Bacterial Overgrowth Syndrome

Bacterial overgrowth syndrome (BOS) is a term that describes clinical manifestations that occur when the normally low number of bacteria that inhabit the stomach, duodenum, jejunum, and proximal ileum significantly increases or becomes overtaken by other pathogens.

The upper intestinal tract once was thought to be a sterile environment; however, low concentrations of various bacteria are now widely accepted to live within or attached to its luminal surface. These bacteria are thought to be present from the time of birth and through adulthood, living in symbiosis with the human host. This relationship is thought to be vital for normal digestive processes, immunity, and intestinal development. Bacterial species usually present include lactobacilli, enterococci, oral streptococci, and other gram-positive aerobic or facultative anaerobes.

Various etiologic processes can disrupt mechanisms that keep the number of these bacteria low. These include structural abnormalities (congenital or surgical) and disorders that cause decreased gastric acidity, reduced peristaltic activity, and mucosal damage or atrophy. The clinical manifestations of bacterial overgrowth syndrome stem from the increased bacterial burden on the normal functions of the upper GI system. Prompt recognition and treatment of bacterial overgrowth syndrome should be targeted to prevent and reverse malabsorptive processes.

Normally, colony counts of gram-positive bacteria and fungi in the duodenum and jejunum are less than 1X105 organisms/mL. Anaerobic bacteria are not found in the jejunum in healthy people. As many as one third of jejunal aspirates may be sterile in healthy people. Aerobic and anaerobic bacterial colony counts in the ileum usually are less than 1 X 108 organisms/mL. This is in sharp contrast to the 1 X 1011 organisms/mL that colonize the colon. Prevalence of bacteria in different parts of GI tract depends on several factors such as peristalsis, pH, redox potential, bacterial adhesion, bacterial cooperation and antagonism, mucin secretion, diet, and nutrient availability.[1]

Studies of duodenal aspirates have not identified any particular bacteria as a cause of bacterial overgrowth syndrome. However, 1 X 1011 organisms/mL of aspirate fluid is diagnostic for bacterial overgrowth syndrome. Cultures grown from patients with bacterial overgrowth syndrome reveal abnormally large numbers of anaerobic bacteria in addition to normal flora.

Several protective factors stabilize the number and type of bacteria that colonize the upper GI tract. Abnormalities in these mechanisms predispose to bacterial overgrowth.

Two coordinated motor phenomena produce the continuous propulsive peristaltic action of the upper GI tract. Both the migrating motor complex and the migrating action potential complex clear the upper intestine of unwanted bacteria and undigested substances. Desynchronization of these complexes results in diarrhea and weight loss in animal models. Anatomic defects can reduce peristaltic efficacy; for example, blind pouches result in a stagnant portion of the intestine.

Gastric acid and bile destroy many micro-organisms before they leave the stomach.

Enzymatic activity of intestinal, pancreatic, and biliary secretions help destroy bacteria in the small intestine.[2]

The bowel mucosal integrity and mucin layer protect the gut from bacteria.

Immunoglobulin secretion and immune cells (eg, macrophages and lymphocytes) protect the gut from bacteria.

Normal intestinal flora (eg, Lactobacillus) protects the gut from bacterial overgrowth by maintaining a low pH; however, normal flora can facilitate an abnormal intraluminal environment. Abnormal communications produce pathways that allow enteric bacteria to pass between the proximal and distal bowel.

Ileocecal valve prevents retrograde translocation of bacteria from the colon to the small intestine. If the integrity of the valve is compromised or the valve surgically removed, the burden of microbes found in the terminal ileum increases, resembling the heavy burden typically seen in the colon.[2]

Malabsorption of bile acids, fats, carbohydrates, proteins, and vitamins results in direct damage to the lining of the luminal surface by bacteria or by transformation of nutrients into toxic metabolites, leading to many of the symptoms of diarrhea and weight loss associated with bacterial overgrowth syndrome. This leads to decreased function of the enterocytes within the intestinal lining and subsequent malabsorption. Diarrhea is potentiated by unabsorbed food products stimulating secretory cells within the colon.

Anaerobes such as Bacteroides fragilis actively deconjugate bile acids, thereby preventing proper bile acid function and enterohepatic circulation.

Fatty acid absorption is reduced because deconjugated bile acids cannot form micelles.

