Small intestinal bacterial overgrowth
Small intestine bacterial overgrowth (SIBO), also termed bacterial overgrowths, or small bowel bacterial overgrowth syndrome (SBBOS), is a disorder of excessive bacterial growth in the small intestine. Unlike the colon (or large bowel), which is rich with bacteria, the small bowel usually has fewer than 10,000 organisms per millilitre. Patients with bacterial overgrowth typically develop symptoms including nausea, bloating, vomiting, diarrhea, malnutrition, weight loss and malabsorption, which is caused by a number of mechanisms.

The diagnosis of bacterial overgrowth is made by a number of techniques, with the gold standard being an aspirate from the jejunum that grows in excess of 105 bacteria per millilitre. Risk factors for the development of bacterial overgrowth include dysmotility; anatomical disturbances in the bowel, including fistulae, diverticula and blind loops created after surgery, and resection of the ileo-cecal valve; gastroenteritis-induced alterations to the small intestine; and the use of certain medications, including proton pump inhibitors.

Small bowel bacterial overgrowth syndrome is treated with an elemental diet or antibiotics, which may be given in a cyclic fashion to prevent tolerance to the antibiotics, sometimes followed by prokinetic drugs to prevent recurrence if dysmotility is a suspected cause.

Signs and symptoms

Bacterial overgrowth can cause a variety of symptoms, many of which are also found in other conditions, making the diagnosis challenging at times. Many of the symptoms are due to malabsorption of nutrients due to the effects of bacteria which either metabolize nutrients or cause inflammation of the small bowel, impairing absorption. The symptoms of bacterial overgrowth include nausea, flatus, constipation, bloating, abdominal distension, abdominal pain or discomfort, diarrhea, fatigue, and weakness. SIBO also causes an increased permeability of the small intestine. Some patients may lose weight. Children with bacterial overgrowth may develop malnutrition and have difficulty attaining proper growth. Steatorrhea, a sticky type of diarrhea where fats are not properly absorbed and spill into the stool, may also occur.

Patients with bacterial overgrowth that is longstanding can develop complications of their illness as a result of malabsorption of nutrients. Anemia may occur from a variety of mechanisms, as many of the nutrients involved in production of red blood cells are absorbed in the affected small bowel.  Iron is absorbed in the more proximal parts of the small bowel, the duodenum and jejunum, and patients with malabsorption of iron can develop a microcytic anemia, with small red blood cells. Vitamin B12 is absorbed in the last part of the small bowel, the ileum, and patients who malabsorb vitamin B12 can develop a megaloblastic anemia with large red blood cells.
In older adults, small bowel bacterial overgrowth is associated with a higher frequency of diarrhea, a lower body mass index, and a significantly lower serum albumin concentration.

Etiology and risk factors

Certain people are more predisposed to the development of bacterial overgrowth because of certain risk factors.  These factors can be grouped into four categories: (1) disordered motility or movement of the small bowel or anatomical changes that lead to stasis, (2) disorders in the immune system, (3) interference with the production of proteolytic enzymes, gastric acid, or bile, and (4) conditions that cause more bacteria from the colon to enter the small bowel.

Absence or impairment of the migrating motor complex (MMC), a cyclical motility pattern in the small intestine, and phase III of the MMC in particular, is associated with the development of SIBO. Problems with motility may either be diffuse, or localized to particular areas. 

MMC impairment may be a result of post-infectious irritable bowel syndrome, drug use, or intestinal pseudo-obstruction among other causes. There is an overlap in findings between tropical sprue, post-infectious irritable bowel syndrome and small intestinal bacterial overgrowth in the pathophysiology of the three conditions and also SIBO can similarly sometimes be triggered by an acute gastrointestinal infection.  Diseases like scleroderma and possibly celiac disease cause diffuse slowing of the bowel, leading to increased bacterial concentrations.  More commonly, the small bowel may have anatomical problems, such as out-pouchings known as diverticula that can cause bacteria to accumulate. After surgery involving the stomach and duodenum (most commonly with Billroth II antrectomy), a blind loop may be formed, leading to stasis of flow of intestinal contents. This can cause overgrowth, and is termed blind loop syndrome. Other anatomic abnormalities such as tumors may also lead to stasis or motility issues. 

