INTRODUCTION — Small intestinal bacterial overgrowth (SIBO) is a condition in which colonic bacteria are seen in excess in the small intestine. When present, this overabundance of organisms can result in intestinal symptoms and, in extreme cases, malabsorption.
This topic will review the etiology and pathogenesis of SIBO. The clinical manifestations, diagnosis, and treatment of SIBO are discussed separately. (See "Small intestinal bacterial overgrowth: Clinical manifestations and diagnosis" and "Small intestinal bacterial overgrowth: Management".)
INTESTINAL MICROBIOME
Overview — The stomach and proximal small bowel normally contain relatively few bacteria due to the presence of gastric acidity and the effects of peristalsis. Lactobacilli, enterococci, gram-positive aerobes, or facultative anaerobes predominate in concentrations of 104 organisms/mL in the mid to distal jejunum [1]. The concentration of coliforms rarely exceeds 103 organisms/mL [2]. Bacteroides, the predominant organism in the colon, is rarely found in the proximal small bowel.
The microbiology of the terminal ileum represents an intermediary zone between the aerobic flora found in the stomach and proximal small bowel and the dense population of anaerobic organisms found in the colon. The concentration of organisms may be as high as 109/mL and includes enterobacteria and other coliforms. If the ileocecal valve is dysfunctional or surgically absent, the microbiology of the terminal ileum resembles that of the colon. (See "Spatial organization of intestinal microbiota in health and disease", section on 'Stomach and duodenum'.)
In the colon, the concentration of microorganisms may exceed 1012/mL. The organisms are predominantly anaerobes such as Bacteroides, Lactobacillus, Clostridium, and bifidobacteria, although multiple species coexist. (See "Spatial organization of intestinal microbiota in health and disease", section on 'Bacteria in the colon'.)
Protective mechanisms against bacterial overgrowth — Several host defense mechanisms prevent excessive colonization by bacteria:
●Gastric acid and bile (as a detergent) destroy many microorganisms in ingested food and prevent them from passing through the proximal digestive tract.
●Digestion by proteolytic enzymes helps destroy bacteria in the small intestine.
●An intact ileocecal valve and the antegrade motility pattern of the ileum inhibit retrograde translocation of bacteria from the colon to the small bowel [3,4].
●The largest fraction of immunoglobulins secreted in the human body is the secretory IgA originating in the gastrointestinal tract, which aids in preventing bacterial proliferation [5]. (See "Structure and biologic functions of IgA".)
EPIDEMIOLOGY — The exact prevalence of small intestinal bacterial overgrowth is unclear. However, intestinal motility disorders, including irritable bowel syndrome and chronic pancreatitis, are estimated to account for approximately 90 percent of cases [6-8]. (See "Pathophysiology of irritable bowel syndrome", section on 'Bacterial overgrowth' and "Chronic pancreatitis: Clinical manifestations and diagnosis in adults".)
ETIOLOGY — Disorders that affect one or more of the protective mechanisms can lead to small intestinal bacterial overgrowth (SIBO). In general, SIBO can be divided into categorical causes as follows:
Functional and motility disorders — The classic mechanism for cleansing the small bowel of debris and preventing SIBO is the migrating motor complex (MMC) and in particular, phase III of the MMC [9]. A lack of interdigestive phase III activity is seen in irritable bowel syndrome, narcotic use, intestinal pseudo-obstruction, and diabetes. Small bowel motility may be affected in patients with acute or chronic radiation enteritis. More extreme motility disorders, such as scleroderma, can progress to include neuropathy and even myopathy of the gut, which further reduce flow, leading to SIBO [10-14]. (See "Treatment of irritable bowel syndrome in adults", section on 'Antibiotics' and "Pathophysiology of irritable bowel syndrome", section on 'Bacterial overgrowth'.)
Anatomic disorders — Anatomic abnormalities can lead to SIBO by causing stasis. Anatomic disorders associated with SIBO include adhesions from previous surgery; strictures due to radiation, inflammatory bowel disease, or tumors of the small bowel; small intestinal diverticulosis; blind intestinal loops; reversed segments; and gastric bypass for the treatment of obesity [15].
Metabolic and systemic disorders — Diabetes mellitus can cause SIBO due to intestinal neuropathy. Disorders such as pancreatic insufficiency and cirrhosis can predispose to SIBO by changing the quantity and composition of these digestive enzymes or bile, thereby allowing microbes to grow. (See "Diabetic autonomic neuropathy of the gastrointestinal tract", section on 'Diabetic diarrhea'.)
