficiently to influence breath-test abnormalities. The high normalization rates reported in the historical study are striking, but the lack of a randomized comparator and practical issues of tolerability limit its routine interpretation. Nevertheless, these findings emphasize substrate availability as a potentially important therapeutic target. [13] Conventional dietary interventions require particular nuance. Low-FODMAP diets may reduce fermentation, gas production, and bloating without necessarily eliminating microbial overgrowth. This distinction may explain why some patients improve clinically despite persistent breath-test abnormalities, whereas normalization of a breath test does not guarantee complete symptom resolution in the presence of IBS, dysmotility, visceral hypersensitivity, or another underlying disorder. Symptom control is clinically meaningful, but claims that a diet “treats SIBO” should distinguish symptom modification from objective eradication.

Kefir and kombucha occupy an especially interesting position because their popularity exceeds the amount of SIBO-specific evidence. Their microbial communities and fermentation-derived metabolites provide biological plausibility, but product composition can vary substantially. The current lack of controlled SIBO trials should not be interpreted as evidence of ineffectiveness. It is more appropriately regarded as an evidence gap and a potential field for future clinical investigation. Another important issue is the historical tendency to combine hydrogen-positive SIBO and methane-positive breath tests. Methane is produced predominantly by methanogenic archaea, and intestinal methanogen overgrowth may differ biologically and therapeutically from bacterial overgrowth. Future trials should therefore report hydrogen- and methane-predominant phenotypes separately whenever possible. [1,3] Taken together, the available evidence suggests that the future of SIBO management may involve a broader therapeutic model than microbial eradication alone. Probiotics may modify microbial competition and host– microbial interactions; botanical compounds may combine antimicrobial and microbiome-modulating properties; elemental diets alter fermentable substrate availability; conventional diets modify fermentation; and interventions directed at gastrointestinal motility may address an important mechanism of recurrence. These mechanisms are not mutually exclusive. Future approaches may ultimately combine interventions directed at microbial burden, intestinal motility, luminal substrate availability, mucosal integrity, and the underlying predisposing disorder. This integrated pathophysiological framework, linking the major factors contributing to SIBO with the potential sites of action of non-antibiotic and adjunctive interventions, is illustrated in Figure 2.

Fig 2 This framework also helps explain recurrence. If dysmotility, altered anatomy, medication exposure, or another predisposing condition persists after microbial suppression, recolonization is biologically plausible. Long-term management should therefore include identification and, whenever possible, correction of factors responsible for SIBO development.

The current literature does not support replacing all conventional SIBO treatment with a single “natural” therapy. Rather, it suggests a spectrum of interventions with different degrees of clinical investigation. Importantly, a lower position within the evidence hierarchy should not automatically be interpreted as lack of efficacy. In several instances—particularly kefir and kombucha—the appropriate conclusion is insufficient evidence rather than evidence of ineffectiveness.

Several limitations recur throughout the literature. Diagnostic definitions have changed over time, and studies use different substrates, sampling intervals, and thresholds for breath-test positivity. Populations include patients with IBS, systemic sclerosis, chronic liver disease, previous bariatric surgery, and other conditions. Therapeutic interventions are similarly heterogeneous, and several studies combine non-antibiotic approaches with antibiotics. Many studies are small and evaluate short-term outcomes, whereas recurrence is a central feature of SIBO. Future studies should assess not only breath-test normalization but also durability of response, recurrence, gastrointestinal symptoms, nutritional outcomes, quality of life, tolerability, and safety.

