Glucose breath test
Lactulose breath test
More specific but less sensitive
More sensitive by less specific
Readily absorbed by small bowel
What positive means
High likelihood of SIBO
Could be SIBO but cannot rule out rapid transit
Could miss distal SIBO
Higher false positive rate
Ease of use
Breath testing has become the mainstay of diagnosing SIBO for its simplicity compared to direct culture and has been useful in assessing the outcome of treatment as well. In studies of SIBO and treatment with antibiotics, the breath test has also been important in predicting outcomes. For example, in a trial of antibiotics for rifaximin, a reduction in breath hydrogen was associated with a greater improvement in symptoms among patients with IBS .
Methane as a Special Case
During breath testing, the focus over the last four decades had been the hydrogen level. Now recent data suggest a greater importance of methane as a marker of disease. Methane appears to be a marker of constipation. In a series of studies, it is now clear that methane is associated with clinical constipation as well as a more constipated Bristol Stool Score . Physiologic data suggest that methane gas itself slows intestinal transit . Methane on the breath test also has a proportional relationship with constipation [22, 24–26]. The greater the methane, the more severe the constipation clinically .
In the era of the microbiome , methane is interesting in that this gas is produced not by bacteria but by a group of older organisms, the Archaea. Discoveries surrounding methane and the microbiome have allowed the identification of the organism primarily responsible for gastrointestinal methane production. This organism is Methanobrevibacter smithii . Like its byproduct methane, M. smithii levels in the colon appear to be proportional to the degree of constipation .
The understanding of this relationship between methane and constipation continues to grow. While older studies suggested that the methanogenic Archaea were relegated to the colon (in particular the left colon), more recent evidence suggests they have a presence in the small intestine as well [28, 29].
Symptoms of SIBO
Logically, having a greater abundance of microbes in the gut would lead to a greater capacity for gas production. Consistent with this, bloating is one of the most common features of SIBO. This can lead to cramping and abdominal distress or discomfort. Flatulence or belching is also common. Traditionally, changes in bowel function have often been attributed to SIBO. Depending on the cause, these could range from diarrhea to steatorrhea, such as in the case of the blind loop syndrome .
More recently, with the growing understanding of the microbiome, methane and the presence of M. smithii are associated with a particular constellation of symptoms. These include bloating, constipation, and even greater body weight [22, 27, 30–35].
It is because of this wide variety of symptoms that bacterial overgrowth may need to be considered in a large number of patients with gastrointestinal complaints.
Conditions Associated with SIBO
As mentioned earlier in this chapter, it is important to look at SIBO as an epiphenomenon. There should be a reason for SIBO. Most commonly this is due to a motility problem such as irritable bowel syndrome (IBS) but there are many others (Table 30.2).
Potential conditions associated with SIBO
Stricture (e.g., Crohn’s disease)
Lumen occluding lesions (polyps, tumors)
Achlorhydria (primary and secondary)
Combined variable immunodeficiency
Ehlers Danlos syndrome
The most common disease now associated with SIBO is IBS. This development was initially controversial due to the nature of IBS research at the time. Now there is strong evidence that much of IBS is due to alterations in the intestinal microbiome and SIBO. This thinking formed the basis for a recent approval of rifaximin by the FDA as a treatment of IBS . The mechanism behind the development of SIBO in IBS is still being explored. However, data suggest that the SIBO could be linked to an initial exposure to acute gastroenteritis . In a validated animal model, infection with Campylobacter jejuni , one of the most common causes of acute gastroenteritis [38, 39], precipitates the development of IBS-like symptoms which correlate with the development of SIBO [40, 41]. Newer data demonstrate that this is through the development of autoimmunity to the cytoskeletal protein vinculin which could impair enteric neuromuscular function and anatomy leading to stasis . These anti-CdtB and anti-vinculin antibodies are now being used in a diagnostic test for post-infectious IBS . If these data continue to hold, a subset of IBS is essentially an autoimmune condition resulting from gastroenteritis and subsequent gut neuropathy leading to SIBO.
In addition, new revelations in the study of IBS identified a link between methane and constipation-predominant IBS [22, 24–26]. It is now known that nearly all patients with methane on breath test (“methane overgrowth”) have constipation as a phenotype.
Although there is a great deal of excitement around these developments in IBS, traditional associations between SIBO and motility disorders still hold. For example, patients with pseudo-obstruction can have SIBO due to the ileus pattern. Recall that SIBO can be caused by any reduction in bowel flow. The same is true for gastroparesis. While in gastroparesis the emphasis is poor flow through the stomach, the motor disturbances are not defined by a line of normalcy past the pylorus. The dysfunction often extends into the small bowel leading to SIBO.
As already discussed briefly, mechanical impairments to the flow of small bowel contents will lead to SIBO. The most common of these are intestinal adhesions secondary to previous surgery [1, 3, 44]. While tradition describes blind loops and antrectomy as a common cause of SIBO, these are now rare. Few people have antrectomy for refractory peptic ulcers these days and blind loop syndrome is more uncommon. While bariatric surgery such as Roux-en-Y gastric bypass alters anatomy, the intestinal flow rate is often higher than normal leading to less SIBO compared to older techniques .
