• a)

  Nominal group technique: This technique consists of an in-person meeting of a group of nine to 12 experts, facilitated by a coordinator, to analyze and grade a series of statements/questions. Its main advantage is enabling direct interaction among experts, although it is not exempt from opinion-leader bias. In the present consensus, 12 experts voluntarily participated. All of them previously received the background literature, and one expert was designated to analyze and present the existing level of evidence, prior to discussion of each statement/question.

The statements/questions were presented one-by-one and openly discussed. In some cases, they were reformulated to improve comprehension before the voting round. Two of the participants were in charge of analyzing the responses, according to the established format.19,20

• b)

  Grading format: To obtain a quantitative evaluation, the RAND/UCLA method was used. It employs a nine-point ordinal scale for grading each recommendation. In addition, according to the degree of grade dispersion (range), the level of agreement or consensus reached was determined (Annex, Figure S1).21

• c)

  Description of the grading method: Because the grading system is ordinal, the median (50th percentile) was used as the summary measure. After compiling all expert grading, the median was calculated and the response range was determined (highest and lowest values).22

• d)

  Criteria for defining the level of agreement:

• -

  Strong agreement: when the extreme values of the range fall within the same region of the scale (1–3, 4–6, or 7–9).

• -

  Relative agreement: when the extreme values fall within two adjacent regions. In such a case, the question is discussed again and submitted to a second vote.

• -

  No agreement: when the extreme values fall within non-adjacent regions. The question is discussed again and submitted to a second vote (Annex, Figure S2).

• e)

  Criteria for defining the grade of recommendation:

• -

  Positive recommendation: median within the 7–9 region of the scale.

• -

  Negative recommendation: median within the 1–3 region of the scale.

• -

  No recommendation: median within the 4–6 region of the scale.

• f)

  Criteria for selecting the experts

• -

  Being a gastroenterology specialist.

• -

  Having at least 5 years of experience in conducting and interpreting BTs.

• -

  Having conceptual and technical knowledge of the test (calibration, indications, and interpretation of results).

• -

  Having experience in the treatment of patients with DGBI.

Thirty-two statements/questions were formulated and grouped into four topics for discussion and voting:

• -

  General concepts, indications, and preparation – seven items (Table 1).

  Table 1.

  Statements/questions related to general concepts, indications, and pre-test preparation.

  Statement/question	Recommendation	Agreement
  The BT is a useful method for the management of patients with DGBI	Positive	Strong
  Glucose and lactulose, the substrates used in the BT, enable the evaluation of different pathophysiologic scenarios	Positive	Relative
  Do you consider aspirate and culture a true gold standard for diagnosing SIBO?	Negative	Relative
  Are BTs also considered useful in subjects with IBS-C and functional constipation?	Positive	Strong
  Is the BT a noninvasive test with a low risk of complications?	Positive	Strong
• -

  Procedure – nine items (Table 2).

  Table 2.

  Statements related to the procedure.

  Statement/question	Recommendation	Agreement
  The simultaneous measurement of hydrogen and methane is recommended	Positive	Strong
  Lactulose use is recommended in subjects with disorders of gut-brain interaction	Positive	Relative
  Glucose use is preferred in cases of blind loops, malabsorption, or significant motility disorders	Positive	Relative
  In the BT, sampling every 15−20 min is considered adequate	Positive	Relative
  When lactulose is used, is carrying out sampling up to 180 min considered appropriate?	Positive	Relative
  Is not suspending sampling, even when earlier values indicate overgrowth, advisable?	Positive	Relative
  Documenting patient symptoms during the test is important	Positive	Strong
• -

  Test interpretation – six items (Table 3).

  Table 3.

  Statements related to breath test interpretation.

  Statements	Recommendation	Agreement
  A flat H2 curve indicates the predominance of a H2-consuming microbiota	Positive	Strong
  In cases of a flat H2 curve and normal CH4 values, the possibility of intestinal sulfide overproduction should be considered	Positive	Strong
  An elevated baseline H2 may indicate inadequate pre-test preparation	Positive	Strong
  An adequate cutoff value for diagnosing SIBO is ≥20 ppm of H2 above the baseline within 90 min	Positive	Relative
  The accepted cutoff value for diagnosing IMO is a CH4 level ≥10 ppm at any time during the test	Positive	Strong
• -

  Treatment – 10 items (Table 4).