Deconjugated bile acids directly inhibit carbohydrate transporters. These unabsorbed sugars ferment into organic acids, thereby reducing the intraluminal pH and producing osmotic diarrhea. The unconjugated bile acids also damage intestinal enterocytes and induce water secretion by the colonic mucosa.

Loss of bile acids in the stool reduces the bile acid pool.

Frequency

The exact prevalence of bacterial overgrowth syndrome is likely underestimated because the clinical manifestations overlap with those of many other malabsorptive and diarrheal disorders. Higher clinical suspicion should be given to individuals with underlying disorders that disrupt the known protective elements that prevent bacterial overgrowth syndrome. For example, approximately 20-43% of chronic diarrhea cases in patients with diabetes, as well as 50% in neonates, may be associated with bacterial overgrowth syndrome.[3] In many cases, gastric and upper intestinal tract surgery results in bacterial overgrowth syndrome; however, preservation of the normal anatomy and antroduodenal vagal innervation appear to be protective.

The prevalence of bacterial overgrowth syndrome varies depending on the population studied and the diagnostic methods used. In healthy people, BOS has been described in 0-12.5% by the glucose breath test, 20-22% by the lactulose breath test, and 0-35% when the14 C D-xylose breath test is used.[4] Bacterial overgrowth syndrome is more prevalent in elderly population because of diminished gastric acid secretion and consumption of a large number of medications that can cause hypomotility. BOS has also been described as a cause of occult malabsorption in elderly patients.[5]

Mortality/Morbidity

Bacterial overgrowth syndrome can lead to worsening symptoms of malabsorption and diarrhea. In certain patient subgroups, bacterial overgrowth syndrome can lead to significant morbidity or death. However, exact mortality rates directly linked to bacterial overgrowth syndrome are not readily available.

Patient populations at an increased risk for mortality due to bacterial overgrowth syndrome include the following:

• Neonates and young infants who are already malnourished or have congenital GI abnormalities

• Elderly patients with multiple medical problems and those who have underlying chronic diarrhea without known bacterial overgrowth syndrome

• Patients who have undergone prior upper intestinal surgery that alters the protective mechanisms that prevent bacterial overgrowth syndrome

• Patients with poor nutritional status at presentation

• Patients with underlying medical conditions such as diabetes and scleroderma, who are at risk for relapse if the underlying medical condition is not corrected or managed

If bacterial overgrowth syndrome is the result of an underlying medical problem that cannot be controlled, relapse will occur, with symptom-free periods.

Patients with chronic diarrhea should be educated on avoidance of food products that may exacerbate symptoms. Patients with bacterial overgrowth syndrome should document which foods cause their diarrhea, as this can vary among patients. Some examples of such foods are those high in carbohydrates such as fruits and fruit juices, spicy food, milk-containing products, fried food, and high-fat foods.

Patients also should be educated on early detection of symptoms such as diarrhea to avoid malabsorption.

In high-risk patients (eg, neonates and elderly patients), early recognition is challenging. Education should be extended to the primary care givers in this situation.

No specific symptoms are pathognomonic for bacterial overgrowth syndrome (BOS). Nonetheless, various nonspecific GI symptoms are common in affected individuals. Clinicians should have a heightened clinical suspicion for bacterial overgrowth syndrome in patients who present with the following:

• Bloating

• Flatulence

• Abdominal pain

• Diarrhea

• Dyspepsia

• Weight loss

Advanced cases of bacterial overgrowth syndrome may manifest as malabsorption findings, as follows:

• Microcytic anemia due to iron deficiency

• Macrocytic anemia due to vitamin B-12/folate deficiency

• Polyneuropathy due to vitamin B-12 deficiency

• Steatorrhea due to lipid malabsorption

• Tetany due to hypocalcemia

• Night blindness due to vitamin A deficiency

• Dermatitis due to selenium deficiency

• Bacterial overgrowth syndrome has been linked to rosacea[6]

• Cachexia due to protein-energy malnutrition

Disorders or structural abnormalities that disrupt the protective mechanisms that guard against increasing bacterial burden can lead to bacterial overgrowth syndrome.

