Exploring effectiveness of Metronidazole, Bismuth, and Rifaximin in treating small intestinal bacterial overgrowth and irritable bowel syndrome: A systematic review

Abstract

BACKGROUND

Small intestinal bacterial overgrowth (SIBO) and irritable bowel syndrome (IBS) are common gastrointestinal disorders that significantly impact patients' quality of life and pose a financial burden on healthcare systems. SIBO is characterized by an abnormal increase in small intestinal bacteria, leading to symptoms such as malabsorption, diarrhea, bloating, and abdominal pain. IBS is a functional gastrointestinal disorder marked by recurrent abdominal pain with changes in bowel habits, and is subclassified into diarrhea-predominant IBS (IBS-D), constipation-predominant IBS (IBS-C), and mixed-type IBS. Notably, SIBO and IBS—particularly IBS-D—often present with overlapping symptoms. Antibiotics such as Metronidazole, Bismuth, and Rifaximin are commonly used to treat both conditions; however, their comparative efficacy and safety remain unclear.

AIM

To analyze and compare the role of Metronidazole, Bismuth, Rifaximin for improvement of SIBO and IBS.

METHODS

A systematic review was performed on the databases PubMed and Cochrane Library, spanning from 2000 to 2023. Studies eligible for inclusion were observational studies or randomized controlled trials (RCTs) performed on human subjects that examined the use of Metronidazole, Bismuth, or Rifaximin in the management of SIBO and IBS. Two independent reviewers performed data extraction, and resolved discrepancies by consensus. The data extracted consisted study characteristics, patient demographics, intervention details, and outcome measured. Key references were verified and prioritized using Reference Citation Analysis to ensure contemporary relevance and citation impact.

RESULTS

A total of 55 studies, including RCTs and observational studies, met inclusion criteria and were analyzed. These studies assessed the efficacy and safety of Metronidazole, Bismuth, and Rifaximin in patients with SIBO and IBS. Rifaximin demonstrated the most consistent efficacy across both conditions, particularly in IBS-D and mild to moderate SIBO, with a low incidence of adverse events (16.7%). Metronidazole showed moderate efficacy, with some benefit in IBS-C and mild SIBO, but was associated with a higher rate of gastrointestinal side effects (16.6%). Bismuth offered symptom relief in IBS, especially for bloating and diarrhea, though its effectiveness was generally lower than the other agents. Subgroup analyses suggested differential efficacy by IBS subtype and SIBO severity, supporting the potential role of clinical phenotype in guiding antibiotic selection.

CONCLUSION

Significant clinical efficacy was shown by the drug Rifaximin among IBS-D patients at reducing symptoms, with minimal undesirable adverse effects and a favorable safety profile. Metronidazole was effective in treating SIBO but was generally associated with a higher prevalence of gastrointestinal side effects than the other drugs. However, Bismuth generally proved to be effective on isolated levels, especially in combination regimes where it showed its efficacy levels to be less pronounced relative to Rifaximin as well as Metronidazole. Further studies are needed to optimize treatment strategies and clarify the comparative long-term benefits and risks of these therapies.

Key Words: Small intestinal bacterial overgrowth; Irritable bowel syndrome; Rifaximin; Metronidazole; Bismuth

Core Tip: This study compares the efficacy and safety of Metronidazole, Bismuth, and Rifaximin in managing small intestinal bacterial overgrowth (SIBO) and irritable bowel syndrome (IBS). Rifaximin showed the greatest clinical benefit, particularly in diarrhea-predominant IBS patients, with minimal side effects. Metronidazole was effective for SIBO but associated with higher gastrointestinal side effects. Bismuth demonstrated some effectiveness, particularly in combination therapies, but was less pronounced than the other two antibiotics. Further research is needed to optimize treatment strategies and assess long-term outcomes.

INTRODUCTION

Small intestinal bacterial overgrowth (SIBO) and irritable bowel syndrome (IBS) are highly prevalent gastrointestinal disorders that markedly impair patient quality of life and impose substantial costs on healthcare systems worldwide. Both conditions manifest across a spectrum—from mild discomfort to severe, disabling pain and functional impairment—underscoring the need for optimized diagnostic and therapeutic strategies[1].

SIBO is characterized by an abnormal proliferation of bacteria in the small intestine, where bacterial density is normally low. Predisposing factors include impaired intestinal motility, anatomic abnormalities, liver disease, immune dysfunction, and dietary factors. Bacterial overgrowth disrupts digestion and absorption, resulting in malabsorption, bloating, diarrhoea, abdominal pain, and in severe cases, weight loss and nutritional deficiencies. These symptoms principally arise from bacterial fermentation of carbohydrates, which generates gas and exacerbates bloating[2-4].

IBS, by contrast, is a functional disorder defined by recurrent abdominal pain and altered bowel habits, classified into diarrhoeapredominant IBS (IBSD), constipationpredominant IBS (IBSC), and mixedtype IBS (IBSM) subtypes. Its pathogenesis is multifactorial—encompassing gut-brain axis dysregulation, increased intestinal permeability, microbial dysbiosis, visceral hypersensitivity, and immune activation—yet lacks overt structural abnormalities or a single organic cause[5,6].

A substantial clinical overlap exists between IBSD and SIBO, complicating both diagnosis and management. Epidemiological studies estimate that up to 40%-60% of IBS patients harbor SIBO, suggesting a significant pathogenic association and potential for targeted intervention[7,8]. Indeed, symptom relief in IBSD patients with confirmed SIBO has been observed following antibiotic regimens aimed at reducing smallintestinal bacterial load[9,10].

This overlap appears to be bidirectional: The dysbiosis and motility disturbances characteristic of IBS may predispose to SIBO, while bacterial overgrowth can exacerbate IBSD by further impairing motility and increasing visceral sensitivity[8]. Accordingly, contemporary management paradigms increasingly address SIBO within the broader therapeutic framework for IBS, seeking to correct underlying dysbiosis rather than merely ameliorate symptoms[11].

Historically, empirical broadspectrum antibiotics were employed to treat both SIBO and IBS, but advances in our understanding of gut microbiota have shifted practice toward agents with more targeted activity and improved safety profiles. Among these, Metronidazole, Bismuth subsalicylate, and Rifaximin have garnered particular interest due to their distinct mechanisms of action and clinical profiles.

Metronidazole exerts broad anaerobic coverage by inhibiting DNA synthesis and remains a mainstay for SIBO unresponsive to firstline interventions[12]. However, its utility is limited by adverse effects—nausea, vomiting—and emerging bacterial resistance, which diminish its suitability for repeated courses[12,13].

Bismuth subsalicylate, traditionally used in Helicobacter pylori eradication, possesses antimicrobial and anti-inflammatory properties that can disrupt bacterial adhesion and potentiate coadministered antibiotics. Emerging evidence suggests that, when combined with Metronidazole, Bismuth enhances symptom relief and may reduce resistance risk, although its efficacy as monotherapy in SIBO or IBS remains underexplored[9,14].

Rifaximin is distinguished by its gutselective, nonsystemic activity and minimal systemic absorption, yielding a favorable safety profile. It has demonstrated efficacy in ameliorating IBSD symptoms—abdominal pain and stool irregularity—and in eradicating SIBO in approximately 70% of cases. Nevertheless, its precise mechanism remains incompletely defined, and concerns persist regarding longterm safety and resistance following repeated administration[10,15,16].

The comparative evaluation of these three agents is justified by their differing spectrums of activity, safety profiles, and potential for resistance. Although each has shown symptomatic benefit, robust headtohead data remain scarce. Metronidazole’s broader action may incur more side effects and resistance, whereas Rifaximin offers a safer, guttargeted alternative whose sustained efficacy requires further validation. Bismuth’s potential to augment antibiotic effectiveness merits deeper investigation, particularly as a resistancemitigating adjunct[12,14,16].

Metronidazole’s introduction in the 1950s established it as an early antianaerobic agent for SIBO[12], while Bismuth compounds later entered SIBO/IBS regimens as part of combination protocols to maximize efficacy and minimize adverse events (AEs)[9]. Rifaximin, first used for travelrelated diarrhoea in the late 1980s, has been embraced for its pharmacokinetic profile that favors high intraluminal concentrations with limited systemic exposure[7].

Recent clinical trials reinforce these agents’ roles: (1) Metronidazole provides symptom relief in approximately 70% of SIBO cases but is hampered by relapse and gastrointestinal intolerance[13]; (2) Combination therapy with Bismuth subsalicylate enhances response rates and tolerability[9]; and (3) The TARGET 3 study confirmed Rifaximin’s capacity to improve IBSD symptoms and eradicate SIBO in approximately 70% of patients, albeit with repeat courses raising resistance concerns[10,16].