  Table 4.

  Statements related to treatment.

  Statement	Recommendation	Agreement
  If SIBO is diagnosed in an adult population, using a nonabsorbable antibiotic, such as rifaximin, is recommended	Positive	Strong
  The recommended treatment duration with rifaximin is 10–14 days	Positive	Strong
  The recommended rifaximin dose is 550 mg three times a day	Positive	Strong
  Regarding IMO, the simultaneous administration of two antibiotics (rifaximin plus neomycin or rifaximin plus metronidazole) is recommended.	Positive	Relative
  Regarding IMO with constipation, adding a prokinetic agent is considered useful	Positive	Relative
  In patients with overgrowth who initially responded well, the same antibiotic may be indicated if there is relapse	Positive	Strong

The ranges and medians for each of the 32 statements/questions are described in the Annex section (Tables S1, S2, S3, S4)

• 1

  The BT is a useful method for managing patients with DGBI. Strong agreement and Positive recommendation.

Although there are conflicting opinions on the usefulness of the BT in functional gastrointestinal disorders, the expert group coincided in considering it a valuable tool, supported by the direct experience of the participants in the systematic performance and interpretation of said tests.

Despite the fact that some studies have questioned the usefulness of the BT due to variability in orocecal transit time, observed in tests with both lactulose23,24 and glucose,25 the present consensus recognizes that the BT provides information that other tests do not. In particular, it enables the identification of IMO, a diagnosis that can only be made through said test, making it possible to adjust antibiotic treatment according to the presence of SIBO, IMO, or both. Without a doubt, the BT has both advantages and limitations that must be taken into account in a clinical context. The identification of different patterns, such as the presence of flat-line H2 and CH4 and/or elevated baseline H2, enhances its usefulness in the management of patients with DGBI.26

• 2

  Glucose and lactulose, the substrates used in the BT, enable the evaluation of different pathophysiologic scenarios. Relative agreement and Positive recommendation.

Glucose is a monosaccharide that is absorbed in the proximal small intestine, albeit in cases of accelerated transit, it can reach the colon. In contrast, lactulose, because it is a nonabsorbable disaccharide, enables the detection of the bacterial contact in both the small intestine and colon.27,28

In their review, Khoshini et al. analyzed the diagnostic accuracy of BTs with lactulose and glucose, compared with culture. The sensitivity of glucose varied between 20% and 93%, with a specificity of 30%–86%, whereas lactulose had a sensitivity of 31%–68% and a specificity of 44%–100%.29 A meta-analysis concluded that glucose has greater sensitivity and specificity than lactulose: they evaluated 14 studies, determining sensitivity of 42.0% and 54.5% and specificity of 70.6% and 83.2% for lactulose and glucose, respectively.30

Another meta-analysis compared sensitivity and specificity of the BT with different substrates in patients with IBS, reporting 72.2% sensitivity and 66% specificity for lactulose. For glucose, sensitivity was considerably lower (15.7%) and specificity reached 97%, indicating a great capacity for ruling out false positives.31 In summary, although glucose has high specificity, its sensitivity is low, and so a positive test with glucose confirms the presence of SIBO but a negative result does not rule it out. In contrast, lactulose has higher sensitivity but limited specificity, resulting in a high positive result rate, reinforcing the need for cautious interpretation.32,33

During the meeting, the fact that most of the studies evaluating BT accuracy compared their results with intestinal aspirate and culture, a method no longer considered a true gold standard, was discussed. That limitation is crucial, given that the reported sensitivity and specificity for glucose and lactulose are based on a reference standard with numerous restrictions, such as those addressed in the next section.

