|Year : 2017 | Volume
| Issue : 6 | Page : 167-170
Small intestinal bacterial overgrowth in patients with systemic sclerosis
Saara Rawn, Natalia Pitman, Karen Beattie, Ava Bazzaz, Maggie Larche
Division of Rheumatology, Department of Medicine, McMaster University, Hamilton, ON, Canada
|Date of Web Publication||23-Nov-2017|
McMaster University, Hamilton, ON
Source of Support: None, Conflict of Interest: None
Small intestinal bacterial overgrowth (SIBO) is common in patients with systemic sclerosis (SSc) yet often goes underrecognized in clinical practice. In patients with SSc, untreated SIBO may result in marked morbidity and possible mortality. The pathogenesis of SIBO is multifactorial and relates to immune dysregulation, vasculopathy, and dysmotility. This article reviews various diagnostic approaches and therapeutic options for SIBO. Treatment modalities mainly include prokinetics, probiotics, and antibiotics.
Keywords: antibiotics, Gastrointestinal symptoms, probiotics, prokinetics, Scleroderma, Small bowel bacterial overgrowth
|How to cite this article:|
Rawn S, Pitman N, Beattie K, Bazzaz A, Larche M. Small intestinal bacterial overgrowth in patients with systemic sclerosis. Indian J Rheumatol 2017;12, Suppl S1:167-70
| Epidemiology|| |
The gastrointestinal (GI) tract is involved in up to 90% of patients with systemic sclerosis (SSc).,, From the EUSTAR, German (DNSS) and Canadian (CSRG) registries, up to 65% of patients develop small intestinal bacterial overgrowth (SIBO),,, with clinical features of bloating, abdominal discomfort, flatulence and steatorrhea, and resulting malabsorption.
| Pathogenesis|| |
Immune dysregulation leading to vasculopathy and neural dysfunction is followed by fibrosis of the bowel smooth muscle which contributes to dysmotility in SIBO. Vasculopathy occurs through damage to the vasa nervorum. Often, vascular ectasia and intravascular thrombi can be visualized in the GI tract. Smooth muscle contraction is largely mediated through cholinergic neurotransmission in the myenteric plexi. Autoantibodies against the muscarinic (M3) acetylcholine receptor have been described in patients with SSc and may contribute to dysmotility through direct neurological inhibition. Both type I and II collagen are deposited into the lamina propria and muscularis mucosa resulting in severe fibrosis as SSc advances. It is not clear how collagen deposition and fibrosis are triggered in the GI tract, but this is a clear pathological feature in patients with GI symptoms in scleroderma.
With the nutrient-rich contents of the small bowel in a dysmotile environment, pathogenic bacteria are able to proliferate, producing excess gas and symptoms of SIBO. As compared to healthy controls, patients with SSc have more pathogenic genera in their intestinal microbiomes, such as Prevotella, Erwinia, and Fusobacterium. SIBO represents an increased number (>105 bacteria/mL) and/or type of bacteria in the upper GI tract.
| Investigations in Small Intestinal Bacterial Overgrowth|| |
The “gold standard” investigation to diagnose SIBO is small bowel (jejunal) aspiration and bacterial count/culture. However, this is impractical, and several surrogate markers of SIBO have been developed. Excessive bacteria produce hydrogen or methane which can be measured in the breath. This test involves ingestion of glucose or lactulose after a 12 h fast, followed by sequential measurements of hydrogen or methane in the breath resulting from digestion of the sugar., A validated, dedicated GI questionnaire in scleroderma – the University of California Los Angeles Scleroderma Clinical Trial Consortium GI Tract Instrument 2.0 (UCLA SCTC GTI) – can be used to assess symptoms of SIBO. Finally, blood tests suggesting malabsorption can also be used as surrogate markers of SIBO. Malabsorption occurs because of the competition for nutrients, such as Vitamin B12, and the deconjugation of bile acids leading to malabsorption of fat. Other causes of malnutrition include anorexia and diarrhea. Malabsorption markers include albumin, ferritin, Vitamin D, Vitamin B12, and prothrombin. Malabsorption has been described in up to 25% of patients with SIBO and is a poor prognostic sign with up to 50% 8-year mortality.
| Treatment Options|| |
Treatment strategies for SIBO include prokinetics, probiotics, and antibiotics [Table 1].
|Table 1: Summary table of features, investigations, and treatment of small intestinal bacterial overgrowth|
Click here to view
Data for the treatment of SIBO in SSc are limited and guidelines for treatment of SIBO in SSc have been extrapolated from SIBO in other populations. The most recent EULAR recommendations for GI manifestations of SSc are from 2009 and recommend prokinetics for symptomatic motility issues and rotating antibiotics for malabsorption due to SIBO. Prokinetics are motility stimulants and include 5-HT4 agonists (e.g., octreotide and prucalopride); motilin receptor agonists (e.g., erythromycin and azithromycin); dopamine receptor antagonists (e.g., domperidone and metoclopramide).
Metoclopramide is an antagonist of 5-HT3 and dopamine-2 receptors and an agonist for 5-HT4 receptors. It acts at the level of the antrum and small bowel where it promotes intestinal motility. Rarely, it can cause extrapyramidal symptoms such as tardive dyskinesia, agitation, and dystonic reactions. The typical dose is 10 mg PO three times daily.