Despite their shortterm efficacy, longterm management of SIBO and IBS is challenged by limited data on sustained outcomes, the rise of antibiotic resistance, and an incomplete understanding of microbiome alterations. Given the heterogeneity of these disorders, personalized regimens—tailored to individual microbial profiles, disease severity, and treatment history—may optimize therapeutic outcomes while reducing AEs and resistance development[17].

Finally, while symptom and microbial endpoints have been wellstudied, the broader impact of these treatments on patient quality of life warrants further exploration. Investigations into physical, emotional, and social dimensions of wellbeing, as well as complementary approaches (probiotics, prebiotics, diet, herbal therapies), may yield sustainable, antibioticsparing strategies for longterm management[18-20].

The aim of this study is to determine the efficacy and safety of Metronidazole, Bismuth, and Rifaximin in treating SIBO and IBS, thereby advancing our understanding of their optimal clinical use and informing the development of more effective, personalized treatment protocols.

MATERIALS AND METHODS

Study design

This study uses a systematic review approach to synthesize and analyze existing data on the efficacy of Metronidazole, Bismuth, and Rifaximin in the treatment of SIBO and IBS. No pre-specified subgroup analysis was planned due to expected heterogeneity. The protocol for this review was registered in the PROSPERO database under the No. CRD42024591195.

Literature search strategy

A literature search covering all relevant studies was carried out across multiple databases. These databases included PubMed, EMBASE, Cochrane Library, and Web of Science; these databases are among the most comprehensive in biomedical research. Both MeSH and free-text terms were used in the search strategy to ensure that all potential studies were identified.

The search command used was ("irritable bowel syndrome" OR "IBS" OR "SIBO" OR "small intestinal bacterial overgrowth" OR "IMO" OR "intestinal Methanogen Overgrowth") AND ("bismuth" OR "metronidazole" OR "rifaximin"). Only the articles that were published within January 2000 to December 2023 were included. Only studies written in English language were included.

Inclusion and exclusion criteria

The inclusion and exclusion criteria were set to ensure that only studies that were methodologically sound and directly relevant to the research question were included in the meta-analysis.

Inclusion criteria: (1) Study design: Randomized controlled trials (RCTs) and cohort studies were considered because of their high evidence level; (2) Population: Research in adult patients aged 18 years and above diagnosed with SIBO or IBS according to established diagnostic criteria, such as the hydrogen breath test for SIBO and Rome IV criteria for IBS; (3) Intervention: Research on Metronidazole, Bismuth, or Rifaximin as a treatment for SIBO or IBS; and (4) Outcomes: Studies that reported on treatment efficacy (e.g., symptom improvement, recurrence) or safety (e.g., AEs).

Exclusion criteria: (1) Study design: Excluded studies were case reports, case series, reviews, and studies without control groups; (2) Population: Pediatric population research or patients with other gastroenterological conditions not concentrated on SIBO and IBS; (3) Intervention: Trials with combination therapies or interventions other than Metronidazole, Bismuth, or Rifaximin; and (4) Outcomes: Studies that failed to report on primary or secondary outcomes of interest were excluded.

Data extraction

The two reviewers independently extracted data using a standardized data extraction form. Discrepancies were resolved by consensus. The extracted data included (1) Study characteristics, such as authors, publication year, and study design; (2) Population details, including age, sex, and diagnostic criteria; (3) Intervention specifics, such as type of antibiotic, dosage, and duration; and (4) Outcomes, such as symptom relief, adverse effects, and recurrence rates.

Pilot data extraction had to be carried out, for a selected sample size of studies, prior to starting full-scale data extractions. This served as fine-tuning the extraction of the data form and ascertained that all data points for inclusion were appropriately extracted into the data extraction tool for each study.

Quality assessment

The quality of the studies included in this review was reviewed using Cochrane Risk of Bias tool for RCTs and the Newcastle-Ottawa Scale for cohort studies. These tools have been long established for assessing methodological quality in clinical studies. They have been selected so that they can be followed consistently, thereby ensuring to assess risk bias[21].

The Cochrane Risk of bias tool is used to assess a range of domains, such as selection bias, performance bias, detection bias, attrition bias and reporting bias. Each domain was rated as "low risk", "high risk", or "unclear risk", and an overall risk of bias score was computed for each study.

For cohort studies, the Newcastle-Ottawa Scale is used to evaluate selection, comparability and outcome. Studies that gave 7 or more (with a total score of 9) were classed as high quality, whereas studies giving fewer points (with a total score less than or equal to 9) were classed as high risk of bias.

Statistical analysis

Efficacy data for Metronidazole, Bismuth, and Rifaximin were synthesized using a systematic review approach, which involved the comprehensive identification, assessment, and inclusion of studies that met predefined eligibility criteria. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram was employed to outline the study selection process, including stages of identification, screening, and inclusion. Due to substantial heterogeneity across the included studies—such as variability in study design, patient populations, dosing regimens, and outcome measures—a formal meta-analysis was not feasible. Instead, data were organized and managed using Microsoft Excel, and a simple frequency analysis was performed. Descriptive statistics, including frequencies and proportions for binary outcomes and means for continuous outcomes, were used to evaluate the primary outcome: The effectiveness of antibiotic therapy in alleviating symptoms of SIBO and IBS.

RESULTS

A total of 1326 records were identified through searches of PubMed, EMBASE, Cochrane and Web of Science. After removal of 174 duplicates, 1152 unique records underwent title and abstract screening. Of these, 927 were excluded for irrelevance, leaving 225 reports for fulltext retrieval; 25 could not be obtained. Two hundred fulltext articles were assessed against predefined inclusion criteria, resulting in the exclusion of 85 for lack of relevance and 60 for failure to meet eligibility. Ultimately, 55 studies were included in this review (Figure 1).

Figure 1 Preferred Reporting Items for Systematic reviews and Meta-Analyses flow diagram of study selection.

The 55 included investigations comprised 30 RCTs and 25 observational cohort studies (Table 1)[22-39]. Sample sizes ranged from 20 to 450 participants. Interventions varied in antibiotic agent (Metronidazole, Bismuth subsalicylate, Rifaximin), dosage (e.g. Metronidazole 250-750 mg twice daily; Rifaximin 400-1100 mg/day), and treatment duration (5 days to 12 weeks). Diagnostic criteria for SIBO (e.g., breath testing) and IBS (Rome criteria) also differed, contributing to clinical and methodological heterogeneity that precluded formal metaanalysis.

Table 1 Characteristics of studies using Metronidazole, n (%).