5. Conclusions

Non-antibiotic approaches to SIBO constitute a promising but heterogeneous therapeutic field. Probiotics currently have the largest body of direct clinical evidence, with Saccharomyces boulardii and selected multispecies preparations showing particularly interesting results. Berberine has emerged as a promising botanical therapy, while herbal combinations and elemental diets have also demonstrated clinically relevant signals. Dietary interventions may provide meaningful symptom relief, although evidence for eradication of SIBO remains limited. Kefir, kombucha, and other fermented foods represent an important evidence gap. Their biological plausibility and widespread use justify clinical investigation, but current evidence is insufficient to establish therapeutic efficacy specifically for SIBO. Lack of evidence should not be interpreted as evidence of lack of effect. Overall, available findings suggest that non-antibiotic therapy should be understood within a broader pathophysiological framework. Rather than focusing exclusively on eradication of microorganisms, future management strategies may increasingly target the intestinal ecosystem, including microbial composition, fermentable substrate availability, motility, epithelial barrier function, and the underlying factors that predispose to recurrent overgrowth.

Declarations

Ethics Approval and Consent to Participate Not applicable. This article is a narrative review of previously published literature and did not involve new research with human participants or animals.

Consent for Publication Not applicable.

Availability of Data and Materials No new datasets were generated or analyzed for this narrative review. All information discussed in the article derives from previously published sources.

Competing Interests The author declares that they have no competing interests.

Funding

No specific funding was received for the preparation of this manuscript.

Acknowledgments

Language, Translation, And Artificial Intelligence Assistance The manuscript was initially drafted by the authors in Portuguese and subsequently translated into English. ChatGPT (OpenAI) was used as an editorial tool to assist with English-language translation, organization, and stylistic refinement. The author critically reviewed and edited the resulting text, verified the scientific content and references, and take full responsibility for the final manuscript.

Table 1: Hierarchy of evidence for non-antibiotic and adjunctive therapies in small intestinal bacterial overgrowth. Evidence hierarchy Intervention Highest evidence / key study Main quantitative findings Current interpretation / major

limitations

Level I – evidence synthesis Probiotics – overall Zhong et al.; Niño et al. (18 trials; 14 controlled; 9 randomized; 496 probiotic-treated and 480 controls)

Largest direct non-antibiotic evidence base, but marked heterogeneity in strains, doses, populations, diagnostic criteria, and outcomes.

Level I – evidence synthesis Berberine Bayesian network meta-analysis: 30 RCTs; 1,552 participants; 12 interventions [11] Favorable probabilistic ranking for SIBO eradication; emerging direct comparative evidence.

Promising; network ranking should not be interpreted as definitive direct superiority. clinical evidence Saccharomyces boulardii García-Collinot et al. [10]; randomized open-label pilot; systemic sclerosis; n=40 Eradication: 55% metronidazole+SB; 33% SB; 25% metronidazole. H₂ reductions and symptom improvement also reported.

Interesting monotherapy and adjunctive signal; small disease-specific trial with substantial attrition. clinical evidence Multispecies probiotics Kwak et al. [9]; chronic liver disease + SIBO SIBO resolution 24% with probiotics vs 0% placebo (P<0.05).

Supports formulation-specific benefit; small disease-specific population. clinical evidence Bacillus clausii Scarpellini et al. [7]; 30 vs 30 17/30 (56.6%) vs 12/30 (40%) with metronidazole.

Possible benefit; small older study and reporting limitations.

Level II/III – heterogeneous controlled evidence Other probiotic combinations Soifer et al. [8], Stotzer et al. [17], and other probiotic studies summarized in Niño et al. [6] Soifer: clinical improvement 20/25 (82%) vs 13/25 (52%) with metronidazole; other studies were neutral.

Inconsistent; effects should not be generalized across probiotic formulations.

Potential benefit; non-randomized treatment selection. Lack of difference does not establish equivalence.

Level IV – uncontrolled clinical evidence Elemental diet Pimentel et al. [13]; 93 evaluable participants Breath-test normalization ≈80% after 14 days and ≈85% after 21 days.

Large preliminary signal, but uncontrolled design and practical tolerability limitations.

Level III – adjunctive comparative evidence Probiotic after rifaximin Rosania et al. [14]; n=40 Symptom response 83.3% with rifaximin→L. casei vs 66.6% with rifaximin→short-chain FOS; P=0.57.