The microorganisms found in the intestine of subjects with SIBO may vary, depending on the underlying pathophysiologic mechanism.34–36 For example, in cases of hypochlorhydria or the prolonged use of PPIs, there is a predisposition to SIBO with Gram-positive flora, whereas the mechanisms related to anatomic alterations (blind loop, diverticulosis) or with significant motility disorders that compromise bacterial clearance predispose to SIBO with a predominance of Gram-negative microorganisms.37

It was also noted that when lactulose reaches the colon early due to accelerated orocecal transit, the measured gases could reflect colonic fermentation rather than SIBO. This implies that in certain cases, lactulose may evaluate colonic fermentative activity rather than the exclusive presence of SIBO.

• 3

  Is it appropriate to consider aspirate and culture a true gold standard for the diagnosis of SIBO? Relative agreement and Negative recommendation.

The consensus concluded that intestinal aspirate and culture should not be regarded as a gold standard for diagnosing SIBO. Historically, that method has been used as the reference for determining sensitivity and specificity of glucose or lactose-based BTs. However, as previously stated, it has numerous limitations: it is invasive and costly, only a small number of microorganisms can be cultured, samples are obtained solely from the proximal small bowel segments, and there is a risk of contamination. Cutoff values have also varied over time, from >105 CFU/mL to > 103 CFU/mL, explaining the different criteria employed across studies.38

Despite those limitations, a study based on gene sequencing (rRNA) found that a culture with a threshold of >103 CFU/mL correlated well with clinical symptoms, BT results, and gene sequencing.39 Nevertheless, there is not enough evidence for considering the method a true gold standard.

• 4

  Is the post-treatment performance of a BT to evaluate its therapeutic efficacy recommendable? No agreement and Negative recommendation.

The routine performance of a BT for monitoring SIBO resolution is not recommended, given that clinical improvement may be sufficient for evaluating treatment response. Test repetition may be considered only in cases of persistent symptoms or early relapse, following the guidelines that suggest the indication of a new BT under those circumstances.

• 5

  BTs are also considered useful in subjects with IBS-C and functional constipation. Strong agreement and Positive recommendation.

Patients with IBS, specifically those with IBS-C, present with SIBO and/or IMO more frequently,40 which may contribute to gastrointestinal dysfunction and symptom persistence.

In such cases, the BT is useful for diagnosing overgrowth as a potential underlying cause or contributing factor.

The evaluation of excessive CH4 production is recommended in patients with constipation, with or without abdominal pain, because IMO has been associated with intestinal motility disorders. However, the BT is not considered an adequate method for evaluating orocecal transit time.41

• 6

  Is suspending PPIs before performing a BT recommendable? No agreement and Negative recommendation.

This was the only recommendation that did not achieve consensus in the preliminary survey, nor did it achieve agreement at the in-person meeting, but a negative recommendation was issued. Even though PPIs may cause dysbiosis and SIBO, as recognized in other consensus statements, their discontinuation before a BT is not recommended.

• 7

  The BT is a noninvasive test with a low risk of complications. Strong agreement and Positive recommendation.

The BT requires ingesting a solution of glucose or lactulose, fermentable substrates that may produce mild gastrointestinal discomfort, such as bloating, diarrhea, pain, or a swelling sensation. To ensure result validity and minimize interference, an 8–12-h fasting period before the test is recommended (Table 5).

In the specific case of glucose, its rapid absorption in the proximal small intestine may cause a transitory increase in blood glucose, which is especially relevant for diabetic patients, who must control their glucose levels to prevent episodes of hyperglycemia or hypoglycemia.42

• 8

  The simultaneous measurement of H2 and CH4 is recommended. Strong agreement and Positive recommendation.

Around 35% of healthy subjects harbor CH4-producing microorganisms (archaea) in their intestine.43 Said archaea consume H2 to produce CH4, which is why increased CH4 excretion in breath samples tends to coincide with a reduction in H2 excretion. Basing results solely on normal H2 values may underestimate the presence of competing H2-consuming microorganisms and mask H2-producing microorganisms.44 Therefore, only measuring exhaled H2 may lead to interpreting the test as normal, even though there is overgrowth of other microbes. On the other hand, elevated H2 does not rule out simultaneous overgrowth of methanogenic archaea, a situation that requires a different treatment regimen.

