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Small Intestinal Bacterial Overgrowth
Introduction
Small intestinal bacterial overgrowth (SIBO) is the presence of excess colonic bacteria in the small intestine. These excess organisms result in multiple intestinal symptoms like abdominal pain, bloating, diarrhea, and rarely malabsorption. [1]. The proximal small intestine typically contains relatively few bacteria due to the presence of stomach acid and the effects of peristalsis. Lactobacilli, enterococci, facultative anaerobes, and gram-positive anaerobes are predominantly organisms in the small intestine. The concentration of organisms rarely exceeds ten organisms/mL in the jejunum. Bacteroids, Lactobacillus, Clostridium, and bifidobacteria, the predominant organisms in the colon, are seldom seen in the proximal small intestine. [2] The terminal ileum microbiome is intermediate between the proximal small intestine (aerobic flora) and colon (densely anaerobic); in the absence of an ileocecal valve terminal ileum, the microbiome is similar to the colon with ten organisms/ml. When the protective mechanisms (peristalsis, stomach acid) against excessive bacterial growth fail, small intestinal bacterial overgrowth (SIBO) can manifest. Due to recent advances in medicine and increased awareness and understanding, SIBO is considered by most clinicians as a differential diagnosis in patients with non-specific gastrointestinal complaints.
Etiology
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Etiology
The etiology of small intestinal bacterial overgrowth is complex. It can be from motility, anatomic, immune, gastric hypochlorhydria, and metabolic and other systemic disorders.
Important host defense mechanisms against bacterial overgrowth in the small intestine are gastric acid and bile, peristalsis, proteolytic digestive enzymes, intact ileocecal valve, and secretory IgA. When these protective barriers fail, SIBO occurs. Gastric acids and bile destroy and prevent bacteria from passing through the intestines after ingesting food. So, SIBO is associated with achlorhydria.[3] Also, proteolytic enzymes digest and degrade bacteria in the intestines. So, chronic pancreatic insufficiency is associated with SIBO.[3] Migrating motor complexes are responsible for peristalsis and cleansing of the small intestine and prevent retrograde translocation of bacteria.[4] SIBO is associated with disorders of abnormal gastrointestinal motility, such as irritable bowel syndrome, narcotic use, post-radiation enteropathy, hypothyroidism, diabetes mellitus, and scleroderma.[3]
An intact ileocecal valve and antegrade motility of the ileum prevent retrograde translocation of colonic bacteria.[5] Anatomic abnormalities lead to stasis of the bowels, which may predispose them to SIBO. Such anatomic disorders may include small intestinal diverticulosis, bowel strictures, post-operative adhesions, gastric bypasses with blind intestinal loops, and ileocecal resection.[3] Lastly, the gastrointestinal tract's secretory immunoglobulin Ig A abundance prevents bacterial proliferation and maintains intestinal immunity. [6] Immunodeficiency disorders, such as acquired immune deficiency syndrome, combined variable immunodeficiency, and IgA deficiency, are associated with an increased risk of SIBO.[7]
Epidemiology
The actual prevalence of small intestinal bacterial overgrowth is vastly unknown. Irritable bowel syndrome, intestinal motility disorders, and chronic pancreatitis are the most predominant cause of SIBO and account for 80-90% of cases. [8] SIBO is more prevalent in the female population and elderly individuals. [9] The incidence of SIBO increases with age, secondary to hypochlorhydria and intestinal dysmotility. In many cases, more than one cause for SIBO can be identified.
Pathophysiology
An abnormally high number of bacteria is identified in SIBO. Overabundant bacteria in the small intestines do not always correlate with disease activity. Clinical manifestations only occur when inflammation from invasive strains of bacteria is present. [7] Invasive strains of bacteria can produce enzymes or endotoxins, which damage the epithelial cell layer, resulting in symptoms. [10]The most common species identified in SIBO are Escherichia coli, Aeromonas, and Klebsiella species. [11] Anaerobes cause direct epithelial injury and produce enterotoxins, whereas aerobes only produce enterotoxins, resulting in intestinal inflammation. [10] Bacterial overgrowth can even affect bowel motility.