Metabolic causes of SIBO are also common. Diabetes has a dual effect on the development of SIBO. It is theoretically possible that hyperglycemia is a risk, yet acute hyperglycemia itself (not necessarily chronic) can have profound inhibiting effects on intestinal motility [45–48]. As diabetes is very common, this may be a common cause of chronic intestinal symptoms in diabetic subjects.
More obvious is the association between achlorhydria and bacterial overgrowth [2, 3, 49]. In this case, the lack of gastric acid leads to easier colonization of the upper intestinal tract by bacteria. Often in this case, the colonization is due to oral flora (less gram negative bacteria). This is also true for the iatrogenic causes of low acid such as use of proton pump inhibitors [3, 50]. However, this may be more complicated as reduced acid reduces the protons needed to fuel methane production. In one study, the use of proton pump inhibitors was associated with a lower prevalence of methane on breath testing .
A number of disorders of immune function are also associated with SIBO. Conditions that reduce immunity of the gut such as IgA deficiency and combined variable immunodeficiency can reduce the response to gut microbes leading to SIBO [6, 52, 53]. Advance HIV and its effect on immune function has also been an important cause of SIBO in the past. Better treatments of HIV have made this less common now.
In addition to diseases of reduced immune function, autoimmune disease has been associated with SIBO as well although the mechanisms by which this occurs are less clear. In the case of scleroderma, the changes in gut motor function (neuropathy) are an obvious cause of SIBO [6, 54]. However, lupus and fibromyalgia  are less well understood.
Finally, medications can have an impact on the development of SIBO. Acid-reducing drugs have already been discussed. Yet, the greatest impact may be opiate agonists. In studies from the 1990s it was demonstrated that even a short course of opiate agonists could lead to SIBO even in healthy volunteers . With growing reports of opiate prescription and overuse, this could be an important cause of SIBO.
Treatment and Management of SIBO
Management of SIBO comprises three goals: (i) controlling disease flares (induction of remission); (ii) decreasing the chance of recurrence after induction of remission (maintenance of remission); and (iii) identifying and addressing the modifiable underlying cause(s) .
Induction of Remission
Antibiotics remain the mainstay of treatment for SIBO. Systematic review of the literature has shown that at least 23 trials have assessed the efficacy of antibiotics in management of SIBO . Several antibiotics have been shown to be effective in treatment of SIBO, including clindamycin, metronidazole, neomycin, rifaximin, tetracycline, ampicillin, amoxicillin, chloramphenicol, ciprofloxacin, erythromycin, and trimethoprim/sulfamethoxazole. It is not possible to pool the results of all of these studies as the antibiotic type, dose, duration, and definition of response were variable among these studies. As compared to placebo, antibiotics are more efficacious in eradication of bacterial overgrowth (51% vs. 10%), yielding a number to treat of 2 .
Rifaximin remains the most extensively studied drug in treatment of SIBO. In a small study of 21 subjects Di Stefano et al. observed a higher rate of SIBO eradication with rifaximin (70%) as compared to tetracycline (27%) . Similarly, Lauritano et al. assessed the efficacy of rifaximin 400 mg thrice daily as compared to metronidazole 250 mg thrice daily in 142 SIBO patients. After 1 month, glucose breath test normalized in 63% of patients in the rifaximin group versus 44% in the metronidazole group (P < 0.05) . The number of dropouts was significantly greater in the metronidazole group. One other advantage of rifaximin is its long-term safety profile even with repeated courses of therapy. The TARGET 3 trial, which assessed 2579 patients with diarrhea-predominant IBS, showed that adverse events are statistically similar between patients who repeated courses of rifaximin compared to placebo .
While the exact dosing and duration of rifaximin in treatment of SIBO remains to be determined, we recommend a course of 550 mg thrice daily for a total of 10–14 days for induction of remission in hydrogen-predominant SIBO.
In contrast, treatment of SIBO patients with excessive methane production with rifaximin alone may not be sufficient. This is likely due to resistance of methanogenic archaea to numerous antibiotics including rifaximin . There has been only one randomized controlled trial which systematically evaluated the effect of antibiotics in patients with methane-predominant bacterial overgrowth. Pimentel et al.  randomized 31 patients with constipation and excessive methane production to neomycin (500 mg twice daily) plus placebo or neomycin plus rifaximin (550 mg thrice daily) for 2 weeks and followed by a 4-week observation period. Patients treated with rifaximin plus neomycin showed a statistically significant improvement in constipation severity, bloating, and straining compared to the neomycin-alone group. Similar to this study, we recommend combination antibiotic therapy for methane-predominant bacterial overgrowth for a total of 14 days. Anecdotally, neomycin alone, metronidazole (500 mg thrice daily), or amoxicillin-clavulanic acid may also be considered in these patients. Further studies are required to systematically address the efficacy of such regimens in methane-predominant SIBO.
As a practical pearl, we prefer systemic antibiotic therapy rather than nonabsorbable antibiotics (e.g., neomycin and rifaximin) in treatment of SIBO in patients with a blind loop or surgical Roux limb. Nonabsorbable antibiotics may not fully reach the microbial content of blind loops.