Clinical and experimental studies indicate that CH4 acts as a gastrointestinal motility inhibitor and that its concentration correlates inversely with stool form and frequency, as well as with constipation severity.45,46 Excess CH4 excretion, predominantly due to Methanobrevibacter smithii, is measured through a BT and an accepted cutoff value is ≥10 ppm. This phenomenon is known as IMO, but the criterion for defining excessive CH4 production is not as precise as that with H2. In patients with elevated CH4, values tend to be higher at the baseline and elevations during the test are not as obvious as with H2.47,48

• 9

  Lactulose is recommended in subjects with DGBI. Relative agreement and Positive recommendation.

The role of SIBO in the pathogeny of DGBI, such as IBS, is a subject of debate.49 A systematic review and meta-analysis concluded that SIBO was more frequent in IBS than in controls, with an odds ratio (OR) of 4.9. Based on cultures, 35% of the subjects with IBS presented with SIBO, compared with 8.3% of the controls. In addition, the use of lactulose as a substrate offered greater diagnostic yield, compared with culture and glucose.50 Most of the present consensus experts expressed a preference for lactulose use in subjects with DGBI because it allows both early (small intestine) and late (ileum and colon) intestinal fermentation to be assessed, considering that late fermentation could be more prevalent in patients with DGBI.

• 10

  Glucose is preferred in cases of blind loop, malabsorption, or other significant motility disorders. Relative agreement and Positive recommendation.

The term “small intestinal bacterial overgrowth” or SIBO was originally coined to describe cases of malabsorption in patients with anatomic or functional gastrointestinal alterations, such as postoperative blind loops, fistulas, jejunal diverticula, or chronic intestinal pseudo-obstruction.

In studies employing small-bowel aspirate and culture as the reference pattern, the glucose BT has been suggested to have higher sensitivity and specificity than the test with lactulose.51

Therefore, albeit with relative agreement, glucose is recommended particularly in patients with classic SIBO associated with severe symptoms, malnutrition, or overt malabsorption.

• 11

  In the BT, sampling every 15−20 min is considered adequate. Relative agreement and Positive recommendation.

In the BT, sampling frequency should follow a standard protocol to guarantee accurate results. The procedure consists of taking a baseline breath sample before ingesting the substrate (glucose or lactulose) and then continuing with the collection at regular intervals, usually every 15−20 min, to adequately register the variations in gas production.52,53

• 12

  In the BT with lactulose, sampling should be carried out for up to 180 min. Relative agreement and Positive recommendation.

In glucose breath tests, the result tends to be obtained within the first 90 min, with some authors suggesting the test can be completed at that time. However, when lactulose is used, the arrival of the substrate into the colon enables the fermentative response in the distal segments (ileum and colon) to be evaluated, which can only be observed if sampling extends up to 180 min.54

• 13

  Not discontinuing sampling, even if earlier values indicate overgrowth, is advisable. Relative agreement and Positive recommendation.

As stated before, especially when lactulose is the substrate, extending the test up to 180 min allows a comprehensive fermentation profile to be established, which is useful if the AUC of total gas excretion is to be calculated.

• 14

  Calculating the AUC is considered useful. No agreement but Positive recommendation.

This item did not reach the required consensus level. However, the panel decided to issue a positive recommendation, given that several members were of the opinion that the AUC could provide clinically valuable complementary information.

The AUC analysis is advantageous,55,56 given that instead of being based on a cutoff value (increase in H2 ≥20 ppm above the baseline in 90 min and CH4 ≥10 ppm), gas production can be quantified over time, offering a more complete view of the bacterial metabolic activity in the intestine.

This is especially useful for differentiating transient elevated gas levels from sustained levels, as well as for identifying findings that may not be apparent with an approach based solely on fixed thresholds.

Some patients with microbial overgrowth may not meet the diagnostic criteria of SIBO/IMO but have mild, sustained increases throughout the test, which could be detected by the AUC. Not all alterations observed in the BT are strictly consistent with SIBO; some cases may reflect another type of intestinal dysbiosis, and in such settings, the AUC could be a useful tool for their detection.