In SIBO, the endoscopic and histopathological appearance of the mucosa is usually healthy. Nonspecific endoscopic changes may include mucosal edema, loss of vascularity, patchy erythema, or rarely ulceration.[12] Nonspecific histopathological findings may include villous blunting, cryptitis, intraepithelial lymphocytosis, and eosinophilia.[13]
Histopathology
The endoscopic findings and histopathologic examination of the small intestine and colon mucosa are normal in most cases. Nonspecific endoscopic findings include mucosal edema, erythema, easy friability from abnormal vascular patterns, and rarely ulcerations.[12] Villous blunting, atrophy, increased intraepithelial lymphocytes, and eosinophilia are nonspecific histologic examination findings.[14]
Toxicokinetics
Improper digestion and malabsorption result in small intestinal bowel obstruction symptoms. Fat malabsorption from bacterial deconjugation of bile can lead to weight loss, diarrhea, and vitamin A, D & K deficiencies.[15] Carbohydrate malabsorption causes abdominal distension( from hydrogen, carbon dioxide, and methane), excess flatus, and acidic stool. [16] Decreased mucosal uptake can cause protein malabsorption. Generally, SIBO is associated with normal or elevated folate levels but decreased B12 levels. Vitamin B12 deficiency occurs from ileal mucosal damage to cobalamin binding sites. Vitamin B1 and B3 deficiencies occur due to bacterial overutilization.[17]
History and Physical
The clinical manifestations of small intestinal bacterial overgrowth classically include a combination of abdominal discomfort with bloating, flatulence, or chronic watery diarrhea. Steatorrhea and weight loss from fat malabsorption may also manifest, especially with altered gut anatomy (blind loop syndrome).[18] SIBO causes vitamin deficiencies, specifically B12, causing weakness, sensory ataxia, and paresthesia. Severe Vit D deficiency from malabsorption can present with perioral numbness, hand and feet paresthesia, and muscle cramps from hypocalcemia.
D-lactic acidosis is a rare neurological syndrome that can present with altered mental status, slurred speech, seizures, and ataxia. This syndrome results from bacterial fermentation of unabsorbed carbohydrates. Patients with SIBO associated with short bowel syndrome or a jejunoileal bypass can develop this syndrome.[19] SIBO has been implicated in developing nonalcoholic fatty liver disease and hepatic encephalopathy.[20] Unless severe malnutrition is evident, physical examination in these patients is generally nonrevealing. Rarely succussion splash from fluid-filled lops can be identified.
Evaluation
There is no validated gold standard diagnostic test for SIBO.[2] When a patient presents with signs and symptoms concerning SIBO, the diagnosis garners further support with a positive carbohydrate breath test or a bacterial concentration of more than 1000 colony-forming units/mL in a jejunal aspirate culture.[21] A carbohydrate breath test is a noninvasive, fast, and inexpensive test.[22] The test uses the principle that the metabolism of either lactulose or glucose as its carbohydrate substrate by bacteria will produce either hydrogen or methane. This product will then be absorbed and excreted in the patient's breath.[21] A rise of more than 20 parts per million from baseline in hydrogen within 90 minutes or a methane level of more than ten parts per million are positive results.[21] Results may be falsely positive in patients with short bowel syndrome. Low anaerobic organism counts may result in false negative results. In a review by Romagnuolo J et al., the sensitivity of the glucose breath test is 20-93%, and specificity is 45-86%.[23] The lactose breath test has 17-68% sensitivity and 44-86 % specificity.[24] In an appropriate clinical setting with no risk factors, breath tests can be used for SIBO diagnosis.
A bacterial concentration of less than 10 is diagnostic of SIBO, but it is invasive, time-consuming, and expensive, as it is obtained during an upper endoscopy. The results are also poorly reproducible and can lead to false results from patchy bacterial overgrowth or contamination with oropharyngeal flora.[25] Other laboratory findings that support a diagnosis of SIBO may include vitamin levels and markers of malnutrition.[18] Once there is a suspicion of SIBO, additional testing to identify the etiology merits consideration. Anatomic and mucosal abnormalities can be investigated with abdominal imaging and endoscopies. Testing for disorders of abnormal gastrointestinal motility, pancreatic insufficiency, and immunodeficiencies can be considered case-by-case.[3] Rarely, endoscopy with small bowel biopsy is used.
In patients without specific risk factors for SIBO, upper and lower endoscopies are generally performed to rule out other causes like atrophic gastritis and Crohn disease. If endoscopies are normal, imaging studies are done to rule out partial obstruction, diverticula, fistula, or other inflammatory findings. Magnetic enterography increases the sensitivity of diagnosing small intestinal bowel strictures but is costly.
A thorough evaluation of the cause of SIBO should be worked up, as SIBO is associated with cirrhosis, kidney disease, chronic pancreatitis, and immunodeficiency disorders.[4] Other abnormal laboratory results commonly seen are macrocytic anemia, low B12, thiamine, and niacin levels, elevated folate, vitamin K levels, and increased fecal fat content. Very rarely, microcytic anemia or hypoalbuminemia are reported.
Treatment / Management
The initial mainstay of treatment is antibiotics to eradicate bacterial overgrowth and repletion of any nutritional deficiencies. Metronidazole, ciprofloxacin, tetracycline, amoxicillin-clavulanate, neomycin, and rifaximin are antibiotics used in the treatment, with rifaximin being the most investigated.[26] For patients with hydrogen-predominant bacterial overgrowth, rifaximin 1650 mg/day for two weeks is an effective therapy (Grade 2c).[26] For patients with methane-predominant bacterial overgrowth, combining neomycin 1000 mg/day and rifaximin 1650 mg/day for two weeks is an effective therapy.[27] Associated vitamin and mineral deficiencies (Vitamin B12, iron, thiamine, niacin, and other fat-soluble vitamins) should be treated accordingly.(A1)
Approximately 45 percent of patients will have recurrent SIBO following antibiotic therapy completion, with higher recurrence rates in older adults, post-appendectomy, and chronic use of proton pump inhibitors.[28] In patients with early recurrence, i.e., within three months, the second course of antibiotics is given. In patients with late recurrence beyond three months, antibiotics are provided only with positive carbohydrate breath testing. Recurrent SIBO is treatable either with the same initial or alternating antibiotic.