Immune disorders — Combined variable immunodeficiency, IgA deficiency, and acquired immunodeficiency (eg, HIV) are associated with an increased risk of SIBO. Intestinal immunity is important in maintaining the correct microbial composition in the small intestine. Pathogenic bacteria may be able to dampen the local immune system, hence disrupting normal gastrointestinal function [16]. (See "Gastrointestinal manifestations in primary immunodeficiency".)
PATHOPHYSIOLOGY
Bacterial overgrowth — Small intestinal bacterial overgrowth (SIBO) is usually associated with abnormally high bacterial populations in the small intestine. However, the presence of excess numbers of bacteria in the small bowel does not identify whether or not the bacteria are doing any harm, a point that is often misunderstood. Inflammation that occurs in patients with clinical manifestations of SIBO is likely due to invasive strains of bacteria, which result in a variety of epithelial changes [16]. Multiple organisms are typically present in varying numbers. Studies suggest that three main organisms are responsible for SIBO and include Escherichia coli, Klebsiella spp, and Aeromonas [14].Other common species include streptococci, Bacteroides, and Lactobacillus [17].
Facultative anaerobes may injure the intestinal surface by direct adherence and production of enterotoxins. Aerobic bacteria produce enzymes and metabolic products that are also capable of inducing epithelial cell injury [18]. Clinically significant SIBO is diagnosed when bacterial counts exceed 103 organisms/mL in a patient with typical clinical features (eg, abdominal pain, bloating, diarrhea) [2,19]. (See "Small intestinal bacterial overgrowth: Clinical manifestations and diagnosis", section on 'Jejunal aspirate culture'.)
Intestinal effects
Motility and nutrient absorption — Impaired absorption of nutrients in SIBO results from either maldigestion in the intestinal lumen, or from malabsorption at the level of the intestinal microvillus membrane due to enterocyte damage. However, it is notable that malabsorption is usually seen in only severe cases of SIBO, usually due to iatrogenic SIBO such as blind loop syndrome [19].
●Fat malabsorption – Fat malabsorption can lead to weight loss, steatorrhea, and deficiencies of fat-soluble vitamins A, D, and K. Fat malabsorption results from bacterial deconjugation of bile acids and the toxic effect of free bile acids on the intestinal mucosa [20,21]. At physiologic pH, bile acids are fully ionized, preventing their absorption in the proximal small intestine and permitting sufficient concentrations for solubilization of dietary fat. However, deconjugated bile salts resulting from SIBO are reabsorbed by the jejunum, which may lead to insufficient concentrations for normal fat absorption. Bacterial deconjugation also leads to the production of lithocholic acid, which may be toxic to intestinal epithelium, resulting in impaired absorption of fat and other nutrients. Hydroxylated fatty acids (and free bile acids) also stimulate the secretion of water and electrolytes, leading to diarrhea. (See "Small intestinal bacterial overgrowth: Clinical manifestations and diagnosis", section on 'Clinical features'.)
●Carbohydrate malabsorption – Intraluminal degradation of carbohydrates leads to the production of short-chain fatty acids (butyrate, propionate, acetate, lactate) as well as carbon dioxide, hydrogen, and methane, which may be associated with acidic stools, abdominal distension, and flatulence. In addition, enterocyte damage from the effect of bile acids or from the bacteria themselves may reduce enterocyte disaccharidase activity and the transport of monosaccharides [22].
●Protein malabsorption – Protein malabsorption results from decreased mucosal uptake of amino acids, and the intraluminal degradation of protein precursors by bacteria [23]. SIBO may also result in a reversible form of protein-losing enteropathy [24]. (See "Protein-losing gastroenteropathy".)
●Vitamin B12 malabsorption – Although enteric bacteria synthesize cobalamin, they also successfully compete with the host for its absorption. Only anaerobes are able to utilize vitamin B12 coupled to intrinsic factor, and their eradication is necessary to restore normal ileal absorption. Malabsorption of vitamin B12 may result in anemia and neurologic disturbances. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies" and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)
Bacteria also synthesize folic acid. Unlike cobalamin, however, folic acid is released into the small bowel lumen, where it can be absorbed. Thus, patients with SIBO rarely have folate deficiency.
Bacterial overgrowth may also disturb small bowel motility, causing nausea, anorexia, and bloating [25].
Morphology and histopathology — The endoscopic appearance and histopathology of the small intestine and colon are normal in most patients with SIBO. Nonspecific changes in the small intestine and colon include mucosal edema, loss of normal vascular pattern, patchy erythema, friability, and, in rare cases, ulceration may be seen [26-28].
Histopathological changes in patients with SIBO are also nonspecific and include villous blunting, cryptitis, intraepithelial lymphocytosis, and eosinophilia [29].
Systemic effects — Production of toxins and increased intestinal permeability in SIBO have been associated with systemic complications.