Likewise, in the follow-up assessment, a BT that shows a decrease in the AUC after treatment could more accurately reflect clinical improvement than the analysis based solely on absolute gas values.

In patients with rapid or delayed bowel transit, the elevation of gas levels could occur earlier or later than expected; in such cases, the AUC may be a more robust measurement by not depending on the exact time of the increase.

The AUC could also contribute to the interpretation of prolonged BTs (>120 min), for which there are no internationally accepted reference values. In the methanogenic phenotypes, the AUC has been shown to be useful for quantifying CH4 production and correlating it with constipation severity,57 better reflecting its impact by occurring in a sustained or plateau-like manner.58

• 15

  If exhaled breath samples are to be stored, they should be processed the same day. No agreement but Positive recommendation.

Volatile compounds, such as H2 and CH4, can slowly diffuse through the walls of the collection tubes or chemically react if they are not properly sealed, potentially altering results. Therefore, the recommendation is to process the samples the same day they are collected. However, in some cases, they may be temporarily stored if they meet certain criteria: they must be collected in hermetically sealed containers (plastic syringes are the most widely used device) and stored in refrigeration to minimize diffusion and microbial activity. Under those conditions, they can remain stable for approximately 24−48 h, but beyond that amount of time, the accuracy of the results may be compromised.59 Temperature fluctuations during storage or transport can also cause the gases to expand or contract, altering their concentration.60 Hydrogen is known to dissipate faster than CH4 due to its greater reactivity and diffusibility.61–63 Nevertheless, in other studies, no significant difference in H2 concentrations between samples analyzed early and those analyzed late was observed, but CH4 concentrations showed a significant increase in samples stored for a longer time.64

• 16

  It is important to document patient symptoms during the test. Strong agreement and Positive recommendation.

In some patients with DGBI, there may be dysfunctions in central and peripheral control mechanisms of visceral sensory perception.65,66 When a poorly absorbed carbohydrate reaches the colon, its metabolism produces gases and short-chain fatty acids, which may trigger symptoms of pain, bloating, or diarrhea. Said symptoms are not always due to microbial overgrowth, but rather to individual intolerance to intestinal fermentation.67–69 In that context, nonabsorbable lactulose BTs may provide the added value of evaluating patient symptoms regardless of the quantity of excreted gases. Specific questionnaires for adults and children have been developed and validated for adequate symptom assessment.70,71

• 17

  The exclusive measurement of H2 may increase the number of false negatives. No agreement but Positive recommendation.

It is important to simultaneously measure H2 and CH4. Methanogenic archaea utilize four moles of H2 to produce one mole of CH4, and so elevated CH4 levels may reduce H2 values in exhaled breath. As previously stated, if only H2 is measured, the result may be erroneously interpreted as normal when it is not. In addition, a sulfide-producing microbiota, dietary sulfate, or an acidic colonic pH72 may reduce H2 excretion by up to 20%, increasing the possibility of false negative results.73

• 18

  A flat H2 curve indicates the predominance of a H2-consuming microbiota. Strong agreement and Positive recommendation.

Minimal H2 excretion, previously attributed to the predominance of non-H2-producing microorganisms, is currently interpreted as a consequence of the predominance of H2-consuming microorganisms. The “flat-line” pattern is defined as stable H2 production, ≤3 ppm, with no increases >1 ppm above the baseline and in the absence of CH4.74,75

• 19

  In cases of a flat H2 curve and normal CH4 values, the possibility of intestinal sulfide overproduction should be considered. Strong agreement and Positive recommendation.

When a “flat-line” pattern is identified (defined as low H2 production in the absence of CH4), a predominantly non-methanogenic H2-consuming microbiota is supposed, i.e., H2 consumption is caused by hydrogen sulfide (H2S)-producing microorganisms.76

• 20

  An elevated baseline H2 may indicate inadequate pre-test preparation. Strong agreement and Positive recommendation.