An elemental diet can be used in cases where patients cannot tolerate antibiotics or fail to respond to antibiotic treatment (after two times). Limited observational studies suggest remission induction of SIBO symptoms, but poor palatability and high cost limit their use. In an observational study, 80% of patients attained remission (normalization of breath tests and resolution of symptoms) within two weeks.[29](B2)
Treating the underlying cause will help in the prevention of recurrent symptoms. Antibiotic prophylaxis (5-10 days every two weeks or monthly) should be reserved for patients with more than 4 episodes in a year. Antibiotics are generally rotated over two to three months. SIBO-associated colitis and ileitis usually should resolve with SIBO treatment. If severe symptoms persist, they should be evaluated for IBD. If symptoms do not improve following two courses of treatment, the clinician should consider alternative diagnoses.[30]
Probiotics, low fermentable oligo, di, and monosaccharide (FODMAP) diet, and statins have no proven role in the resolution of SIBO. Some patients show symptomatic improvement but are not effective alone.
Differential Diagnosis
Diagnoses that produce chronic diarrhea should be in the differential and investigated while evaluating small intestinal bacterial overgrowth. Irritable bowel syndrome (IBS), celiac disease (CD), and inflammatory bowel disease (IBD) all have considerable overlap with SIBO. Irritable bowel syndrome has recurrent abdominal pain related to bowel movements and is associated with a change in stool frequency or appearance.[31] Celiac disease and SIBO have similar clinical symptoms; however, celiac disease will have positive celiac serologies and a negative carbohydrate breath test.[32] Both Crohn disease and SIBO have patchy mucosal inflammation. However, Crohn disease additionally could demonstrate transmural inflammation and granulomas on biopsy and perianal involvement with anal fissures and fistulas.[33]
Prognosis
The prognosis depends on the etiology of the underlying condition, which is causing small intestinal bacterial overgrowth.[3] Most cases have a good prognosis, rarely require hospital admissions, and are associated with complications.
Complications
Severe chronic small intestinal bacterial overgrowth can result in significant weight loss and severe malnutrition, leading to substantial morbidity and mortality. Early recognition of SIBO can treat the maldigestion of nutrients and prevent malnourishment. If left untreated, SIBO can lead to intestinal failure.[34]
SIBO is associated with excess ammonia production and precipitate hepatic encephalopathy in patients with underlying liver disease. SIBO from short bowel syndrome or jejunal bypass can present with D-lactic acidosis (confusion and ataxia from bacterial fermentation of unabsorbed carbohydrates).[19] The role of SIBO in non-alcoholic steatohepatitis is unclear, and further studies are needed.
Consultations
Patients with unexplained chronic diarrhea or signs and symptoms of significant malnutrition should be referred to a gastroenterologist for further evaluation.
Deterrence and Patient Education
Any patients diagnosed with small intestinal bacterial overgrowth should have additional testing to determine the etiology and treatment against the underlying condition to prevent recurrent SIBO. Treatment of disorders associated with abnormal intestinal motility, including Crohn's disease, irritable bowel syndrome, post-radiation enteropathy, diabetes mellitus, hypothyroidism, and scleroderma, should be better optimized and well-controlled. Prokinetics can be useful as adjunctive therapy for these patients.[35] Opioids, which decrease intestinal motility, and proton pump inhibitors, which cause achlorhydria, should be avoided in these patients.[36] Surgical interventions can be considered in patients with anatomical abnormalities who have recurrent SIBO.[35] There is limited research on chronic antibiotic prophylaxis, and probiotics are ineffective in prevention.[37] However difficult to strictly adhere to, there may be a role for an elemental diet.[29]
Enhancing Healthcare Team Outcomes
Small intestinal bacterial overgrowth is an under-recognized condition with significant morbidity and mortality. The optimal management of SIBO is by an interprofessional team of primary care physicians, gastroenterologists, surgeons, dieticians, pharmacists, and nurses. Early recognition leads to more favorable outcomes and can prevent severe malnutrition. Once SIBO is diagnosed and the patient is on antibiotics, further management should be directed at treating the underlying etiology to prevent further recurrences.
Nursing should monitor treatment effectiveness and progress during initial treatment and verify patient compliance. The patient's calorie intake and weight assessments should be frequently monitored during and after treatment to ensure adequate recovery from their illness. Nursing should follow all these areas and report any concerns to the treating clinician. The pharmacist can assist with agent selection, verifying dosing parameters, and performing medication reconciliation. The pharmacist should also work directly with the clinician and nurse regarding potential drug-condition interactions (eg, opioids, PPIs). SIBO management requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists collaborating across disciplines to achieve optimal patient results. [Level 5] The overall outcome depends on the underlying condition's management. If the etiology is not well managed, the overall prognosis is grave.[3] [Level 2]
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