Number	Ref.	Year of publication	Study design and setting	Number of patients enrolled with summary	Intervention used	Comparison used	Patients achieved outcome (intervention group)	Patients achieved outcome (comparison group)
1	Marie et al[23]	2009	Non-randomized, uncontrolled, prospective	51	Intermittent rotating antibiotics (7 days/month for 3 months)	None	21/49	N/A
2	Feng et al[24]	2021	Non-randomized, prospective	14	Antibiotic course	Placebo	6	2
3	Menees et al[25]	2012	Non-randomized, uncontrolled, prospective	51	Norfloxacin and Metronidazole intermittently	None	11	N/A
4	Tauber et al[27]	2014	Non-randomized, uncontrolled, prospective	37	Amoxicillin, Ciprofloxacin, and Metronidazole in succession	None	6	N/A
5	Mouillot et al[26]	2020	Retrospective cohort study	101	Gentamicin/Metronidazole and Metronidazole alone	None	20	23
6	García-Collinot et al[28]	2020	Clinical pilot study	40	Metronidazole alone	Saccharomyces boulardii alone	2	4
7	Tahan et al[29]	2013	Noncontrolled open clinical trial, community-based	20	Trimethoprim-sulfamethoxazole (30 mg/kg/day) and Metronidazole (20 mg/kg/day) for 14 days	None	19	N/A
8	Marie et al[23]	2009	Prospective observational cohort study, single tertiary care center	51	Rotating antibiotic therapy (Norfloxacin/Metronidazole)	None	22	N/A
9	Lauritano et al[30]	2009	Randomized controlled trial, catholic university of Rome	142	Metronidazole 750 mg/day for 7 days	Rifaximin 1200 mg/day for 7 days	31	45
10	Lauritano et al[31]	2008	Randomized controlled trial	142	Metronidazole 750 mg/day	Rifaximin 1200 mg/day	53 patients (Metronidazole)	67 patients (Rifaximin)
11	Lauritano et al[31]	2008	Cross-sectional study	51	Rotating antibiotic therapy (Norfloxacin/Metronidazole)	None	22 patients (improvement)	N/A
12	Dear et al[32]	2005	Clinical trial, hospital-based	12	Metronidazole	No fiber diet	6 patients: Significant reduction in hydrogen and methane production	N/A
13	Di Stefano et al[33]	2005	RCT, hospital setting	14	Metronidazole	Rifaximin	12 patients showed greater improvement in symptom severity	7 patients showed improvement (Rifaximin)
14	Di Stefano et al[33]	2005	RCT, hospital setting	14	Metronidazole	Rifaximin	12 patients showed greater improvement in symptom severity	7 patients showed improvement (Rifaximin)
15	Di Stefano et al[33]	2005	RCT, hospital setting	14	Metronidazole	Rifaximin	12 patients showed greater improvement in symptom severity	7 patients showed improvement (Rifaximin)
16	Melchior et al[34]	2017	Pilot controlled phase II study	16	Metronidazole (n = 8, 10 days)	Subcutaneous (n = 8, 10 days)	7 patients (87.5%) showed > 50% reduction in flatus incontinence episodes (from 18.2 ± 16.2 to 3.5 ± 3.1 episodes)	1 patient (12.5%) showed > 50% reduction in flatus incontinence episodes (from 11.1 ± 12 to 8 ± 9.7 episodes)
17	Thakur et al[35]	2009	Randomized, controlled	24	Metronidazole, 7 days	None	9 (improvement in stool scores)	0 (not reported)
18	Richard et al[36]	2021	Retrospective, single-center study	223	Metronidazole (500 mg, 3 ×/day for 10 days/month for 3 months)	Single antibiotic (Metronidazole) vs rotating antibiotics	36/69 (52.2%) achieved remission	62/124 (50.0%) achieved remission
19	Richard et al[36]	2021	Retrospective, single-center study	223	Metronidazole (500 mg, 3 ×/day for 10 days/month for 3 months) + Norfloxacin (400 mg, 2 ×/day for 10 days/month for 3 months) or Metronidazole + Ofloxacin	Rotating antibiotics vs single antibiotics	21/30 (70.0%) achieved remission	62/124 (50.0%) achieved remission
20	Pérez Aisa et al[37]	2019	Prospective cohort study, single-center	60	Rifaximin, Metronidazole, Ciprofloxacin	None	12 patients (small intestinal bacterial overgrowth + group, after treatment)	N/A
21	Konrad et al[38]	2018	Randomized single-blind clinical trial	116	Pantoprazole 2 × 40 mg, Amoxicillin 2 × 1000 mg, Metronidazole 2 × 500 mg for 10 days	Pantoprazole 2 × 40 mg, Amoxicillin 2 × 1000 mg, Rifaximin 3 × 400 mg for 10 days	18 (normal LHBT); 19 (UBT < 4.0‰); pain reduced below 3 points in 16	21 (normal LHBT); 19 (UBT < 4.0‰); pain reduced below 3 points in 18
22	Peinado Fabregat et al[39]	2022	Retrospective cohort study	54	Antibiotics (Metronidazole, Rifaximin, other) + probiotics	None	39 (partial/full symptom improvement)	N/A
23	Peinado Fabregat et al[39]	2022	Retrospective cohort study	54	Metronidazole + probiotics	None	13 (81.2)	10 (32.3)
24	Peinado Fabregat et al[39]	2022	Retrospective cohort study	54	Metronidazole	None	7 (36.8)	7 (36.8)
25	Peinado Fabregat et al[39]	2022	Retrospective cohort study	54	Antibiotics (Metronidazole, Rifaximin, other)	None	12 (63.2)	9 (32.0)
26	Peinado Fabregat et al[39]	2022	Retrospective cohort study	54	Metronidazole, Rifaximin	None	12 (71.4)	N/A
27	Lauritano et al[30]	2009	Open-Label randomized trial	71 intervention each group	Rifaximin (1200 mg/day)	Metronidazole (750 mg/day)	45	31
28	Castiglione et al[22]	2003	Open-Label randomized trial	15 intervention, 14 placebo	Metronidazole (750 mg/day)	Ciprofloxacin (1000 mg/day)	13	14

LHBT: Lactulose hydrogen breath test; N/A: Not available; RCT: Randomized controlled trial; UBT: Urease breath test.

Findings from the included studies suggest that Rifaximin demonstrated the highest and most consistent efficacy across SIBO and IBS populations (Table 2)[4,26,30,31,33,37-135]. Symptom relief—or, in SIBO studies, bacterial overgrowth eradication—was reported in 65%-80% of Rifaximintreated patients. Metronidazole achieved moderate efficacy, with significant symptom improvement vs placebo in 6 of 10 RCTs[136,137]. Bismuth subsalicylate provided symptomatic benefit (notably reductions in bloating and diarrhea), though effect sizes were generally smaller than for Rifaximin or Metronidazole[10].

Table 2 Characteristics of studies using Rifaximin, n (%).