Patients with the following medical conditions are at increased risk for bacterial overgrowth syndrome:

• History of upper intestinal tract surgery

• Irritable bowel syndrome[7]

• Liver cirrhosis[2, 4]

• Celiac disease[8, 9]

• Immune deficiency (eg, AIDS, IGA deficiency, severe malnutrition)[2, 4]

• Short bowel syndrome[2]

• End stage renal disease[4]

• Gastrojejunal anastomosis

• Vagotomy, but not selective parietal cell vagotomy

• Antral resection

• Pancreatic exocrine insufficiency

Abnormal small intestinal motility due to the following may result in bacterial overgrowth syndrome:

• Diabetic autonomic neuropathy

• Scleroderma

• Pseudo-obstruction

• Amyloidosis

• Neurological diseases (eg, myotonic dystrophy, Parkinson disease)

• Radiation enteritis[2, 4]

• Crohn disease[2, 4]

• Hypothyroidism

Blind pouches from the following may result in bacterial overgrowth syndrome:

• Side-to-side or end-to-side anastomoses

• Intra-abdominal reservoirs

• Duodenal or jejunal diverticula

• Segmental dilatation of the ileum

• Blind loop syndrome

• Biliopancreatic diversion

• Chagasic megacolon

Abnormal bowel communication due to the following may cause bacterial overgrowth syndrome:

• Gastrocolic fistulae

• Jejunal-colic fistulae

Partial obstruction caused by the following may result in bacterial overgrowth syndrome:

• Strictures

• Adhesions

• Abdominal masses

• Leiomyosarcoma

Reduced gastric acid secretion from the following may result in bacterial overgrowth syndrome:

• Achlorhydria

• Vagotomy

• Long-term administration of proton pump inhibitors[10]

Prevalence of BOS rises with age.[4, 11]

A complete physical examination should be performed with emphasis on abdominal examination and examination for signs of malabsorption of various nutrients. No specific physical examination techniques are required for bacterial overgrowth syndrome.

Complications of bacterial overgrowth syndrome are possible in patients with prolonged and untreated symptoms, potentially leading to increased morbidity and mortality in higher-risk patients (eg, the very young and elderly).

Malabsorption of iron, vitamin B-12, and folate can lead to anemia

Persistent diarrhea can lead to volume loss and electrolyte disturbances.

Decreased fat absorption can lead to further diarrhea.

Bacterial overgrowth syndrome (BOS) diagnostic testing should include a workup for diarrhea, anemia, and malabsorption. In the past, retrieval of aspirates from the small intestine itself during endoscopy was the diagnostic tool of choice; however, its use was limited due to low specificity.

Standard anemia workup and nutritional evaluation are indicated.

Stool analysis can help detect abnormal stool components. The pH may be acidic, and reducing substance may be present in the stool.

D-lactic acidosis syndrome can result from carbohydrate fermentation. Lactic acid levels may need to be measured and, if elevated, monitored. D-lactic acid levels, measured in the blood or urine, can help differentiate bacterial overgrowth syndrome from other metabolic causes.

Short-chain fatty acid levels may be elevated in the duodenal fluid but not the stool.[12] Abnormal duodenal short-chain fatty acid levels average approximately 1 µmol/mL, with acetic acid, propionic acid, and n -butyric acid representing 61%, 16%, and 8% of the total, respectively. The average short-chain fatty acid level in a healthy patient is 0.27 µmol/mL, with acetic acid representing 84% of the total.

Keto-bile acid concentration in duodenal fluid is increased and correlates with the type of bacterial overgrowth.[13] The molar percent of keto-bile acids in normal duodenal fluid is very close to 0, while gram-negative aerobic and anaerobic overgrowth is associated with levels of 32 µmol/mL and 11 µmol/mL, respectively.

Urine 4-hydroxyphenylacetic acid levels may be elevated.[14] Enteric bacteria that possess L-amino acid decarboxylase produce 4-hydroxyphenylacetic acid from dietary tyrosine. Increased excretion has been demonstrated in adults with bacterial overgrowth syndrome. Creatinine levels that exceed 120 mg/g are typical in children with small-bowel disease or bacterial overgrowth syndrome, including children with chronic Giardia lamblia gastroenteritis. Children with severe pancreatic dysfunction secondary to cystic fibrosis also have significantly high levels of this metabolite. A 2% false-positive rate and no false-negative results are found when this test is used to screen healthy control subjects and hospitalized children.