Disorders of the immune system can cause bacterial overgrowth. The use of immunosuppressant medications to treat other conditions can cause bacterial overgrowth, as evidenced from animal models.  Other causes include inherited immunodeficiency conditions, such as common variable immunodeficiency, IgA deficiency, and hypogammaglobulinemia. HIV/AIDS is also associated with an increased risk of SIBO.

Systemic or metabolic disorders may lead to conditions allowing bacterial overgrowth as well. For example, diabetes can cause intestinal neuropathy, pancreatitis leading to pancreatic insufficiency can impair digestive enzyme production, and bile may be affected as part of cirrhosis of the liver. Proton pump inhibitors, a class of medication that are used to reduce stomach acid, is associated with an increased risk of developing SIBO.

Finally, abnormal connections between the bacteria-rich colon and the small bowel can increase the bacterial load in the small bowel. Patients with Crohn's disease or other diseases of the ileum may require surgery that removes the ileocecal valve connecting the small and large bowel; this leads to an increased reflux of bacteria into the small bowel.  After bariatric surgery for obesity, connections between the stomach and the ileum can be formed, which may increase bacterial load in the small bowel.

Certain species of bacteria are more commonly found in aspirates of the jejunum taken from patients with bacterial overgrowth. The most common isolates are Escherichia coli, Streptococcus, Lactobacillus, Bacteroides, and Enterococcus species. Proteobacteria, and Enterobacteriaceae in particular, have been especially implicated in small bowel bacterial overgrowth with a reduction in other phyla such as Firmicutes.

Related conditions

In recent years, several proposed links between SIBO and other disorders have been made. However, the usual methodology of these studies involves the use of breath testing as an indirect investigation for SIBO. Breath testing has been criticized by some authors for being an imperfect test for SIBO, with multiple known false positives.

Irritable bowel syndrome
Some studies reported up to 80% of patients with irritable bowel syndrome (IBS) have SIBO (using the hydrogen breath test). IBS-D is associated with elevated hydrogen numbers on breath tests while IBS-C is associated with elevated methane numbers on breath tests. Subsequent studies demonstrated statistically significant reduction in IBS symptoms following therapy for SIBO. 

Various mechanisms are involved in the development of diarrhea and IBS-D in bacterial overgrowth. First, the excessive bacterial concentrations can cause direct inflammation of the small bowel cells, leading to an inflammatory diarrhea. The malabsorption of lipids, proteins and carbohydrates may cause poorly digestible products to enter into the colon.  This can cause diarrhea by the osmotic drive of these molecules, but can also stimulate the secretory mechanisms of colonic cells, leading to a secretory diarrhea.

There is a lack of consensus however, regarding the suggested link between IBS and SIBO. Other authors concluded that the abnormal breath results so common in IBS patients do not suggest SIBO, and state that "abnormal fermentation timing and dynamics of the breath test findings support a role for abnormal intestinal bacterial distribution in IBS." There is general consensus that breath tests are abnormal in IBS; however, the disagreement lies in whether this is representative of SIBO. More research is needed to clarify this possible link.

Fibromyalgia
Fibromyalgia is a poorly understood pain condition. Lactulose breath testing has shown that patients with fibromyalgia have a more pronounced degree of abnormal results compared to both IBS patients and the general population. This study also demonstrated positive correlation between the amount of pain and the degree of abnormality on the breath test. A subsequent study also demonstrated increased prevalence of intestinal hyperpermeability, which some believe occurs commonly with SIBO. One study showed that nearly all fibromyalgia sufferers have unidentified airway constriction during sleep in the form of upper airway resistance syndrome (UARS)--which is known to cause similar symptoms to fibromyalgia. One explanation being that it results from airway inflammation (as indicated by high tumor necrosis factor alpha (TnF-A) readings) caused directly or indirectly by SIBO and/or altered intestinal permeability. More research into this possible link is needed.