Adjunctive/sequential evidence; does not establish probiotic monotherapy efficacy.

Level III/IV – adjunctive evidence Herbal + probiotic/prebiotic supplementation Redondo-Cuevas et al. [16]; randomized adjunctive study; n=179 No significant overall reduction in breath-test gas concentrations; some symptom/remission signals reported in subgroups.

Multiple simultaneous interventions; difficult to attribute effects to an individual component.

Level V – Low-FODMAP / dietary substrate restriction Narrative/systematic literature; direct eradication evidence remains limited [1, 4] No convincing controlled evidence establishing SIBO eradication.

May improve fermentation-related symptoms; should not be equated with eradication.

Level V – Kefir No adequate SIBO-specific controlled therapeutic trial identified in the reviewed clinical literature [4, 6] No reliable SIBO-specific effect estimate.

Evidence gap, not evidence of ineffectiveness; biologically plausible microbiome-modulating fermented food.

Level V – Kombucha No adequate SIBO-specific controlled therapeutic trial identified in the reviewed clinical literature [4, 6] No reliable SIBO-specific effect estimate.

Evidence gap, not evidence of ineffectiveness; composition and biological effects may vary.

Level V – Other fermented foods / nutraceuticals Mechanistic or limited clinical literature; no established SIBO-specific efficacy [4] Insufficient direct controlled SIBO data.

Exploratory; product-specific effects require direct clinical evaluation.

Note: The evidence hierarchy is descriptive and reflects the design of the available literature; it is not a formal certainty-of-evidence grading system. A low position in the hierarchy, particularly for kefir and kombucha, indicates insufficient direct SIBO-specific investigation and should not be interpreted as evidence of ineffectiveness.

Table 2: Key clinical studies evaluating non-antibiotic and adjunctive interventions for small intestinal bacterial overgrowth. Study Population / design Intervention Comparator Duration Main objective outcome Main clinical findings Main limitations Pimentel et al., 2004 93 evaluable patients with IBS and abnormal LBT; uncontrolled study Exclusive elemental diet (Vivonex Plus) None 14 days; additional 7 days if LBT remained abnormal LBT normalization 74/93 (80%) normalized LBT by day 15; five additional patients normalized by day 21, for an overall rate of 85%. Patients achieving normalization had greater symptom improvement than nonresponders No randomized comparator; selected IBS population; historical LBT criteria; tolerability/adherence considerations Scarpellini et al., 2006 Patients with IBS and SIBO; comparative study Bacillus clausii Metronidazole As reported in original study Breath-test improvement 17/30 (56.6%) improved with B. clausii vs 12/30 (40%) with metronidazole Published as supplement abstract; limited methodological information available Gabrielli et al., 2009 Patients with SIBO; clinical study/letter Bacillus clausii — — Breath-test response Subsequent publication supporting evaluation