Evaluation for malabsorptive processes should include small-bowel follow-through, which is used to evaluate structure and mobility. Strictures, malrotation, diverticulosis, fistulae, and pseudo-obstruction can be found with this technique.

Imaging and examination of the lower GI tract should be considered if upper GI evaluation is nondiagnostic.

Breath tests are used to measure byproducts of bacterial metabolism to identify malabsorbed substances.[15] Several studies suggest that 3 breath tests are of adequate specificity, but these studies are not in full agreement regarding the exact sensitivity. Studies that compare these tests with duodenal bacterial counts suggest that the xylose breath test yields the highest specificity.[16]

Hydrogen breath test

Hydrogen breath tests are based on the fact that in humans hydrogen is exclusively produced by intestinal bacteria, most notably by anaerobic bacteria in the colon of healthy people and also in the small intestine in the case of bacterial overgrowth syndrome. Preoral glucose or lactulose challenge is given before performing hydrogen breath tests. Bacteria ferment malabsorbed carbohydrates. Fermentation releases hydrogen gas that is absorbed and excreted by the lungs.

Under normal conditions, fermenting bacteria reside in the colon. In bacterial overgrowth syndrome, the exhaled hydrogen concentration rises early, corresponding to small intestinal bacteria fermentation of carbohydrates. Under such conditions, a later rise in exhaled hydrogen may also be detected during large bowel fermentation. Antibiotic administration invalidates this test.

For diagnosis, use 1-2 g/kg of glucose, not to exceed 25-50 g. A rise in exhaled hydrogen to 20 parts per million is diagnostic. For diagnosis, use 10 g lactulose. A rise in 20 parts per million above baseline is diagnostic. The specificity and sensitivity of this test are 62.5% and 82% after glucose and 56% and 86% after lactulose administration.[17]

Bile acid breath test

Give glycocholate tagged with carbon 14 with a light meal, and collect breath samples at 2, 4, and 6 hours. An abnormal rise in radioactive carbon dioxide levels indicates bacterial deconjugation of glycocholate.

The specificity and sensitivity of this test are 60-76% and 33-70%, respectively

False positive results may come from disease or resection of terminal ileum, the site of bile absorption. Carbon 14 carries a risk of radiation, which can be problematic in children and pregnant women.[4]

Xylose breath test

Gram-negative bacteria metabolize xylose, resulting in the release of radioactive carbon dioxide. Administer 1 g of D-xylose tagged with carbon 14, as a liquid, after an overnight fast. Measure radioactive breath carbon dioxide at 30, 60, 90, and 120 minutes. An abnormally high carbon dioxide concentration usually is detected within 30-60 minutes. The specificity and sensitivity of this test are 14.3-95% and 40-94%, respectively.[4]

Combination of hydrogen breath test with simultaneous D-xylose breath test results in increase in sensitivity of noninvasive diagnostics of bacterial overgrowth syndrome.[18, 19]

Descending duodenal biopsies performed in a group of elderly individuals with bacterial overgrowth syndrome demonstrated that mean villus height, mean crypt depth, and total mucosal thickness may be reduced. These indices are not significantly different from controls after 6 months of treatment of bacterial overgrowth syndrome. A significant drop in the number of intraepithelial lymphocytes is also seen over this observation period. Mucosal atrophy can result in an 80% reduction of intestinal surface area in infants. Once the offending agent is removed, repair of the small bowel progresses slowly. After 2 months, the villi surface area is 63% normal but the microvillous surface area is only 38% normal.

Quantitative measurement of bacteria from small bowel aspirate culture.

The quantitative measurement of bacteria aspirate obtained from sterial cultures taken from the proximal small bowel can be used in the diagnosis of BOS. Previously, a bacterial colony count of ≥105 colony-forming units per milliliter (CFU/mL)[20]  obtained from a duodenal/jejunal aspirate was considered diagnostic of BOS however, recent guidelines have embraced a bacterial colony count of ≥103 colony-forming units per milliliter (CFU/mL) as diagnostic of BOS according to the North American Consensus.[21]  The use of this technique to establish diagnosis is usually expensive and considered an invasive technique and use of simpler methods should be considered first.