“Elevated baseline H2” is defined as a H2 value ≥20 ppm in a lactulose or glucose BT before substrate ingestion. Elevated H2 levels related to inadequate adherence to the pre-test low fermentation diet or insufficient fasting time are commonly observed, and so if those conditions cannot be guaranteed, repeating the test is recommended. Nevertheless, depending on the context, when there is strong clinical suspicion, said pattern may be interpreted as suggestive of intestinal microbial overgrowth.77,78

• 21

  An adequate cutoff value for diagnosing SIBO is an elevation ≥20 ppm of H2 above the baseline value within 90 min. Relative agreement and Positive recommendation.

Some of the consensus experts questioned the specificity of the 20 ppm threshold for H2, citing potential false positives due to physiologic variations or rapid bowel transit. However, that value continues to be widely accepted for its simplicity and clinical applicability.79 Regarding lactulose, the double-peak diagnostic criterion (traditionally interpreted as one attributed to SIBO and the other to colonic fermentation) is no longer considered necessary. During our meeting, increases from 12 to 19 ppm above the baseline value were proposed as “borderline or inconclusive”, and in such cases, the presence of typical symptoms (diarrhea, bloating, or abdominal pain) during the first 90 min, could serve as an additional support criterion for diagnosing overgrowth.

• 22

  The accepted cutoff value for diagnosing IMO is a CH4 level ≥10 ppm at any time during the test. Strong agreement and Positive recommendation.

The optimum criterion for defining excessive CH4 excretion is not exact, a point on which the experts coincided. However, until new evidence is produced, the suggested cutoff value for a CH4-positive BT is a level ≥10 ppm at any time during the test. According to Shaker et al., 96.4% of the CH4-positive tests (IMO) were identified within the first 90 min, regardless of the baseline values. Based on those findings, some researchers suggest that measuring can be stopped at 90 min, but others recommend extending the test up to 180 min, especially when lactulose is used and H2 and CH4 are simultaneously measured.80

During the expert panel discussion, certain technical aspects, such as the type of instrumentation and calibration gases utilized, were posited to influence the cutoff values for defining IMO. To reduce false positives, an “unequivocal diagnosis” of IMO, when two or more measurements of CH4 are ≥ 15 ppm within the first 90 min, was suggested.

• 23

  If SIBO is diagnosed in an adult population, using a nonabsorbable antibiotic, such as rifaximin, is recommended. Strong agreement and Positive recommendation.

SIBO is not a disease per se but rather a syndrome that responds to an underlying disease that must be identified and treated. Management of the predisposing disorders not only helps alleviate condition symptoms but also prevents recurrence after successful treatment. Thus, detecting and adequately treating those predisposing conditions is essential.81,82

Even though there are different strategies for controlling SIBO, rifaximin is the most widely studied broad-spectrum antibiotic.83,84 Other antibiotics have also been studied, including norfloxacin, ciprofloxacin, metronidazole, doxycycline, neomycin, cotrimoxazole, and amoxicillin with clavulanic acid.

Rifaximin, a structural rifampicin analogue, inhibits bacterial RNA synthesis by binding to polymerase RNA. It is a nonabsorbable antimicrobial, efficacious against aerobic, anaerobic, Gram-positive, and Gram-negative bacteria. In May 2015, the FDA approved rifaximin for the treatment of IBS-D.85 It has a favorable safety profile because it does not create resistance, its systemic absorption is minimal (0.5%), its toxicity level is low, there are few adverse effects, and few medication interactions. Its main limitation is its higher cost, in relation to other antimicrobials.86

A meta-analysis of 10 studies (Shah, et al.) included 1,356 patients and primarily evaluated rifaximin use (eight studies). The general BT normalization rate with rifaximin was 49.5% (95% CI 44.0–55.1). Other antibiotics, such as metronidazole, neomycin, and ciprofloxacin, were also efficacious, with a combined BT normalization rate of 51.1% (IC 95% CI 46.7–55.5) for the antibiotics, compared with 9.8% (95% CI 4.6–17.8) for placebo. A meta-analysis of four studies in that review favored antibiotics over placebo for BT normalization, with an odds ratio of 2.55 (95% CI 1.29–5.04).87

Likewise, a recent systematic review analyzed six studies that compared the efficacy of antibiotics compared with placebo in a total of 196 patients with SIBO, 101 of whom received antibiotics and 95 received placebo or no treatment. Clinical improvement was significantly better in the antibiotic group (relative risk [RR] [95% CI] of 2.46 [1.33–4.55], p = 0.004).88

• 24

  The recommended duration of treatment with rifaximin is 10–14 days. Strong agreement and Positive recommendation.