Rosacea
Intestinal bacteria may play a causal role in the dermatological condition rosacea.  A recent study subjected patients to a hydrogen breath test to detect the occurrence of SIBO.  It was found that significantly more patients were hydrogen-positive than controls indicating the presence of bacterial overgrowth (47% v. 5%, p<0.001).

Hydrogen-positive patients were then given a 10-day course of rifaximin, a non-absorbable antibiotic that does not leave the digestive tract and therefore does not enter the circulation or reach the skin.  96% of patients experienced a complete remission of rosacea symptoms that lasted beyond 9 months.  These patients were also negative when retested for bacterial overgrowth.  In the 4% of patients that experienced relapse, it was found that bacterial overgrowth had returned.  These patients were given a second course of rifaximin which again cleared rosacea symptoms and normalized hydrogen excretion.

In another study, it was found that some rosacea patients that tested hydrogen-negative were still positive for bacterial overgrowth when using a methane breath test instead.  These patients showed little improvement with rifaximin, as found in the previous study, but experienced clearance of rosacea symptoms and normalization of methane excretion following administration of the antibiotic metronidazole, which is effective at targeting methanogenic intestinal bacteria.

These results suggest that optimal antibiotic therapy may vary between patients and that diverse species of intestinal bacteria appear to be capable of mediating rosacea symptoms.

This may also explain the improvement in symptoms experienced by some patients when given a reduced carbohydrate diet.  Such a diet would restrict the available material necessary for bacterial fermentation and thereby reduce intestinal bacterial populations.

Diagnosis

The diagnosis of bacterial overgrowth can be made by physicians in various ways. Malabsorption can be detected by a test called the D-xylose test.  Xylose is a sugar that does not require enzymes to be digested. The D-xylose test involves having a patient drink a certain quantity of D-xylose, and measuring levels in the urine and blood; if there is no evidence of D-xylose in the urine and blood, it suggests that the small bowel is not absorbing properly (as opposed to problems with enzymes required for digestion).

The gold standard for detection of bacterial overgrowth is the aspiration of more than 105 bacteria per millilitre from the small bowel. The normal small bowel has less than 104 bacteria per millilitre. Some experts however, consider aspiration of more than 103 positive if the flora is predominately colonic type bacteria as these types of bacteria are considered pathological in excessive numbers in the small intestine. The reliability of aspiration in the diagnosis of SIBO has been questioned as SIBO can be patchy and the reproducibility can be as low as 38 percent. Breath tests have their own reliability problems with a high rate of false positive. Some doctors factor in a patients' response to treatment as part of the diagnosis.

Breath tests have been developed to test for bacterial overgrowth. These tests are either based on bacterial metabolism of carbohydrates to hydrogen, methane, or hydrogen sulfide, or based on the detection of by-products of digestion of carbohydrates that are not usually metabolized. The hydrogen breath test involves having the patient fast for a minimum of 12 hours then having them drink a substrate usually glucose or lactulose, then measuring expired hydrogen and methane concentrations typically over a period of several hours.  It compares well to jejunal aspirates in making the diagnosis of bacterial overgrowth. Carbon-13 (13C) and carbon-14 (14C) based tests have also been developed based on the bacterial metabolism of D-xylose.  Increased bacterial concentrations are also involved in the deconjugation of bile acids.  The glycocholic acid breath test involves the administration of the bile acid 14C glychocholic acid, and the detection of 14CO2, which would be elevated in bacterial overgrowth.

Blood tests may check for the anti-CdtB and anti-vinculin biomarkers which are highly specific, but have low sensitivity, and may thus rule in, but not rule out, a diagnosis.

Some patients with symptoms of bacterial overgrowth will undergo upper endoscopy, or visualization of the stomach and duodenum with an endoscopic camera.  Biopsies of the small bowel in bacterial overgrowth can mimic those of celiac disease, making the diagnosis more challenging.  Findings include blunting of villi, hyperplasia of crypts and an increased number of lymphocytes in the lamina propria.