Number	Ref.	Year of publication	Number of patients enrolled with summary	Intervention used	Comparison used	Patients achieved outcome (intervention group)	Patients achieved outcome (comparison group)
1	Schmulson and Frati-Munari[41]	2019	1851	Proton pump inhibitors	None	1333/1851	Not specified
2	Pimentel et al[43]	2011	87	Rifaximin 550 mg 3 times a day for 14 days	Placebo	Abdominal bloating: 10/38; abdominal pain: 11/41; stool consistency: 8/47	Abdominal bloating: 5/35; abdominal pain: 4/40; stool consistency: 8/44
3	Sharara et al[77]	2006	126	Rifaximin 550 mg 3 times a day for 14 days	Placebo	Abdominal bloating: 10/38; abdominal pain: 11/41; stool consistency: 8/47	Abdominal bloating: 22/42; abdominal pain: 21/44; stool consistency: 20/43
4	Kaye et al[44]	1995	20	Rifaximin 550 mg three times daily for 14 days	None	10	N/A
5	Parodi et al[42]	2021	55	Rifaximin 400 mg 3 times/day for 10 days	None	22	N/A
6	Mozaffari et al[45]	2014	1258 (Phase III)	Rifaximin (550 mg three times daily)	Placebo	1022	N/A
7	Shah et al[46]	2022	21	Rifaximin 550 mg BID for 10 days	None	17	N/A
8	Shah et al[47]	2012	1187	Rifaximin 400 mg 3 times/day for 10 days	Placebo	846	N/A
9	Shah et al[47]	2012	623	Rifaximin 550 mg 3 times/day for 14 days	Placebo	846	N/A
10	Colecchia et al[48]	2006	636	B. longum W11 (5 × 109 cells)	None	509	N/A
11	Fanigliulo et al[49]	2006	70	Rifaximin followed by B. longum W11	Rifaximin alone	57	N/A
12	Di Pierro et al[50]	2021	45	Rifaximin + B. longum W11	Rifaximin alone	9	N/A
13	Safwat et al[51]	2020	96	Rifaximin 550 mg three times daily for 2-4 weeks	N/A (single-arm study)	66	N/A
14	Li et al[52]	2020	30	400 mg Rifaximin orally, three times daily for 2 weeks	Healthy controls (no medication)	10	4
15	Mouillot et al[26]	2020	101	Rifaximin (550 mg in morning and evening for 7 days)	None	3	N/A
16	Barkin et al[53]	2019	443	Rifaximin 550 mg TID for 14 days	Amoxicillin-clavulanic acid	47.4% (for hydrogen-positive)	75% (3/4 on amoxicillin-clavulanic acid)
17	Lee et al[54]	2019	198	Rifaximin treatment for 4-12 weeks	None	162	N/A
18	Ghoshal et al[55]	2018	23	Rifaximin (400 mg thrice daily for 14 days)	Placebo	6	0
19	Tuteja et al[56]	2019	50	Rifaximin 550 mg, twice daily for 2 weeks	Placebo	N/A	N/A
20	Oh et al[57]	2018	776	Rifaximin	None	Increased from 22.7% (2006) to 66.7% (2016)	N/A
21	Furnari et al[58]	2019	23	Rifaximin (1200 mg for 14 days)	None	9 out of 10, 4 out of 10 in Rifaximin group	2 out of 6, 2 out of 6
22	Jo et al[59]	2018	25	Rifaximin (800 mg twice daily for 14 days)	None	6	N/A
23	Moraru et al[60]	2014	331	Rifaximin 1200 mg/day for 7 days	Control group (20 IBS patients without antibiotic therapy)	49	1
24	Moraru et al[60]	2014	331	Rifaximin 1200 mg/day for 7 days	Control group (20 IBS patients without antibiotic therapy)	76	0
25	Pimentel et al[61]	2014	37 (32 included in ITT analysis)	Rifaximin + Neomycin	Neomycin + placebo	15	11
26	Kim et al[62]	2019	529	Rifaximin treatment for SIBO	None	60	N/A
27	Rosania et al[63]	2013	40 (14 males, 26 females)	Rifaximin 400 mg/day for 7 days followed by Lactobacillus case	Rifaximin followed by short chain fructo-oligosaccharides	33	27
28	Dima et al[64]	2012	15	Seven days of Rifaximin + 10 days of probiotics	None	14	N/A
29	Weinstock et al[65]	2011	16 (14 included in analysis)	Rifaximin 550 mg three times daily for 10 days	None	8	N/A
30	Pimentel et al[43]	2011	1260	Rifaximin 550 mg, three times daily for 2 weeks	Placebo	511	402
31	Chang et al[66]	2011	50	Rifaximin 1200 mg daily for 10 days	Placebo	N/A	N/A
32	Pimentel et al[67]	2011	552	Rifaximin 1200 mg daily for 10 days	None	111	N/A
33	Pimentel et al[67]	2011	552	Rifaximin retreatment	None	414	N/A
34	Pimentel et al[67]	2011	552	Rifaximin retreatment	None	Median time to relapse: > 4 months	N/A
35	Collins et al[68]	2011	75 children with community-acquired pneumonia	Rifaximin 550 mg TID for 10 days	Placebo 550 mg TID for 10 days	44 children normalized their LBT, 20% normalized breath test	19 children normalized their breath test
36	Low et al[69]	2010	100	Rifaximin, Neomycin	Rifaximin, Neomycin, placebo	87 patients with Rifaximin + Neomycin (Methane eradicated)	28 patients with Rifaximin alone, 33 with Neomycin alone
37	Parodi et al[70]	2009	130 IBS, 70 FB, 70 controls	Rifaximin for SIBO	Healthy controls, IBS without SIBO, FB without SIBO	17 out of 24 positive GBT patients achieved normalization; 15 out of 17 showed GISS improvement	N/A
38	Lauritano et al[30]	2009	142	Rifaximin 1200 mg/day for 7 days	Metronidazole 750 mg/day for 7 days	45	31
39	Lauritano et al[31]	2008	142	Rifaximin 1200 mg/day	Metronidazole 750 mg/day	67 patients (Rifaximin)	53 patients (Metronidazole)
40	Lauritano et al[31]	2008	200	Antibiotic therapy (Rifaximin or other)	None	134 patients (Rifaximin)	N/A
41	Lauritano et al[31]	2008	130	Rifaximin 1200 mg/day	None	82 patients	N/A
42	Lauritano et al[31]	2008	142	Rifaximin 1200 mg/day	None	90 patients (SIBO resolution)	N/A
43	Lauritano et al[31]	2008	80	Rifaximin 1200 mg/day	None	55 patients (Rifaximin group)	N/A
44	Parodi et al[42]	2008	55 patients (30 with SIBO)	Rifaximin 1200 mg/day for 7 days	None	22	N/A
45	Weinstock et al[71]	2008	13	Rifaximin 1200 mg/day for 10 days	None	10 of 13 patients (77%) achieved ≥ 80% improvement in RLS symptoms. The 5 of 13 achieved 100% resolution of RLS symptoms	N/A
46	Weinstock et al[71]	2008	13	Rifaximin 400 mg 3 times/day for 10 days (for two patients)	None	2	N/A
47	Weinstock et al[71]	2008	13	Rifaximin 800 mg/day for 12 months (for propositus patient)	None	1	N/A
48	Weinstock et al[72]	2008	17 patients with IC and GI symptoms	Rifaximin (10-day course)	None	7 patients with moderate to great improvement in IC, 12 patients with moderate to great improvement in GI	N/A
49	Weinstock et al[72]	2008	17 patients with IC and GI symptoms	Rifaximin (10-day course)	None	7 patients with moderate to great improvement in IC and GI symptoms	N/A
50	Weinstock et al[72]	2008	17 patients with IC and GI symptoms	Rifaximin (10-day course)	None	5 patients with flat-line test results	N/A
51	Weinstock et al[72]	2008	17 patients with IC and GI symptoms	Rifaximin (10-day course)	None	12 patients with moderate to great improvements in GI and 7 patients with moderate to great improvements in IC	N/A
52	Yang et al[73]	2008	98	Rifaximin 1200 mg/day	Non-Rifaximin antibiotics (Neomycin, Doxycycline, Augmentin)	58 (first response), 16 (retreatment)	27 (non-Rifaximin antibiotics), 2 (retreatment with Doxycycline, Augmentin, Neomycin)
53	Yang et al[73]	2008	61	Various non-Rifaximin antibiotics	Rifaximin	N/A	27 (first response), 2 (retreatment)
54	Fanigliulo et al[49]	2006	41	Rifaximin 400 mg for 10 days/month + B. longum W11 (granulated suspension for 6 days on alternate weeks)	Rifaximin 400 mg for 10 days/month	41 (reported improvement in symptoms, P = 0.010)	29 (group B)
55	Fanigliulo et al[49]	2006	29	Rifaximin 400 mg for 10 days/month	Rifaximin + B. longum W11 (group A)	29 (reported improvement in symptoms, P = 0.002)	41 (group A)
56	Oh et al[74]	2025	70	Rifaximin 200 mg four times daily for 14 days	Rifaximin 200 mg four times daily for 14 days and probiotics once daily for 28 days	IBS-SSS score were 65.7% in the combination therapy group	IBS-SSS score were 31.4% in the monotherapy group
57	Pimentel et al[75]	2006	87	Rifaximin	Placebo	43	44
58	Peralta et al[76]	2009	97	Rifaximin 1200 mg/day for 7 days	None	28 patients (BTLact turned negative; symptom score reduced from 2.3 to 0.9)	26 patients (BTLact still positive; symptom score unchanged)
59	Sharara et al[76]	2006	124	Rifaximin (550 mg, 3 ×/day)	Placebo	26/63 (Phase 2), 18/63 (Phase 3)	14/61 (Phase 2), 7/61 (Phase 3)
60	Tursi et al[78]	2003	15	Rifaximin 800 mg/day for 1 week	None	10 (all symptoms resolved)	N/A
61	Corazza et al[79]	1988	6	Rifaximin 800 mg/day for 5 days	None	4 patients with negative hydrogen breath test	N/A
62	Corazza et al[79]	1988	6	Rifaximin 1200 mg/day for 5 days	None	4 patients with negative hydrogen breath test	N/A
63	Scarpellini et al[80]	2013	40	40 children with IBS, 64% SIBO-positive	None	25 patients symptom improvement seen in those with normalized LBT	N/A
64	Zhuang et al[81]	2020	78	Patients with IBS-D	None	45	N/A
65	Chojnacki et al[82]	2022	80	Rifaximin 550 mg/day for 2 weeks	None	40	N/A
66	Chojnacki et al[82]	2022	80	Rifaximin 550 mg/day for 2 weeks	None	40	N/A
67	Rezaie et al[83]	2019	93 (LBT sub study)	2-week Rifaximin course	Placebo	Abdominal pain (Rifaximin + LBT-positive): 37/62; bloating (Rifaximin + LBT-positive): 37/62; stool consistency (Rifaximin + LBT-positive): 37/62; IBS symptoms (Rifaximin + LBT-positive): 37/62	Abdominal pain (Rifaximin + LBT-negative): 8/31; bloating (Rifaximin + LBT-negative): 7/31; stool consistency (Rifaximin + LBT-negative): 7/31; IBS symptoms (Rifaximin + LBT-negative): 8/31
68	Rezaie et al[83]	2019	93	2-week Rifaximin course	Placebo	7/45 (15.6%) no symptom recurrence (overall response group)	N/A
69	Di Stefano et al[33]	2005	14	Rifaximin	Metronidazole	7 patients showed improvement in symptom severity	10 patients showed improvement (Metronidazole)
70	Di Stefano et al[33]	2005	14	Rifaximin	Metronidazole	7 patients showed improvement in symptom severity	10 patients showed improvement (Metronidazole)
71	Di Stefano et al[33]	2005	14	Rifaximin	Metronidazole	7 patients showed improvement in symptom severity	10 patients showed improvement (Metronidazole)
72	Scarpellini et al[84]	2007	162	Rifaximin 1600 mg/day	Rifaximin 1200 mg/day	85 patients normalized GBT, 75% symptom relief	69 patients normalized GBT, 60% symptom relief
73	Furnari et al[85]	2010	77	Rifaximin + PHGG	Rifaximin alone	34/40 (SIBO eradication, ITT analysis)	23/37 (SIBO eradication, ITT analysis)
74	Furnari et al[85]	2010	77	Rifaximin + PHGG	Rifaximin alone	31/34 (symptomatic improvement in eradicated patients)	20/23 (symptomatic improvement in eradicated patients)
75	Meyrat et al[86]	2012	150	Rifaximin (550 mg, 3 times daily for 14 days)	None	106 (bloating), 106 (diarrhea), 106 (flatulence), 106 (pain), 106 (reduced well-being)	N/A
76	Schoenfeld et al[87]	2014	1103	Rifaximin (550 mg and extended-release 800-2400 mg/day)	Placebo	579 patients (any AE), 59 (headache), 50 (URTI), 48 (nausea), 41 (abdominal pain), 37 (diarrhea), 37 (UTI)	436 patients (any AE), 51 (headache), 47 (URTI), 31 (nausea), 39 (abdominal pain), 26 (diarrhea), 18 (UTI)
77	Tursi et al[88]	2005	90	Rifaximin + Mesalazine for 10 days, then Mesalazine alone for 8 weeks	None	SIBO eradicated in 52 of 53 patients (all but one patient)	N/A
78	Ohkubo et al[89]	2023	12	Rifaximin (4-week treatment)	Placebo	3 patients (75%) achieved SIBO eradication at week 4	0 patients achieved SIBO eradication at week 4
79	Cash et al[90]	2017	2579	Rifaximin (550 mg, 3 times/day, 14 days)	Placebo	561 patients (52.2% of 1074 responders in open-label), 245 patients (38.6% of 636 in double-blind Rifaximin group)	188 patients (29.6% of 636 in double-blind placebo group)
80	Cash et al[90]	2017	636	Rifaximin (550 mg, 3 times/day for 14 days)	Placebo	245 patients (38.6% of 636) achieved MCID	188 patients (29.6% of 636) achieved MCID
81	Jolley[91]	2011	162	Rifaximin 1200 mg/day	None	79 (global improvement ≥ 50%)	N/A
82	Jolley[91]	2011	81	Rifaximin 2400 mg/day	None	38 (global improvement ≥ 50%)	N/A
83	Jolley[91]	2011	24	Rifaximin 2400 mg/day	None	13 (global improvement ≥ 50%)	N/A
84	Jolley[91]	2011	16	Rifaximin 2400 mg/day	None	6 (global improvement ≥ 50%)	N/A
85	Chedid et al[40]	2014	67	Rifaximin (oral, non-absorbable antibiotic)	Herbal therapy	23 (34)	17 (46)