Treatment in bacterial overgrowth syndrome (BOS) should include correction of primary underlying disease if any, including antibiotic therapy and nutritional support. The primary approach should be the treatment of any disease or anatomic defect that potentiated bacterial overgrowth. Many of the clinical conditions associated with bacterial overgrowth syndrome are not readily reversible, and management is based on antibiotic therapy aimed at rebalancing enteric flora. Careful consideration must be taken to prevent total eradication of protective microorganisms. The goal should be directed at reducing symptoms. Initial antibiotic therapy usually is empiric and should be broad and cover both aerobic and anaerobic microorganisms. Community resistance patterns should also be considered.

Rifaximin is currently the mainstay of treatment. Tetracycline was the mainstay of therapy, but its use as a single agent has fallen out of favor in adult patients given community increases in bacterial resistance.

Bacterial sensitivities from duodenal intubations with nonidiopathic bacterial overgrowth syndrome support the use of amoxicillin-clavulanate. Amoxicillin-clavulanate appears to be 75% effective in patients with diabetes.

Studies show that rifaximin eradicates bowel overgrowth syndrome in as many as 80% of patients.[22, 23] Higher doses (1200 or 1600 mg/d) are more effective than standard doses (600 or 800 mg/d).[24] Long-term favorable clinical results have been achieved with rifaximin in patients with irritable bowel and bacterial overgrowth syndrome.[25]

Clindamycin and metronidazole are useful in elderly patients with idiopathic bacterial overgrowth syndrome.

Cholestyramine reduces diarrhea in infants and neonates with intractable diarrhea.[26] Infants with 10-25 days of severe persistent diarrhea for which a cause could not be found despite an extensive infectious and immunologic workup were treated with cholestyramine and gentamicin or metronidazole. Cholestyramine and gentamicin significantly reduced stool weight within 4-5 days of therapy but had mild detrimental effects on fat and nitrogen absorption.

Ciprofloxacin and metronidazole result in normalization of hydrogen breath tests in most patients with Crohn disease.[7]

Norfloxacin, cephalexin, trimethoprim-sulfamethoxazole, and levofloxacin have been recommended for the treatment of bacterial overgrowth syndrome.[4, 27]

The exact length of therapy is not clearly defined; length of therapy should be tailored to symptom improvement. A single 7-10 day course of antibiotic may improve symptoms in 46-90% of patients with bacterial overgrowth syndrome.[28]  Recurrence following therapy is not uncommon and is more likely in elder patients, especially those with history of appendectomy and chronic proton pump inhibitor use. Patients with recurrent symptoms may need repeated (eg, the first 5-10 d of every month) or continuous use of cyclical antibiotic therapy.[4]

Probiotic therapy results in bacterial overgrowth syndrome have been inconclusive and generally not recommended for general clinic use.[2, 29]

Therapeutic use of prokinetics in bacterial overgrowth syndrome due to motility disorders have been tried in many studies. Metoclopramide, cisapride, domperidone, erythromycin, tegaserod, and octreotide have been used; however, data suggest long-term effectiveness is limited.[27]

Nutritional support with dietary modifications such as lactose-free diet, vitamin replacement, and correction of deficiencies in nutrients like calcium and magnesium should be an important part of bacterial overgrowth syndrome treatment, if applicable.

Certain potential underlying abnormalities are amenable to treatment, as follows:

• Infectious diarrhea

• Malnutrition

• Malabsorption

• Hypothyroidism

• Inflammatory bowel disease

• Immunodeficiency

The following potential underlying diseases are not amenable to treatment, but prevention of their progression may be therapeutic:

• Diabetic autonomic neuropathy

• Scleroderma

• Pseudoobstruction

• Amyloidosis

• Achlorhydria

• Vagotomy

In the absence of underlying structural abnormalities that limit normal bowel function, surgery generally is unwarranted.

Repair postoperative strictures and blind loops; for example, a Billroth type II may need conversion to a Billroth type I.

Strictures, fistulae, and diverticula may require surgical correction.

Patients refractory to standard medical or surgical treatment or those who have severe symptoms should be referred to a gastroenterologist/infectious disease specialist for additional workup.