MR enterography may detect small bowel strictures without the use of radiation. Capsule endoscopy may then be used to detect small bowel transit time if no strictures are found. Antroduodenal manometry may also be used to evaluate motility. However, it is a more difficult test for patients to endure and is not as widely available.

However, some physicians suggest that if the suspicion of bacterial overgrowth is high enough, the best diagnostic test is a trial of treatment.  If the symptoms improve, an empiric diagnosis of bacterial overgrowth can be made.

Treatment
Bacterial overgrowth is usually treated with a course of antibiotics although whether antibiotics should be a first line treatment is a matter of debate. Some experts recommend probiotics as first line therapy with antibiotics being reserved as a second line treatment for more severe cases of SIBO. Prokinetic drugs are other options but research in humans is limited. A variety of antibiotics, including tetracycline, amoxicillin-clavulanate, metronidazole, neomycin, cephalexin and trimethoprim-sulfamethoxazole have been used; however, the best evidence is for the use of rifaximin.

A course of one week of antibiotics is usually sufficient to treat the condition. However, if the condition recurs, antibiotics can be given in a cyclical fashion in order to prevent tolerance.  For example, antibiotics may be given for a week, followed by three weeks off antibiotics, followed by another week of treatment.  Alternatively, the choice of antibiotic used can be cycled.

The condition that predisposed the patient to bacterial overgrowth should also be treated. For example, if the bacterial overgrowth is caused by chronic pancreatitis, the patient should be treated with coated pancreatic enzyme supplements.

If IBS or motility issues are present, it is recommended to wait 4-5 hours between meals in order to allow phase III of the migrating motor complex to become active.

Probiotics are bacterial preparations that alter the bacterial flora in the bowel to cause a beneficial effect. Animal research has demonstrated that probiotics have barrier enhancing, antibacterial, immune modulating and anti-inflammatory effects which may have a positive effect in the management of SIBO in humans. Lactobacillus casei has been found to be effective in improving breath hydrogen scores after 6 weeks of treatment presumably by suppressing levels of a small intestinal bacterial overgrowth of fermenting bacteria. The multi-strain preparation VSL#3 was found to be effective in suppressing SIBO. Lactobacillus plantarum, Lactobacillus acidophilus, and Lactobacillus casei have all demonstrated effectiveness in the treatment and management of SIBO. Conversely, Lactobacillus fermentum and Saccharomyces boulardii have been found to be ineffective. A combination of Lactobacillus plantarum and Lactobacillus rhamnosus has been found to be effective in suppressing bacterial overgrowth of abnormal gas producing organisms in the small intestine.

Probiotics are superior to antibiotics in the treatment of SIBO. A combination of probiotic strains has been found to produce better results than therapy with the antibiotic drug metronidazole and probiotics have been found to be effective in treating and preventing secondary lactase deficiency and small intestinal bacteria overgrowth in individuals suffering from post-infectious irritable bowel syndrome. Probiotics taken in uncomplicated cases of SIBO can usually result in the individual becoming symptom free. Probiotic therapy may need to be taken continuously to prevent the return of overgrowth of gas producing bacteria. A study by the probiotic yogurt producer Nestlé found that probiotic yogurt may also be effective in treating SIBO with evidence of reduced inflammation after 4 weeks of treatment.

An elemental diet has been shown to be highly effective for eliminating SIBO with a two-week diet demonstrating 80% efficacy and a three-week diet demonstrating 85% efficacy. An elemental diet works via providing nutrition for the individual while depriving the bacteria of a food source. Additional treatment options include the use of prokinetic drugs such as 5-HT4 receptor agonists or motilin agonists to extend the SIBO free period after treatment with an elemental diet or antibiotics. A diet void of certain foods that feed the bacteria can help alleviate the symptoms. For example, if the symptoms are caused by bacterial overgrowth feeding on indigestible carbohydrate rich foods, following a FODMAP restriction diet may help.