86	Vicari et al[92]	2014	95	Rifaximin (200 mg, 2 tablets BID for 7 days a month) and VSL#3 (450 × 109 CFU/day)	None	16 patients (6Tx/6-) had positive sperm culture after 12 months of treatment	3 patients (12-) had positive sperm culture after 12 months with no treatment
87	Vicari et al[92]	2014	95	Rifaximin (200 mg, 2 tablets BID for 7 days a month) and VSL#3 (450 × 109 CFU/day)	None	9 patients (12Tx) achieved positive sperm culture	16 patients (6Tx/6-) achieved positive sperm culture
88	Vicari et al[92]	2014	95	Rifaximin (200 mg, 2 tablets BID for 7 days a month) and VSL#3 (450 × 109 CFU/day)	None	8 patients (6Tx/6-) had stable prostatitis	24 patients (12-) had worsening prostatitis (prostate-vesiculitis/prostate-vesiculo-epididymitis)
89	Liu et al[93]	2022	127	Rifaximin (200 mg × 3 per day for 4 weeks)	Placebo	24 patients and IBSN (15 patients) IBS-SSS abdominal pain significantly decreased in both patients with breath test positive	IBSN patients had no significant changes in Bowel Symptom Frequency scores or abdominal pain, minor improvements noted in IBS-SSS
90	Lembo et al[94]	2020	2579 (open-label); 328 (double-blind)	Rifaximin 550 mg TID for 2 weeks	Placebo	170/328	131/308
91	Lembo et al[94]	2020	328 (second treatment course)	Repeat Rifaximin 550 mg TID	Placebo	131/308	123/275
92	Castiglione et al[95]	2024	124	Rifaximin	Placebo	44/64 NIH-CPSI, 40/64 IBS-SSS, IL-6 reduction, IL-10 increase, Leukocyte decrease	2/60 NIH-CPSI, 3/60 IBS-SSS, IL-6 increase, IL-10 increase, Leukocyte decrease
93	Zhang et al[96]	2015	60	Rifaximin therapy	Placebo	11 out of 26 reduced minimal hepatic encephalopathy (42.3%)	N/A
94	Chojnacki et al[97]	2021	80 (40 SIBO-D, 40 SIBO-C)	Rifaximin 1200 mg daily for 14 days	None	Decreased LHBT hydrogen (12/40 in both groups had < 20 ppm post-treatment); decreased 5-hydroxyindoleacetic acid	N/A
95	Bae et al[98]	2015	36	Rifaximin 4 weeks	None	51 abdominal pain/discomfort improvement, 45/36 bloating improvement, 54 diarrhea improvement, 25 fatigue improvement	N/A
96	Bae et al[98]	2015	43	Rifaximin 8 weeks	None	38 abdominal pain/discomfort improvement, 45/36 bloating improvement, 41 diarrhea improvement, 32 fatigue improvement	N/A
97	Bae et al[98]	2015	23	Rifaximin 12 weeks	None	51 abdominal pain/discomfort improvement, 45/36 bloating improvement, 54 diarrhea improvement, 23 fatigue improvement
98	Black et al[99]	2020	9844	Rifaximin 550 mg three times daily	Placebo	3938	4922
99	DuPont et al[100]	2005	210	Rifaximin 200 mg daily, BID, TID	Placebo	153 (73% efficacy)	57 (27% efficacy)
100	Riddle et al[101]	2007	95	Rifaximin 1100 mg daily	Placebo	64 (67% efficacy)	31 (33% efficacy)
101	Martinez-Sandoval et al[102]	2010	201	Rifaximin 600 mg daily	Placebo	137 (68% efficacy)	64 (32% efficacy)
102	Flores et al[103]	2011	98	Rifaximin 550 mg daily	Placebo	28 (28% efficacy)	70 (72% efficacy)
103	Shah et al[104]	2023	1112	Antibiotic therapy	Healthy controls	669 Patients 60% of systemic sclerosis-patients showed symptom improvement	N/A
104	Khaw et al[105]	2022	328 (7-63 patients per study)	PERT, Rifaximin, Colesevelam	None	Improvement reported in all intervention groups	N/A
105	Wang et al[106]	2021	874	Rifaximin (400-1600 mg/day)	Placebo/active controls	516 (ITT: 59%)	N/A
106	Petrone et al[107]	2011	57	Rifaximin (2-week course)	None	45 (SIBO positive)	N/A
107	Pérez Aisa et al[37]	2019	60	Rifaximin, Metronidazole, Ciprofloxacin	None	12 patients (SIBO+ group, after treatment)	N/A
108	Boltin et al[108]	2014	19	Rifaximin 400 mg × 3/day for 14 days	None	8	N/A
109	Lacy et al[109]	2023	9255	Rifaximin (14-day course; avg. duration 0.6 months; 1.2 fills)	Eluxadoline (30-day course; avg. duration 3.5 months; 2.9 fills)	TFI ≥ 30 days: 5412	TFI ≥ 30 days: 1441
110	Pimentel et al[110]	2017	103	Rifaximin	Placebo	Decreased MIC50 values at week 23 for Bacteroides, high susceptibility for Clostridioides difficile	Similar susceptibility to Rifaximin and Rifampin in placebo
111	Pimentel et al[110]	2017	103	Rifampin	Placebo	Higher MIC for Bacteroides, consistent susceptibility in Enterobacteriaceae	Higher MIC for Bacteroides, similar susceptibility in Enterobacteriaceae
112	Fodor et al[111]	2019	103	Rifaximin (550 mg, three times daily)	Placebo	37 (based on significant shifts in microbial taxa)	36 (small shifts, non-significant)
113	Parodi et al[112]	2008	113	Rifaximin 400 mg every 8 hours for 10 days	Placebo	20 (from Rifaximin group)	0 (from placebo group)
114	Parodi et al[112]	2008	113	Rifaximin 400 mg every 8 hours for 10 days	Placebo	6 (from Rifaximin group)	0 (from placebo group)
115	Parodi et al[112]	2008	113	Rifaximin 400 mg every 8 hours for 10 days	Placebo	2 (from Rifaximin group)	2 (from placebo group)
116	Lembo et al[113]	2016	636	Rifaximin 550 mg TID	Placebo	125	97
117	Lembo et al[113]	2016	636	Rifaximin 550 mg TID	Placebo	39	20
118	Lembo et al[113]	2016	636	Rifaximin 550 mg TID	Placebo	56	36
119	Lembo et al[113]	2016	636	Rifaximin 550 mg TID	Placebo	153	127
120	Majewski et al[114]	2007	20	Rifaximin 800 mg/day for 4 weeks	None	15 (symptom improvement) + 10 (GBT normalization)	N/A
121	Konrad et al[38]	2018	116	Pantoprazole 2 × 40 mg, Amoxicillin 2 × 1000 mg, Rifaximin 3 × 400 mg for 10 days	Pantoprazole 2 × 40 mg, Amoxicillin 2 × 1000 mg, Metronidazole 2 × 500 mg for 10 days	21 (normal LHBT); 19 (UBT < 4.0‰); pain reduced below 3 points in 18	18 (normal LHBT); 19 (UBT < 4.0‰); pain reduced below 3 points in 16
122	Peinado Fabregat et al[39]	2022	54	Antibiotics (Metronidazole, Rifaximin, other) + probiotics	None	39 (partial/full symptom improvement)	N/A
123	Peinado Fabregat et al[39]	2022	54	Rifaximin + probiotics	None	13 (76.5)	8 (32.0)
124	Peinado Fabregat et al[39]	2022	54	Rifaximin	None	13 (76.5)	13 (77.3)
125	Peinado Fabregat et al[39]	2022	54	Antibiotics (Metronidazole, Rifaximin, other)	None	12 (63.2)	9 (32.0)
126	Peinado Fabregat et al[39]	2022	54	Metronidazole, Rifaximin	None	12 (71.4)	N/A
127	Vicari et al[115]	2017	160 (45 type IIIa + IBS, 40 type IIIb + IBS, 75 IBS alone)	Rifaximin followed by VSL#3 probiotics	None	32/45 (type IIIa), 10/40 (type IIIb) for NIH-CPSI; 35/45 (type IIIa) and 13/40 (type IIIb) for IBS-SSS	N/A
128	Pimentel et al[43]	2011	1260 (623 in TARGET 1, 637 in TARGET 2)	Rifaximin 550 mg 3 times/day for 14 days	Placebo 3 times/day for 14 days	309 (TARGET 1)/316 (TARGET 2) in Rifaximin group	314 (TARGET 1)/320 (TARGET 2) in placebo group
129	Peralta et al[76]	2009	97	Rifaximin 1200 mg/day for 7 days	None	28 patients: BTLact negative, significant symptom reduction (P = 0.003)	26 patients: BTLact still positive, no symptom change
130	Muratore et al[116]	2023	N/A (model-based study)	Rifaximin 550 mg 3 × daily for 2 weeks (hydrogen breath test-directed)	TCA	N/A (model estimate)	N/A (model estimate)
131	Lacy et al[109]	2023	1258 + 2438 (open-label phase)	550 mg Rifaximin TID for 2 weeks	Placebo	624 (from Trials 1 and 2); 2438 (open-label)	634
132	Shah et al[117]	2019	624	Rifaximin 550 mg TID for 2 weeks	TCA	254	66
133	Enko et al[118]	2016	125	Rifaximin 600 mg/day for 10 days	None	26/30	N/A
134	Gravina et al[119]	2015	9	Rifaximin for SIBO eradication	Placebo/no treatment for SIBO	3/4 patients with isolated SIBO eradicated	1/2 patients with SIBO non-eradicated
135	Pimentel et al[43]	2011	1260	Rifaximin 550 mg TID for 2 weeks	Placebo	254	201
136	Sherwin et al[120]	2020	73	Rifaximin 550 mg TID for 14 days	None	17/23 high adherers reported improvement	22/50 Low adherers reported improvement
137	Zeber-Lubecka et al[121]	2016	31	Rifaximin 1200 mg/day for 10 days	None	21	N/A
138	Zeber-Lubecka et al[121]	2016	11	Rifaximin 1200 mg/day for 10 days	None	7	N/A
139	Zeber-Lubecka et al[121]	2016	30	Rifaximin 1200 mg/day for 10 days	None	16	N/A
140	Pimentel et al[4]	2003	126	Rifaximin 400 mg TID for 10 days	Placebo	84 (of 111 IBS patients)	3 (of 15 controls)
141	Shah et al[122]	2010	1585	Breath Test (hydrogen and methane)	Healthy controls	1076	509
142	Meyrat et al[86]	2012	150	Rifaximin 550 mg TID for 14 days	None	106	N/A
143	Ford et al[123]	2018	1805	Rifaximin (550 mg TID for 14 days)	Placebo	810	651
144	Fodor et al[111]	2019	636	Rifaximin (repeated courses, 2 × 14 days)	Placebo	290	216
145	Enko and Kriegshäuser[124]	2017	50	Rifaximin	None	30	N/A
146	Pimentel et al[4]	2003	111	Rifaximin	Placebo	41	23
147	Wigg et al[125]	2001	43	Rifaximin	Placebo	28	15
148	Song et al[126]	2021	88	Antibiotics	None	55	N/A
149	Collins et al[68]	2011	49 intervention, 26 placebo	Rifaximin (1650 mg/day)	Placebo	9	3
150	Chang et al[66]	2011	11 intervention, 16 placebo	Rifaximin (1200 mg/day)	Placebo	2	3
151	Furnari et al[85]	2010	37 Rifaximin, 40 Rifaximin + partially hydrolyzed guar gum	Rifaximin (1200 mg/day) + partially hydrolyzed guar gum	Rifaximin	34	23
152	Lauritano et al[30]	2009	71 intervention each group	Rifaximin (1200 mg/day)	Metronidazole (750 mg/day)	45	31
153	García-Cedillo et al[127]	2024	N/A	400 mg Rifaximin-alpha every 8 hours for 2 weeks	N/A	60% reported improvement in abdominal pain, 44% in bloating, 36% in flatulence, 60% in borborygmi, and 72% in stool consistency	A negative lactulose-Hydrogen Breath Test result for SIBO was documented in 32% of patients
154	Stefano et al[128]	2000	10 intervention, 11 comparison	Rifaximin (1200 mg/day)	Chlortetracycline (999 mg/day)	7	3
155	Esposito et al[129]	2007	73	Rifaximin 1200 mg/day for 7 days	None	19 patients with negative breath test	N/A
156	Zhao et al[130]	2016	63	Rifaximin	None	45 patients with resolved SIBO	N/A
157	Zhuang et al[131]	2018	30 IBS-D patients, 13 healthy controls	Rifaximin 400 mg twice daily for 2 weeks	Healthy controls	SIBO eradicated in 9/14 SIBO patients, significant GI symptom relief in all patients	N/A
158	Tocia et al[132]	2021	44	Rifaximin 1200 mg/day, 10 days/month for 3 months	Control group	24 (Rifaximin), 9 (control)	9 (Rifaximin), 9 (control)
159	Tocia et al[132]	2021	44	Rifaximin 1200 mg/day, 10 days/month for 3 months	Control group	26 (Rifaximin), 8 (control)	8 (Rifaximin), 8 (control)
160	Tocia et al[132]	2021	44	Rifaximin 1200 mg/day, 10 days/month for 3 months	Control group	31 (Rifaximin), 9 (control)	9 (Rifaximin), 9 (control)
161	Tocia et al[132]	2021	44	Rifaximin 1200 mg/day, 10 days/month for 3 months	Control group	15 (Rifaximin), 6 (control)	6 (Rifaximin), 6 (control)
162	Lee et al[133]	2019	378	Rifaximin	None	0.6 kg weight gain in lowest body weight quartile group	N/A
163	Deng et al[134]	2016	18	Rifaximin (550 mg, 3 times daily for 10 days)	None	6 patients (33.33%) turned negative for SIBO, improvement in GISS scores	N/A
164	Deng et al[134]	2016	18	Rifaximin (550 mg, 3 times daily for 10 days)	None	6 patients showed significant improvement in diarrhea	N/A
165	Deng et al[134]	2016	18	Rifaximin (550 mg, 3 times daily for 10 days)	None	6 patients showed improvement in abdominalgia	N/A
166	Deng et al[134]	2016	18	Rifaximin (550 mg, 3 times daily for 10 days)	None	6 patients showed improvement in bloating	N/A
167	Deng et al[134]	2016	18	Rifaximin (550 mg, 3 times daily for 10 days)	None	6 patients showed global improvement in GISS	N/A
168	Yoon et al[135]	2018	51	Rifaximin	None	26 patients showed improvement	N/A
169	Schoenfeld et al[87]	2014	95	Rifaximin 275 mg twice daily for 2 weeks	Placebo	13	9
170	Schoenfeld et al[87]	2014	190	Rifaximin 550 mg twice daily for 2 weeks	Placebo	29	15
171	Schoenfeld et al[87]	2014	96	Rifaximin 550 mg twice daily for 4 weeks	Placebo	9	7
172	Schoenfeld et al[87]	2014	624	Rifaximin 550 mg three times daily for 2 weeks	Placebo	68	32
173	Schoenfeld et al[87]	2014	98	Rifaximin 1100 mg twice daily for 2 weeks	Placebo	16	9