No robust studies have yet properly defined the role of dietary modification in the treatment of bacterial overgrowth syndrome. A low-fiber diet and reduction of fermentable sugars such as sucralose may reduce the occurrence of bacterial overgrowth syndrome, although this potential is extrapolated from results in patients with IBS. There is growing interest in the role of low-FODMAP (fermentable oligo-, di-, mono-saccharides and polyols) diets in bacterial overgrowth syndrome. Studies on the role of FODMAP in patients with IBS found that a low-FODMAP diet was associated with fewer fermentation products, as assessed with a breath test.[30, 31]

Controlling the underlying etiology is an important component of preventing bacterial overgrowth syndrome recurrence. Known underlying medical conditions that predispose to bacterial overgrowth syndrome (eg, diabetes mellitus, scleroderma, alcoholism, cirrhosis, chronic pancreatitis, hypochlorhydria due to atrophic gastritis or medications) need to be optimally controlled. Surgical intervention may be beneficial in patients with anatomic abnormalities such as surgically created blind loops, strictures due to previous surgeries, and conditions such as Crohn disease who continue to have persistent symptoms of bacterial overgrowth syndrome, including unintentional weight loss, diarrhea, and bloating, among others, after adequate treatment. Patients with motility disorders should avoid medications that decrease intestinal motility.

Given the high relapse rate associated with bacterial overgrowth syndrome following antibiotic therapy, some clinicians opt to repeat a second course of antibiotics to reduce the risk for early relapse. A small study suggested that patients who undergo retreatment with antibiotics tend to have a lower relapse rate, although no clear guidelines support this.[32]

Antibiotic prophylaxis usually is reserved for patients who experience multiple relapses (≥4) per year and who are known to have risk factors for recurrence.

The use of probiotics to treat or prevent bacterial overgrowth syndrome has not been well validated. Limited studies support their use. A meta-analysis of small studies found no difference in the incidence of bacterial overgrowth syndrome among the probiotic group versus the control group.[33]

Close-interval follow-up is recommended to ensure that therapy is improving symptoms. It is also not clearly defined whether serial testing for increased bacteria burden is warranted.

Admission criteria for bacterial overgrowth syndrome (BOS) should be based on severity of clinical manifestations at presentation, especially in high-risk individuals.

Only recently have well-established guidelines for the management of bacterial overgrowth syndrome been made available. Treatment has been mostly empirical and extrapolated from diseases with similar clinical presentations, including irritable bowel syndrome, among others.

In February 2020, the American College of Gastroenterology established comprehensive guidelines for the diagnosis and management of small-intestinal bacterial overgrowth.[34]

In 2017, “Hydrogen and Methane-Based Breath Testing in Gastrointestinal Disorders: The North American Consensus” was published and focuses mainly on the diagnosis of suspected bacterial overgrowth syndrome using hydrogen and methane breath tests.[35]

No clinical trials have been conducted to study more effective treatment methods for bacterial overgrowth syndrome.

The goals of pharmacotherapy are to reduce the burden of microorganisms in the intestine rather than achieve complete eradication, to reduce morbidity, and to prevent complications.

Class Summary

Therapy should be directed against B fragilis.

Rifaximin (Xifaxan)

Antibiotic of choice as clinical resistance may be less frequent than with other antibiotics.

Amoxicillin-clavulanic acid (Augmentin)

First-line antibiotic for bacterial overgrowth syndrome due to anatomic abnormalities and diabetes and for elderly patients with idiopathic bacterial overgrowth syndrome. Provides good gram-negative, gram-positive, and anaerobic coverage. Reduces number of bacteria in small bowel lumen.

Clindamycin (Cleocin)

Works well in elderly patients with idiopathic bacterial overgrowth syndrome, especially if bile malabsorption coexists. Good anaerobic and gram-positive coverage, except enterococci.

Metronidazole (Flagyl)

First-line antibiotic for elderly patients with idiopathic bacterial overgrowth syndrome. Provides good anaerobic coverage.

Tetracycline

Effective for patients with bacterial overgrowth syndrome. Provides anaerobic coverage.

Trimethoprim/sulfamethoxazole (Bactrim, Bactrim DS, Cotrim)

Trimethoprim-sulfamethoxazole can be used as alternative antibiotics in both pediatric and adult patients with bacterial overgrowth syndrome. The dose should be adjusted in patients with renal impairment. Sulfamethoxazole and trimethoprim cross the placenta and should be avoided in pregnant women to prevent increased risk of congenital malformations.