The 10–14-day duration of treatment with rifaximin was widely agreed upon, concurring with the leading international guidelines. Even though comparative studies on optimal treatment duration are limited, all therapeutic regimens proposed in the literature agree on that time range.89

• 25

  The recommended rifaximin dose is 550 mg three times a day. Strong agreement and Positive recommendation.

The rifaximin dose of 550 mg three times a day is supported by the TARGET I and TARGET II clinical trials. In those phase 3, double blind, placebo-controlled trials, patients with IBS without constipation received 550 mg of rifaximin versus placebo, three times a day for two weeks, and were followed for 10 additional weeks. A significantly higher percentage of patients treated with rifaximin experienced adequate overall IBS symptom relief during the first four weeks post-treatment, compared with the placebo group: TARGET I: 40.8% vs 31.2% (p = 0.01), TARGET II: 40.6% vs 32.2% (p = 0.03) and the combined analysis: 40.7% vs 31.7% (p = 0.001). All patients treated with rifaximin had bloating, abdominal pain, and stool consistency improvement.90

Even though there are studies with rifaximin at a dose of 400 mg every 8 h, current evidence supports the use of 550 mg every 8 h as the most effective dose, a criterion widely accepted by specialists.

• 26

  The duration of treatment with rifaximin is modified according to the severity of SIBO. No agreement and No recommendation.

No agreement was reached or recommendation issued on whether patients with elevated gas levels in the BT could require longer treatment duration. The intestinal microbiota is highly dynamic and may experience significant changes in short periods of time, making it difficult to define severity in SIBO solely in relation to isolated gas measurements. Even though elevated values could suggest greater fermentation, and in turn, greater severity of the condition, there are no studies that justify modifying the duration of treatment with rifaximin, based on BT results.

• 27

  In cases of IBS-associated SIBO, a low fermentation diet is advisable for symptom improvement. No agreement but Positive recommendation.

Even though complete agreement on this theme was not reached, a positive recommendation was issued. Dysbiosis associated with SIBO produces an increase in intestinal fermentative activity, which increases with the presence of more fermentable substrates, such as carbohydrates. Therefore, restricting those foods makes sense as symptomatic treatment in patients with SIBO and IBS.

The low fermentable oligosaccharide, disaccharide, monosaccharide, and polyol (FODMAP) diet has been widely studied and has shown efficacy in the treatment of IBS. The first study that evaluated its impact through a double-blind challenge with fructans confirmed the benefits of said restriction in patients with IBS. However, its utility in the treatment of SIBO is still limited. Some studies have explored the impact of different diets on the condition, but their low methodological quality hinders the extrapolation of the results to clinical practice. Therefore, at present, there is insufficient scientific evidence supporting a specific diet as treatment of SIBO.91

• 28

  Regarding IMO, the simultaneous administration of two antibiotics (rifaximin plus neomycin or rifaximin plus metronidazole) is recommended. Relative agreement and Positive recommendation.

In a study conducted on patients with IMO, the combination of rifaximin plus neomycin was superior to the administration of either antibiotic alone. Eighty-five percent of the subjects who received rifaximin plus neomycin had clinical response, compared with 63% in the group that received neomycin alone (n = 8) (p = 0.15) and 56% in the group that received rifaximin alone (n = 39) (p = 0.01). There were no significant differences in the comparison of the neomycin and rifaximin groups. When CH4 eradication was evaluated in the BT, the results were 87% for the rifaximin plus neomycin combination, 33% for neomycin alone, and 28% for rifaximin alone.92

In another study, rifaximin plus neomycin was superior to neomycin alone in improving symptoms in patients with IBS-C and a CH4-positive BT. Constipation severity was significantly lower in the rifaximin plus neomycin group (28.6 ± 30.8), compared with the group receiving neomycin alone (61.2 ± 24.1) (p = 0.0042).93

The expert panel recommended metronidazole as a substitute for neomycin, in cases of intolerance, contraindication, or inability to prescribe it.