of B. clausii for SIBO Brief publication; limited reporting of methodological details Soifer et al., 2010 SIBO; randomized comparative study Multispecies probiotic including Lactobacillus casei, L. plantarum, Streptococcus faecalis and Bifidobacterium brevis Metronidazole As reported in original study Clinical response Symptom improvement reported in 20/25 (82%) probiotic-treated patients vs 13/25 (52%) receiving metronidazole Small sample; symptom-centered outcome; formulation-specific findings Rosania et al., 2013 40 patients receiving sequential treatment Rifaximin followed by Lactobacillus casei Rifaximin followed by short-chain FOS Sequential therapy Clinical response Symptom improvement 83.3% vs 66.6%, respectively (P=0.57) Adjunctive/sequential design prevents assessment of probiotic monotherapy Kwak et al., 2014 Chronic liver disease with SIBO; randomized placebo-controlled trial Six-species probiotic preparation Placebo 4 weeks SIBO resolution by breath testing SIBO resolution 24% vs 0% with placebo (P<0.05) Disease-specific population; relatively small SIBO subgroup Chedid et al., 2014 Newly diagnosed SIBO by LBT; non-randomized comparative study Commercial herbal combinations Rifaximin 1,200 mg/day 4 weeks Negative follow-up LBT 17/37 (46%) herbal vs 23/67 (34%) rifaximin, P=0.24; adjusted OR 1.85 (95% CI 0.77–4.41; P=0.17) Patients selected therapy; non-randomized; study does not establish formal equivalence García-Collinot et al., 2020 40 patients with systemic sclerosis and SIBO; randomized open pilot trial S. boulardii 200 mg BID; or metronidazole + S. boulardii Metronidazole 500 mg BID Cyclic treatment over 2 months SIBO eradication by HBT Eradication: 55% combination, 33% S. boulardii, 25% metronidazole; gastrointestinal symptom improvement in S. boulardii-containing groups Small sample; open label; systemic-sclerosis-specific population; only 29/40 completed 2 months Bustos Fernández et al., 2023 IBS-D with bacterial overgrowth; randomized pilot study S. boulardii CNCM I-745 Control As reported in trial Bacterial overgrowth and microbiota outcomes Study provides additional contemporary direct evidence for S. boulardii in patients with IBS-D and bacterial overgrowth Pilot study; population not necessarily representative of all SIBO phenotypes Redondo-Cuevas et al., 2024 179 participants with hydrogen- or methane-positive breath testing; randomized study Botanical supplements combined with probiotic/prebiotic strategies Study-specific comparator groups According to protocol Breath-gas concentrations and clinical response No clear overall superiority for reducing gas concentrations; clinical response signals were reported in selected analyses Multicomponent interventions; heterogeneous hydrogen/methane phenotypes; difficult to isolate effects of individual components Abbreviations: BID, twice daily; FOS, fructooligosaccharides; HBT, hydrogen breath test; IBS, irritable bowel syndrome; IBS-D, diarrhea-predominant irritable bowel syndrome; LBT, lactulose breath test; OR, odds ratio; SIBO, small intestinal bacterial overgrowth.