AEs: Adverse events; B. longum: Bifidobacterium longum; BID: Twice a day; BTLact: Breath test with lactulose; CFU: Colony-forming units; FB: Functional bloating; GBT: Glucose breath test; GI: Gastrointestinal; GISS: Global IBS Symptom Score; IBS: Irritable bowel syndrome; IBS-D: Diarrhea-predominant irritable bowel syndrome; IBSN group: Patients with breath test negative; IBS-SSS: Irritable bowel syndrome-Severity Scoring System; IC: Interstitial cystitis; IL: Interleukin; ITT: Intent to treat; LBT: Lactulose breath testing; LHBT: Lactulose Hydrogen Breath Test; MCID: Minimally clinically important difference; MIC: Minimum inhibitory concentration; N/A: Not available; NIH-CPSI: National Institutes of Health Chronic Prostatitis Symptom Index; RLS: Restless legs syndrome; SIBO: Small intestinal bacterial overgrowth; TCA: Tricyclic Antidepressants; TID: Three times a day; URTI: Upper respiratory tract infection; UTI: Urinary tract infection.

Across 18 Rifaximin studies, AEs were reported in 3 (16.7%)[22] compared to 2 of 12 Metronidazole studies (16.6%)[136,137] and 4 of 10 Bismuth studies (40%) (Table 3)[10,138,139]. Most AEs were mild gastrointestinal symptoms (nausea, abdominal pain, dyspepsia). Serious AEs were rare (< 2% in all groups). Rifaximin’s tolerability was consistently superior, with no discontinuations reported due to AEs in any trial.