• 29

  Probiotics may be used after completing treatment with antibiotics. No agreement and No recommendation.

No agreement was reached or recommendation issued on this theme, given a lack of robust evidence justifying their systematic use in the treatment or prevention of SIBO.

Even though probiotics may modify the gut microbiota, the available evidence is heterogeneous and low-quality, with disparate results among studies.

In a systematic review with a meta-analysis that included 14 full articles and eight abstracts, probiotics showed a nonsignificant trend toward a lower incidence of SIBO (RR = 0.54; 95% CI 0.19–1.52; p = 0.24). The SIBO eradication rate was 62.8% (51.5–72.8 %) and reached 85.8% when probiotics and antibiotics were combined, compared with the 53.2% with probiotics alone. There was also a significant decrease in H2 concentration (95% CI −44.23 to −28.47 ppm; p < 0.05) and improved abdominal pain, with no relevant changes in stool frequency.

In conjunction, those findings suggest that probiotics may be useful as adjuncts in the treatment of SIBO, but there is no conclusive evidence justifying their prophylactic or routine use.94

A recent study evaluated Saccharomyces boulardii in the treatment of SIBO. It is a yeast that is not altered by antibiotic use, so may be administered together with antimicrobials. In addition, yeast strains arrive at the intestine in larger quantities than those of bacterial probiotics (measured in colony-forming units), due to their resistance to gastric pH. On the other hand, yeast metabolites stimulate the growth of probiotic bacteria. However, results are mixed and most of the studies have limitations, such as a small number of patients, non-comparable diseases, and short follow-up periods.95

• 30

  Prebiotics may be used in SIBO. No agreement and No recommendation.

No agreement was reached or recommendation issued on this theme, given that, as with probiotics, there is insufficient evidence that justifies prebiotic use in the treatment of SIBO.

The available studies have a small number of patients and most of them combine prebiotics with other therapeutic agents, making it difficult to establish precise indications.

Wei and Quigley conducted one of the few studies on prebiotic use, in which a combination of minocycline, probiotics (B. coagulans), and fructo-oligosaccharide prebiotics were administered in a double-blind trial. The patients in the prebiotic group had a significant decrease in pain, bloating, burping, and diarrhea, compared with the control group. In fact, all the patients who received prebiotics informed complete resolution of abdominal pain, whereas said resolution was reported in seven of the 15 patients who received only antibiotics. Other evaluated symptoms, such as nausea, vomiting, and constipation, showed similar improvement in the two groups. Finally, the post-treatment BT was negative for SIBO in 93.3% of the cases.96

• 31

  Regarding IMO with constipation, adding a prokinetic is considered useful. Relative agreement and Positive recommendation.

Methane has been shown to slow bowel transit by reducing phase III peristaltic wave frequency in the small intestine, which may contribute to constipation. Articles in the literature on the use of prokinetics in patients with bacterial overgrowth largely focus on preventing symptom recurrence after antibiotic treatment.97

In cases of constipation persistence after the treatment of IMO, the expert panel considers that adding a prokinetic could be potentially beneficial.

• 32

  In patients with overgrowth who initially responded well, the same antibiotic may be indicated in cases of relapse. Strong agreement and Positive recommendation.

Although there is no specific bibliography endorsing antibiotic re-treatment following SIBO relapse, clinical consensuses support said strategy. Rifaximin is the most widely studied antibiotic in that context, with evidence of safety in multiple studies, among which the TARGET III is the most relevant. In that trial, 636 patients who responded to initial treatment, but experienced symptom recurrence, were randomized into a double-blind phase to receive additional therapy with rifaximin or placebo for 14 days. The percentage of patients who responded was significantly higher with rifaximin (38.1% vs 31.5%; p = 0.03).98

In clinical practice, repeating the same antibiotic is appropriate in patients who had an initial good response and who presented with relapse, emphasizing the need to individualize decisions according to tolerance and comorbidities.