Options to treat SIBO patients refractory to or intolerant of antibiotics are scarce. Elemental diet is a safe alternative for eradication of bacterial overgrowth. Originally developed for patients with short bowel syndrome, elemental diet is absorbed in the proximal small bowel and provides no nutrients to mid and distal small bowel bacteria . A 2-week course of elemental diet has been shown to be effective in 80% of patients with methane- or hydrogen-predominant SIBO. If the breath test does not normalize by week 2, continuation of therapy for another week can increase the success rate to 85% . The main limiting factors in use of elemental diet are cost, palatability, and weight loss. Elemental diet provides an intriguing alternative option for SIBO patients with concomitant inflammatory bowel disease, eosinophilic esophagitis, or eosinophilic gastroenteritis [64, 65].
Statins inhibit HMG-CoA reductase (3-Hydroxy-3-methylglutaryl coenzyme A reductase) which is an integral enzyme in the biosynthesis of archaeol and caldarchaeol, two of the main cell membrane components in archaea , and is also central to the biosynthesis of cholesterol in humans , hence the widespread use of statins to lower cholesterol. In addition to their role in inhibiting cell membrane biosynthesis, the lactone forms of statins have recently been shown to also inhibit methanogenesis directly, by inhibiting a key methanogenesis enzyme F420-dependent methylenetetrahydromethanopterin dehydrogenase (mtd) . Consistent with this, a recent phase II, randomized controlled trial on patients with methane-predominant bacterial overgrowth (NCT02495623) has shown promising results by decreasing methane levels and improving clinical symptoms . Ongoing larger-scale trials and research studies will further clarify the efficacy and safety of statins in management of SIBO.
Maintenance of Remission
Intact peristalsis is integral to keeping the gut microbiome in balance. Hence, one primary strategy to treat SIBO and decrease the number of flares is the use of promotility drugs. This is mainly directed towards facilitation of phase III migrating motor complexes (MMC) or housekeeper waves which occur every 90–120 minutes and sweep through the whole length of the small bowel . These waves clear the small bowel of residual food, secretions, and microorganisms. Several diseases that are associated with SIBO are known to have impaired MMCs, including IBS, opioid-induced dysmotility, diabetes, and bowel obstruction . Several receptors can be targeted to accentuate MMCs including motilin, 5HT4, ghrelin, and acetyl-choline receptors [72, 73].
In a small randomized trial of 34 cirrhotic patients , cisapride (a 5-HT4 agonist) was shown to be superior to placebo and non-inferior to antibiotics in normalization of the breath test. In a retrospective study, SIBO patients who underwent maintenance of remission with tegaserod (another 5-HT4 agonist) had less recurrence as compared to patients with no maintenance therapy, while treatment with erythromycin had a towards trend benefit . Larger prospective studies are required to elaborate the exact dosing, timing, and duration of promotility drugs in maintaining the remission among SIBO patients.
Laxatives and Secretogogues
Similar to promotility drugs, it appears intuitive that dilution of small bowel contents and improving the flow of gut content would help to decrease the bacterial population in the small bowel. However, very limited data exist to support this hypothesis. A recent prospective uncontrolled study has shown that 2 weeks of therapy with lubiprostone was effective in normalization of breath tests in 7 out of 17 patients with SIBO . Future studies are needed to systematically define the role of these classes of medications in the management of SIBO.
Intolerance to fructose and lactose are common findings among patients with SIBO, and avoiding these food ingredients can lead to improvement of associated symptoms . While a low FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet has shown to have a significant effect on gut microbiota, the efficacy of low fermentation diets in eradication of SIBO has not been systematically addressed . Nevertheless, in theory, foods which contain fermentable ingredients provide a more favorable environment for the overgrowth of bacteria in the small bowel and avoiding these food should decrease the risk of bacterial overgrowth.
Treating the Underlying Cause
When possible, it is critical to address the underlying cause of SIBO, otherwise the chance of maintenance of remission will remain low.
Patients with narcotic-induced dysmotility may benefit from partial μ-receptor antagonists (e.g., methylnaltroxone  and naloxegol ), prucalopride , or lubiprostone . Intraabdominal adhesions can significantly impair peristalsis, and lysis of adhesions can be considered in such patients. Recent advanced techniques such as the use of bioabsorbable membranes have shown promising results in decreasing the risk of recurrence of adhesions . Stricturing diseases of the small bowel such as Crohn’s disease, tuberculosis, anastomotic stricture, and NSAID enteropathy should be addressed appropriately with medications, radiation enteritis, endoscopic intervention, or surgery. Underlying inflammatory small bowel diseases such as Crohn’s disease and celiac disease should be treated accordingly. Avoiding diabetic drugs known to slow gut motility (e.g., glucagon-like peptide-1 agonists)  and strict glycemic control are two strategies which can be adopted in patients with diabetic enteropathy and SIBO. Patients with connective tissue diseases and joint-hypermobility syndromes may benefit from promotility drugs.