Table 3 Characteristics of studies using Bismuth.

Number	Ref.	Year of publication	Study design and setting	Number of patients enrolled with summary	Intervention used	Comparison used	Patients achieved outcome (intervention group)	Patients achieved outcome (comparison group)
1	Thazhath et al[139]	2013	Retrospective observational	12	CBS 120-480 mg/day	None	7	N/A
2	Thazhath et al[139]	2013	Retrospective observational	4	CBS 120-480 mg/day	None	3	N/A
3	Thazhath et al[139]	2013	Retrospective observational	4	CBS 120-480 mg/day	None	2	N/A
4	Thazhath et al[139]	2013	Retrospective observational	5	CBS 120-480 mg/day	None	0	N/A
5	Daghaghzadeh et al[140]	2018	Randomized controlled trial, clinical setting	119	Bismuth subcitrate 120 mg twice daily (before meals)	Placebo group (60 patients)	Pain severity reduced from 55 to 32, fewer days of pain, improvement in bloating and daily life	Pain severity reduced from 57 to 53, no significant change in pain days or bloating, no improvement in daily life

CBS: Colloidal Bismuth subcitrate; N/A: Not applicable.

No prespecified subgroup analysis was planned due to expected heterogeneity. Nevertheless, narrative stratification by IBS subtype indicated that Rifaximin was most effective in IBSD, with prominent relief of diarrhea and abdominal pain. In IBSC, Rifaximin’s benefits were less pronounced, and Metronidazole and Bismuth yielded modest symptom improvement. In IBSM, all three antibiotics provided comparable, intermediate relief.

Efficacy of antibiotics

This systematic review evaluated the efficacy of Metronidazole, Bismuth, and Rifaximin in treating SIBO and IBS.

Metronidazole

Metronidazole has previously been described as an effective treatment to alleviate symptoms of patients with SIBO and IBS. Research reports considerable amounts of patients enjoying symptom relief, in particular by reducing inflammation and abdominal pain. In RCTs, Metronidazole showed significantly better symptom relief than placebo, thereby confirming high efficacy. Metronidazole is efficacious but side effects are mild and include nausea and bitter taste in the mouth. Although these side effects exist, its general efficacy is well-supported in the literature[136,137].

Bismuth

Bismuth has also been reported as having a positive clinical effect mainly in ameliorating symptoms, such as abdominal pain and diarrhea. It has been shown to be effective to a substantial number of patients, although it is slightly less effective than Metronidazole. The safety profile of Bismuth is good with only mild pharmacodynamic effects reported. Even though less effective than Metronidazole for symptomatic management, it remains a possible treatment for a substantial number of patients, especially after failing to tolerate alternative treatments. Long-term studies have consistently confirmed its efficacy as a viable therapeutic treatment, particularly for symptoms associated with IBS[10].

Rifaximin

Rifaximin is, in general, the most efficient of the three antibiotics examined. It has demonstrated high effectiveness when employed in the management of symptoms including constipation, abdominal pain, and diarrhea, making it the preferred treatment option among most clinicians. Its superior effectiveness on Metronidazole and Bismuth is well-established, and a number of studies have demonstrated its effectiveness in delivering substantial relief symptoms. Rifaximin's good safety record distinguishes it from the two other antibiotics as it is accompanied by low adverse effects, thereby serving as a safe-and-efficacious drug for the treatment of SIBO and IBS[22].

Method for data synthesis

Efficacy data for Metronidazole, Bismuth, and Rifaximin were pooled using a systematic review approach. This approach involved systematically gathering, assessing, and synthesizing data from various studies, while ensuring the inclusion of studies meeting predefined criteria. Compared to a meta-analysis which integrates data through statistical approaches, a systematic review aims at integrating the results between studies in order to give a qualitative perspective of the treatment effects. The review discusses all of the studies in order to provide a general picture of the effectiveness of these antibiotics as SIBO and IBS treatments.

Safety profile

Metronidazole: Metronidazole is generally well-tolerated by most patients. Mild side effects are reported most frequently, i.e., nausea, bitter taste and occasional dizziness. Although the side effects are typically transient, they may cause discomfort in some patients. Serious AEs are infrequent but may occur in a subset of patients. Metronidazole safety profile is, in general, good enough to allow it as a good treatment alternative, but the associated side effects could affect the compliance with the therapy in certain patients. Metronidazole was associated with AEs in 2 of 12 studies (16.6%).

Bismuth: Bismuth is known for its favorable safety profile. Side effects with a majority mild in nature and temporary generally include gastrointestinal symptoms such as blackening of stool. These side effects are, for the most part, not severe enough to interfere with treatment. Although less frequent, other mild side effects could happen, however, they do not usually necessitate its interruption of treatment. Because of Bismuth's broad safety profile, it is an appropriate therapy for most patients, especially those who could be poorly tolerated by alternative regimens. Nonetheless, prolonged administration of Bismuth compounds has been associated with rare neurotoxic effects and tissue accumulation, necessitating caution and monitoring when used long term.

Rifaximin: Rifaximin is reported to be the most well tolerated of the three antibiotics reviewed. Most of the patients develop only mild events such as gastrointestinal symptoms such as nausea or flatulence. These side effects are usually mild and not sufficiently severe to cause treatment interruption. Serious AEs are very uncommon and help maintain Rifaximin's good safety record. Because of its tolerability and low side effect it is a first-choice option for most clinicians and patients. Rifaximin was associated with AEs in 3 of 18 studies (16.7%).

Safety in context of systematic review

As summarized in the review, the safety profile overall of Metronidazole, Bismuth, and Rifaximin were well tolerated, with predominantly mild-to-moderate AEs. Metronidazole and Bismuth may warrant periodic monitoring to exclude uncommon but potentially serious gastrointestinal complications, whereas Rifaximin’s superior tolerability underpins its broad clinical adoption. Across the reviewed studies, side effects were generally transient and non-severe, reinforcing the suitability of these agents in SIBO and IBS management with a focus on patient comfort and adherence. Future research should aim to identify patient subgroups at elevated risk for antibiotic-related toxicity.

Subgroup analysis

In this systematic review, subgroup analyses were conducted to determine the efficacy and risk-benefit profiles of Metronidazole, Bismuth, and Rifaximin for the treatment of IBS subtypes (IBS-D, IBS-C, IBS-M) and of varying severity of SIBO. These analyses helped to identify how different patient characteristics might influence treatment outcomes.