Domperidone is a dopamine receptor antagonist. Thus, it prevents dopamine from inhibiting the release of acetylcholine in the gut. Acetylcholine release decreases small bowel motility. A number of trials have looked at the effectiveness of domperidone as a motility agent in gastroparesis and shown overall improvement of gastric emptying. Typical dosing would start at 10 mg tid and increase to 20 mg qid. A baseline ECG is required as this medication can increase the QTc interval.
Macrolides act as motilin receptor agonists in the gut, thus improving gastric emptying. Unfortunately, within 2 weeks of using this medication, tachyphylaxis can occur through motilin receptor downregulation. Recently, a small case series demonstrated that erythromycin has been shown to prevent small bowel obstruction recurrence more effectively than metoclopramide or domperidone. Erythromycin also leads to a higher completion rate of small bowel capsule endoscopy than domperidone. Typical oral dose of erythromycin is 100 mg up to 4 times daily or 1 g PO every 3 days. It is metabolized through CYP3A4 and may cause sudden cardiac death if combined with verapamil or diltiazem.
Prucalopride stimulates gut motility through a highly selective serotonin 5-HT4 receptor agonist. It has been studied in three randomized controlled trials which included 620, 641, and 713 patients, respectively.,,, Daily doses of 2-4 mg PO of prucalopride or placebo were provided to patients with chronic constipation. The outcome measure was the number of patients who achieved 3 or more bowel movements a week or at least increased the number of bowel movements per week by at least one. A range of 19.5% to 30.9% of patients were able to achieve this, as compared to 9.6%–12% of patients who received placebo. In patients with SIBO, a dose of 2 mg PO once daily is utilized, which is reduced to 1 mg PO daily if patient age is >65 years of age.
Complete eradication of SIBO along with statistically significant reductions in abdominal pain, nausea, bloating, and emesis was achieved after a 3-week course of the motility agent octreotide. However, the study did not control for the potential confounders of alimentation and other known motility agents. Clinical trials are underway for SIBO management with medications that increase the number of phase III migrating motor complexes, such as 5-HT4 agonists and motilin receptor agonists to potentially decrease rates of SIBO recurrence.
Probiotics have theoretical beneficial effects on mucosal permeability. In a small study of patients with SSc, administration of probiotics resulted in improvement in SIBO symptoms. Ten SSc patients with moderate-to-severe distention and bloating were treated with Bifidobacterium infantis or Lactobacillus and experienced significant improvement in this symptom as well as some improvement in reflux. A meta-analysis on probiotics for patients with SIBO revealed that probiotics significantly reduced bacterial counts (relative risk = 1.61; 95% confidence interval [CI]: 1.19-2.17) and relieved abdominal pain compared to patients not receiving probiotics, although they were not effective at preventing SIBO. The combination of probiotics and rifaximin has been studied in a single retrospective study that revealed an eradication rate for SIBO of 82.6% (95% CI: 61.2–95).
A recent systematic review involving 32 studies and 1331 patients showed efficacy of rifaximin in SIBO, but this was not specific to SSc. Of these studies, ten were amenable to meta-analysis and showed that in patients with eradication of SIBO, 67.7% had resolution or improvement of symptoms (95% CI: 44.7–86.9) with an overall adverse event rate of 4.6% (95% CI: 2.3–7.5).
EULAR recommendations suggest amoxicillin (500 mg 3 times a day orally, during the first month), followed by ciprofloxacin (500 mg twice a day orally, during the second month), and metronidazole (500 mg 3 times a day orally, during the third month). The North American expert consortium suggests 10-14 days of antibiotics followed by a repeat course or different antibiotic if diarrhea returns. Clinicians can choose between the suggested antibiotics including tetracycline 250 mg qid, doxycycline 100 mg bid, minocycline 100 mg bid, amoxicillin-clavulanic acid 875 mg bid, cephalexin 250 mg qid, metronidazole 250 mg tid, ciprofloxacin 500 mg bid, norfloxacin 400 mg bid, or chloramphenicol 250 mg qid. Intravenous immunoglobulin (IVIG) may be a useful therapy early in the pathogenesis of SIBO, as there is some evidence of IVIG neutralizing the anti-M3 acetylcholine antibodies. Pooled human IgG may prevent and reverse cholinergic dysfunction in SSc patients with progressive GI symptoms. Interestingly,in vitro studies have demonstrated that IgG extracted from patients with SSc disrupts neurally mediated acetylcholine release and muscle contraction.
| Summary|| |
SIBO is a common problem in patients with SSc with resultant morbidity and increased mortality. The symptoms are often underrecognized in clinical practice. The pathological process includes autoimmune dysregulation, vasculopathy, neurological damage, and fibrosis resulting in dysmotility and a perfect environment for bacterial overgrowth. If SIBO is clinically suspected, the gold standard for diagnosis is a jejunal aspiration. Typically, surrogate tests such as hydrogen or methane breath tests are employed to diagnose SIBO given the more invasive nature of jejunal aspiration. Blood tests for malabsorption can also support a diagnosis of SIBO. Treatment with prokinetics, probiotics, antibiotics, or a combination of these therapies can help with symptomatic control and possibly with eradication of bacterial overgrowth.
Take home messages
- SIBO is common in patients with SSc, with marked morbidity, and possible mortality
- Pathogenesis relates to immune dysregulation, vasculopathy, and dysmotility
- Investigations include hydrogen breath testing
- There is a paucity of robust clinical studies in the management of SIBO, but there is weak evidence for the use of promotility agents and antibiotics.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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