●Hepatic encephalopathy – Enteric bacteria degrade protein and urea to produce ammonia. Elevated levels of ammonia precipitate hepatic encephalopathy in patients with advanced liver failure. (See "Hepatic encephalopathy: Pathogenesis", section on 'Ammonia'.)
●D-lactic acidosis – D-lactic acidosis is a rare neurologic syndrome in patients with SIBO associated with short bowel syndrome or a prior jejunoileal bypass. It is characterized by altered mental status ranging from confusion to coma, slurred speech, seizures, and ataxia resulting from bacterial fermentation of unabsorbed carbohydrates [30,31]. (See "D-lactic acidosis", section on 'Pathogenesis' and "Small intestinal bacterial overgrowth: Clinical manifestations and diagnosis", section on 'Clinical features'.)
●Nonalcoholic fatty liver disease – Intestinal microbes have been implicated as a potential source of hepatotoxic oxidative injury [32-34]. While some studies have suggested that the prevalence of SIBO may be higher in patients with nonalcoholic steatohepatitis as compared with healthy controls, breath tests were used to establish the diagnosis and total bacterial counts in the feces were not significantly different [35]. Further studies are needed to establish the role of SIBO in the pathogenesis of nonalcoholic fatty liver disease [32]. (See "Pathogenesis of nonalcoholic fatty liver disease", section on 'Intestinal microbes'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Small intestinal bacterial overgrowth".)
SUMMARY
●Small intestinal bacterial overgrowth (SIBO) is a condition in which specific bacteria are present in increased numbers in the small intestine. When present, this overabundance of organisms can result in symptoms such as bloating and diarrhea and, in extreme cases, intestinal inflammation and malabsorption. (See 'Introduction' above.)
●Host mechanisms protect against excessive small intestinal colonization by bacteria. These include the digestion by gastric acid, bile, and proteolytic enzymes; an intact ileocecal valve and antegrade motility pattern of the ileum that inhibit retrograde translocation of bacteria; and secretory IgA, which aids in preventing bacterial proliferation. (See 'Protective mechanisms against bacterial overgrowth' above.)
●The exact prevalence of SIBO is unclear. However, intestinal motility disorders, irritable bowel syndrome, and chronic pancreatitis are estimated to account for approximately 90 percent of cases. (See 'Epidemiology' above.)
●SIBO can occur in association with anatomical abnormalities (eg, diverticula, fistulas, surgical blind loop, ileocecal resections), motility disorders (eg, scleroderma, irritable bowel syndrome), metabolic and systemic disorders (eg, diabetes mellitus, achlorhydria, chronic pancreatitis, cirrhosis) and immune disorders (eg, HIV). (See 'Etiology' above.)
●The nonspecific inflammation that occurs in patients with clinical manifestations of SIBO is likely due to more invasive strains of bacteria, which result in a variety of epithelial changes. Clinically significant SIBO is diagnosed when bacterial counts exceed 103 organisms/mL in a patient with typical clinical features (eg, abdominal pain, bloating, diarrhea). (See 'Pathophysiology' above.)
●Impaired absorption of nutrients in SIBO results from either maldigestion in the intestinal lumen, or malabsorption at the level of the intestinal microvillus membrane due to enterocyte damage. These deficiencies are seen in more extreme cases of SIBO.
•Carbohydrate malabsorption results from the intraluminal degradation of sugars by enteric bacteria. This leads to the production of short-chain fatty acids, carbon dioxide, hydrogen, and methane.
•Fat malabsorption results from bacterial deconjugation of bile acids and the toxic effect of free bile acids on the intestinal mucosa. Hydroxylated fatty acids and free bile acids stimulate the secretion of water and electrolytes, leading to diarrhea.
•Protein malabsorption results from decreased mucosal uptake of amino acids and the intraluminal degradation of protein precursors by bacteria. SIBO may also be associated with a reversible form of protein-losing enteropathy.
•Deficiency in vitamin B12 results from utilization of vitamin B12 coupled to intrinsic factor by anaerobic bacteria.
●Bacterial overgrowth can also disturb small bowel motility, causing nausea, anorexia, and bloating. (See 'Motility and nutrient absorption' above.)
●The endoscopic appearance and histopathology of the small intestine and colon is normal in most patients with SIBO. Nonspecific changes in the small intestine and colon include mucosal edema, loss of normal vascular pattern, patchy erythema, friability, and, in rare cases, mucosal ulceration. Histopathologic changes in extreme cases associated with SIBO include villous blunting, cryptitis, intraepithelial lymphocytosis, and eosinophilia. (See 'Morphology and histopathology' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jon Vanderhoof, MD, and Rosemary Pauley-Hunter, NP-C, who contributed to an earlier version of this topic review.