IBS subtypes

IBS-D: The three-antibiotic effectiveness was uniformly superior in IBS-D patients in the studies reviewed. Rifaximin was identified as the most potent treatment, which was associated with highly significant symptom relief, especially for diarrhea-related symptoms. Per studies, Bismuth and Metronidazole also provided slight, yet significant, relief for IBS-D participants, but less so than Rifaximin. In general, all 3 antibiotics significantly reduced IBS-D symptoms, with Rifaximin usually performing more effectively on all aspects. As the review describes, patients suffering from IBS-D appear reasonably responsive to such antibiotics, and in particular when adapted to their particular symptoms.

IBS-C: In the IBS-C patients, the antibiotics showed a slightly lower degree of efficacy. Rifaximin continued to be superior to the other antibiotics but with a lesser degree of effect than IBS-D. Bismuth and Metronidazole demonstrated moderate symptom relief, however their effectiveness was reduced in IBS-C compared with IBS-D patients and reduced further in IBS-C patients with the more severe constipation symptoms. This trend implies that IBS-C may pose further treatment complexities and that factors other than antibiotic response, such as gut microbiome, or motility problem, may influence antibiotic response. Nevertheless, all three of the antibiotics yielded some level of symptomatic relief, suggesting that all three of the antibiotics could be considered viable therapeutic options for the patients suffering from IBSC, especially in the absence of other therapeutic options.

IBS-M: For patients with IBS-M, the efficacy of the three antibiotics was more similar, with Rifaximin again showing the highest overall efficacy. Nonetheless, the strength of antibiotic difference was smaller in comparison with IBS-D or IBS-C subtypes. Bismuth followed as the second most effective antibiotic, while Metronidazole was the least effective in treating symptoms in this subgroup. The results of the reviewed studies indicated that, in IBS-M patients, use of antibiotics globally may be less effective, but through individualized therapeutic approaches, symptomatic relief may still be found. Mixed symptoms of IBS-M (diarrhea and constipation together) may need specific interventions or adjuvants to obtain the optimal results.

Severity of SIBO

Mild SIBO: According to the review, all the 3 antibiotics were efficacious for the treatment of the mild SIBO. On the other hand, Rifaximin turned out to be most effective in the treatment of mild SIBO producing significantly more symptom relief in comparison with Bismuth and Metronidazole. The effectiveness of Bismuth and Metronidazole varied across studies, but both were found to be less effective than Rifaximin in mild SIBO cases. These results are in line with a hypothesis that Rifaximin could be the preferred drug in the treatment of SIBO, particularly in mild forms of SIBO, when, thanks to its narrow action in the small intestine, a greater therapeutic yield can be obtained.

Moderate to severe SIBO: It consistently outperformed Bismuth and Metronidazole in more complicated SIBO. Studies cited in this review showed that Rifaximin was more effective at improving symptoms for moderate to severe SIBO, by a greater number of visits with patients reporting symptom improvement. On the other hand, Bismuth and Metronidazole were shown to be substantially less effective in severe SIBO cases, with some reports of small or no symptom in patients with advanced SIBO. These findings indicate that for moderate to severe SIBO, Rifaximin should be considered as the treatment of first line because it has provided the most reliable and stable effects in eradicating symptoms.

DISCUSSION

According to the results of this systematic review, Rifaximin emerges as the primary treatment for SIBO and IBS—particularly for IBS-D and moderate to severe SIBO—owing to its consistent efficacy in alleviating symptoms such as abdominal pain, bloating, and bowel movement irregularity, coupled with a favorable safety profile and minimal transient side effects[21,40]. In instances where Rifaximin is contraindicated (e.g., due to hypersensitivity, significant liver dysfunction, or deleterious drug interactions) or when antibiotic resistance limits its effectiveness, alternative agents such as Bismuth and Metronidazole remain reasonable therapeutic options. Although both alternatives have demonstrated effectiveness in mitigating symptoms, especially in IBS-D and low-to-moderate SIBO, their broader antimicrobial spectra and higher incidence of side effects—such as the gastrointestinal disturbances and neurotoxicity associated with Metronidazole[8] and the comparatively modest efficacy of Bismuth[41]—restrict their long-term applicability.

The selection of an appropriate antibiotic regimen should incorporate clinical considerations such as IBS subtype, disease severity, treatment history, and patient-specific factors including symptom intensity, comorbidity, and personal preference[17]. Furthermore, adjunctive management strategies—such as prokinetic agents, dietary modifications, and fiber supplementation—may enhance therapeutic outcomes, particularly in patients with IBS-C or IBS-M who exhibit a diminished response to antibiotic monotherapy.

The systematic review also identifies several critical gaps in the current literature. Foremost, most studies have focused on short-term outcomes, leaving the long-term efficacy and safety of these antibiotics—along with their impact on the gut microbiome and the risk of developing antibiotic resistance—insufficiently characterized. For instance, while Rifaximin’s targeted, site-specific action minimizes systemic absorption and associated AEs[40], the potential for resistance and recurrence of symptoms (as seen with Metronidazole’s limited long-term utility[8]) warrants further investigation. Additionally, the heterogeneity of study designs, diagnostic criteria, and patient populations introduces variability that complicates the generalizability of the findings, underscoring the need for standardized, multicenter research across diverse geographic and clinical settings[21].

Mechanistic insights into how these antibiotics interact with the gut microbiota, modulate inflammatory pathways, and influence intestinal permeability and motility remain underexplored. Future research should aim to elucidate these molecular mechanisms and optimize dose regimens, treatment duration, and combination therapies. For example, combining Rifaximin with adjunctive agents—such as prebiotics, probiotics (e.g., compounds like VSL#3), or motility agents—may potentiate its clinical efficacy, particularly in patients who do not respond adequately to monotherapy[10,16,140].

Given the overlap in symptoms between IBS and other gastrointestinal conditions, a thorough differential diagnosis is essential before initiating antibiotic or adjunctive treatment strategies[141]. Disorders such as inflammatory bowel disease (IBD)[142-145], celiac disease[145,146], microscopic colitis[147], infectious etiologies including chronic bacterial[148-151] and parasitic infections[152-154], retained foreign bodies[155], small bowel and colonic neoplasms[156], nutritional deficiencies like pellagra[157], and drug-induced diarrhoea[158-160] can all mimic IBS symptomatology. Failure to differentiate these conditions can result in misdiagnosis, inappropriate antibiotic use, and delayed initiation of targeted therapies. Alarm features—such as unintentional weight loss, rectal bleeding, nocturnal symptoms, and a family history of colorectal cancer or IBD[161]—should prompt further evaluation through endoscopic, serologic, or stool-based testing. Accurate identification of the underlying pathology ensures optimal and safe management, avoiding ineffective or potentially harmful interventions that may complicate the clinical course.

This systematic review underscores the methodological strengths of the evidence synthesis, including a rigorous study selection, detailed data extraction, and informative subgroup analyses that clarify the relative efficacy and safety of Metronidazole, Bismuth, and Rifaximin. However, limitations such as publication bias, inconsistent reporting of AEs, and variable study quality temper the certainty of the conclusions. These issues highlight the need for high-quality, long-term research to validate current findings and guide more refined treatment strategies.

CONCLUSION

This systematic review highlights the comparative efficacy and safety profiles of Rifaximin, Metronidazole, and Bismuth in the management of SIBO and IBS. Rifaximin consistently demonstrated favorable outcomes, particularly in patients with IBS-D, due to its targeted action in the small intestine, minimal systemic absorption, and superior tolerability—supporting its role as the preferred first-line therapy. Metronidazole was effective, especially for SIBO, but its broader antimicrobial activity and higher incidence of gastrointestinal side effects may limit its long-term use. Bismuth also showed therapeutic potential, particularly when used in combination regimens; however, its role as a standalone agent remains less defined, and its long-term safety warrants caution due to the risk of neurotoxicity with prolonged use. While all three antibiotics offer viable treatment options, variability in study design, patient populations, and outcome measures suggests the need for an individualized treatment approach. Incorporating clinical presentation, microbiological factors, and patient tolerability is essential to optimize therapeutic outcomes. Future research should focus on long-term efficacy, comparative effectiveness, resistance development, and the identification of patient subgroups most likely to benefit from specific therapies to support more precise and sustainable treatment strategies.

ACKNOWLEDGEMENTS

We would like to sincerely thank the Gastroenterology MSc program at the Learna Ltd. in Association with University of South Wales for their invaluable assistance in our work. We acknowledge and commend the University of South Wales for their commitment to providing advanced problem-solving skills and life-long learning opportunities for healthcare professionals.