Table 3: Proposed mechanisms, potential clinical benefits, safety considerations, and limitations of non-antibiotic interventions for SIBO. Intervention Proposed mechanisms relevant to SIBO Potential clinical benefit Main safety / tolerability considerations Principal clinical limitation Probiotics Competitive exclusion; production of antimicrobial metabolites; modification of luminal environment; modulation of microbial composition; potential enhancement of epithelial barrier and mucosal immune responses May reduce microbial overgrowth and fermentation and improve bloating, abdominal pain, diarrhea, and other gastrointestinal symptoms Generally well tolerated; effects and safety depend on organism, host, and clinical setting Major strain, dose, formulation, population, and outcome heterogeneity; “probiotics” should not be considered a single intervention Saccharomyces boulardii Yeast-based microbial competition; antimicrobial and antitoxin activity; modulation of mucosal immunity; potential trophic effects on intestinal epithelium Direct SIBO evidence as monotherapy and potential adjunct to antibacterial treatment Usually well tolerated in studied populations; patient-specific clinical context remains important Evidence derives from relatively small studies and selected populations Bacillus clausii Spore-forming probiotic; potential competitive and microbiota-modulating effects Breath-test improvement reported in SIBO studies Generally reported as well tolerated Evidence base is small; important early study was published as a supplement abstract Multispecies probiotics Multiple potentially complementary microbial effects; competitive exclusion; metabolite production; microbiome modulation Some controlled trials demonstrate improved breath testing and/or symptoms Product-specific tolerability Results from one mixture cannot be extrapolated to another Berberine Potential direct antimicrobial activity; modulation of intestinal microbiota; possible effects on epithelial barrier, inflammation, bile-acid signaling, and gastrointestinal physiology Promising eradication signal in network-level evidence Gastrointestinal tolerability and potential interactions require consideration Strong network-level signal but comparatively limited confirmatory direct SIBO evidence Herbal/botanical combinations Multiple botanical compounds with potential antimicrobial, antifungal, anti-inflammatory, and microbiome-modulating activities Breath-test normalization observed in comparative clinical studies Safety depends on specific constituents, dose, formulation, and concomitant therapies Formulations are heterogeneous and difficult to generalize; strongest comparative study was non-randomized Elemental diet Rapid proximal absorption of nutrients; marked reduction of fermentable substrate reaching distal small bowel; alteration of luminal conditions supporting microbial proliferation High breath-test normalization signal and associated symptom improvement Palatability, adherence, nutritional supervision, and practicality are major considerations Strong uncontrolled signal but lack of randomized comparative evidence Low-FODMAP / fermentable-substrate restriction Reduced delivery of rapidly fermentable carbohydrates; reduced fermentation, gas generation, and luminal distension Potential improvement in bloating, pain, flatulence, and related symptoms Excessive or prolonged restriction may impair dietary variety and nutritional adequacy Symptom improvement should not be interpreted as demonstrated SIBO eradication Prebiotics Selective provision of substrates intended to influence microbial composition and metabolic activity Potential microbiome modulation, particularly following antimicrobial treatment Some fermentable prebiotics may increase gas or bloating in susceptible patients Very limited evidence as stand-alone SIBO treatment Synbiotics Combination of probiotic organisms and substrates intended to support their activity Theoretical complementary microbiome-directed effect Formulation dependent Few SIBO-specific controlled studies; difficult to separate probiotic and prebiotic effects Kefir Complex bacteria/yeast community; fermentation-derived metabolites; possible microbial competition, barrier, and immune effects Plausible microbiome-modulating and gastrointestinal effects Composition varies by preparation; individual tolerance may differ No adequate controlled SIBO-specific therapeutic evidence identified; evidence gap rather than evidence of ineffectiveness Kombucha Fermentation-derived microorganisms, organic acids, and metabolites with potential microbiome effects Biological plausibility for microbiome modulation Highly product- and preparation-dependent No adequate controlled SIBO-specific therapeutic evidence identified; clinical efficacy remains undetermined Other fermented foods Delivery of live microorganisms and fermentation products; potential modification of microbial ecology Possible dietary microbiome support Considerable variation among foods and preparations Cannot extrapolate efficacy from defined probiotic strains to fermented foods as a class Prokinetic strategies* Enhancement of intestinal transit and migrating motor complex activity; reduction of intestinal stasis May theoretically reduce conditions favoring recurrence rather than directly eradicate microorganisms Agent-specific Primarily relevant to recurrence prevention and correction of underlying dysmotility; outside the principal “natural therapy” focus of this review Abbreviations: FODMAP, fermentable oligosaccharides, disaccharides, monosaccharides and polyols; IMO, intestinal methanogen overgrowth; MMC, migrating motor complex; SIBO, small intestinal bacterial overgrowth. Prokinetic strategies are included for pathophysiological context rather than as a principal non-antibiotic “natural” treatment category.

Fig 1: Non-antibiotic and adjunctive approaches to small intestinal bacterial overgrowth according to the hierarchy of available clinical evidence. The figure should distinguish evidence syntheses and controlled clinical evidence from preliminary, indirect, and mechanistic evidence. A lower position indicates less direct clinical investigation rather than demonstrated lack of efficacy.

Fig 2: Pathophysiological mechanisms contributing to small intestinal bacterial overgrowth and potential sites of action of non-antibiotic therapies. The proposed framework integrates impaired intestinal motility and migrating motor complex activity, excessive microbial proliferation, altered microbial ecology, fermentable substrate availability, epithelial barrier dysfunction, and host–microbiota signaling with probiotics, Saccharomyces boulardii, berberine and botanical therapies, elemental and conventional dietary interventions, prokinetic strategies, and fermented foods. Symptom improvement, microbiome modification, and objective SIBO eradication should be depicted as related but non-equivalent outcomes.