Pathogenesis of acute diarrhea in children

INTRODUCTION — Diarrheal diseases have been a major health problem throughout human history. Prior to the advent of modern medicine, severe diarrhea was often fatal and disease outbreaks spread quickly, affecting large populations. Today, despite the success of interventions such as oral and intravenous rehydration therapy, diarrheal diseases remain a substantial cause of mortality and morbidity worldwide, particularly in children and older adults. Worldwide, more than 500,000 children <5 years died from diarrheal diseases in 2017 [1]. The underlying causes of diarrhea in children are numerous and vary by age and geographical location, among other factors.

Regardless of etiology, the evaluation and management of an infant or child with diarrhea require an understanding of the physiology of fluid and electrolyte transport in the gastrointestinal tract. This topic focuses on the pathophysiology of fluid absorption and secretion in diarrhea and a classification of diarrhea relevant to diagnostic evaluations.

Detailed reviews of the diagnostic approach and management of diarrhea in children are found in the following topics:

●(See "Diagnostic approach to diarrhea in children in resource-abundant settings".)

●(See "Approach to the child with acute diarrhea in resource-limited settings".)

●(See "Persistent diarrhea in children in resource-limited settings".)

●(See "Overview of the causes of chronic diarrhea in children in resource-abundant settings".)

DEFINITIONS

Diarrhea — Diarrhea can be defined using one or both of the following measures:

●Stool frequency or consistency – For practical use in the clinical setting, diarrhea is typically defined by stool frequency and consistency. A common definition is the passage of three or more loose or liquid stools per day, or more frequent passage than is normal for the individual [2]. The Bristol stool chart can be used to codify stool consistency [3,4]. Diarrheal stools typically correspond to types 6 and 7 on the Bristol stool chart [5] (or its slightly modified versions for children [6] or infants [7]).

●Stool weight or volume – In hospital settings where the volume of stools can be measured, diarrhea is defined as stool volume of more than 20 grams/kg/day in infants and toddlers (<10 kg) or more than 250 grams/day in older children or teenagers [8].

Chronic diarrhea — Chronic diarrhea is generally defined as diarrhea lasting greater than four weeks [9]. This timeline is selected to distinguish between the acute diarrheal episode, which tends to be self-limited, and more prolonged diarrheal disease that warrants further evaluation and, possibly, intervention. The term persistent diarrhea is sometimes used to describe diarrhea lasting longer than two weeks; other times, the term is used interchangeably with chronic diarrhea.

FLUID MOVEMENT IN THE GASTROINTESTINAL TRACT

Normal fluid absorption and secretion — Large quantities of fluid are transported bidirectionally across epithelial barriers in the gastrointestinal tract for secretion of saliva, gastric juice, bile, and pancreatic fluid and for fluid absorption in the intestine. The quantity of fluid transported in the intestine is second only to the kidney, where approximately 180 L of fluid per day are filtered by the glomerulus and processed by various nephron segments.

In healthy adults, several liters of fluid are absorbed and secreted by the different segments of the intestine each day (figure 1). The salivary glands produce approximately 1.5 L of fluid per day, the stomach secretes 2.5 L of gastric juice, the liver produces 0.5 L of bile, and the pancreas produces 1.5 L of enzyme- and bicarbonate-rich fluid. To balance this, the small intestine absorbs 6.5 L of fluid and the colon additionally absorbs 1.3 L of fluid against significant osmotic gradients.

The small intestine performs most of the fluid absorption (83 percent) in the gastrointestinal tract. Therefore, diseases that affect the small intestine often result in clinically significant diarrhea. Although the colon absorbs a much smaller volume of fluid than the small intestine, it is critical for the generation of formed feces. The intestinal contents enter the colon with a water content of approximately 90 percent and leave the colon as feces, with a water content of 65 to 75 percent. Therefore, significant alteration of colonic function alone can also lead to clinical diarrhea.

Molecular mechanisms — Movement of fluid between the intestinal lumen and blood is driven by the active transport of ions (mainly Na⁺, Cl^–, HCO₃^–, and K⁺) and nutrients (mainly glucose). Fluid absorption or secretion involves the coordinated activity of membrane transporters located on the apical (lumen-facing) and basolateral (circulation-facing) epithelial membranes. The intestinal epithelium is structurally configured into long, finger-like (in three-dimensional pathologic sections) or leaf-like projections (in two dimensions; villi) and glandular tube-like structures (crypts). The stem cells at the base of the crypt provide various differentiated epithelial cell types, including the more numerous enterocytes that ascend and populate the villus structure. In the small bowel, each villus is supported by as many as 10 distinct crypts. In the colon, the crypts are considerably longer than in the small bowel and produce epithelium that covers a flat luminal surface devoid of villi. Functionally, both ion and fluid absorption and secretion occur in enterocytes located in both villi and crypts, although, in the small intestine, secretory processes predominate in crypts and absorptive processes in villi (figure 2).

Intestinal fluid absorption is driven by the active transport of Na⁺ across the epithelium, with parallel Cl^– or HCO₃^– absorption ( (figure 2), panels A and C). The electrochemical driving force for this process is provided by the basolateral Na⁺/K⁺-ATPase that exports intracellular Na⁺. In the small intestine, fluid absorption is facilitated by the Na⁺/H⁺ exchanger 3 (NHE3 [SLC9A3]), Na⁺/glucose cotransporter 1 (SGLT1 [SLC5A1]), and Cl^–/HCO₃^– exchangers (DRA [SLC26A3] and PAT1 [SLC36A1]). Electroneutral fluid absorption is carried out by the coordinated activity of NHE3 with Cl^–/HCO₃^– exchangers (PAT1 for HCO₃^– absorption in the jejunum and DRA for Cl^– absorption in the ileum and colon). Substrate-specific transporters such as SGLT1 facilitate cotransport of Na⁺ across the apical membrane together with D-glucose (or D-galactose), with the electro-neutral glucose transporter GLUT2 (SLC2A2) facilitating glucose exit across the basolateral membrane. In the colon, in addition to electroneutral Na⁺ transport by Na⁺/H⁺ exchange (proximal colon), absorption is facilitated by the epithelial Na⁺ channel (eNaC [SCNN1]) and short-chain fatty acid transporters (sodium-coupled monocarboxylate transporter, or SMCT [SLC5A8]) [10,11].

Intestinal fluid secretion is driven by transepithelial Cl^– secretion through basolateral and apical Cl^– channels and transporters ( (figure 2), panels B and D). Cl^– is transported into the cell at the basolateral membrane by a Na⁺/K⁺/Cl^- symporter (NKCC1 [SLC12A2]), which is driven by the Na⁺ concentration gradient produced by the Na⁺/ K⁺-ATPase. K⁺ channels (KCNQ1-KCNE3 and KCNN4) provide the electrochemical driving force for apical Cl^– exit across Cl^– channels, which are primarily the cyclic-nucleotide-activated cystic fibrosis transmembrane conductance regulator (CFTR) and Ca²⁺-activated Cl^– channels (CaCCs). Enteric nerves and cell surface receptors such as the calcium-sensing receptor (CaSR) are thought to modulate intracellular signaling pathways and hence electrolyte absorption and secretion [12-14].

Pathophysiology of fluid transport in diarrheal disease

Overview — Water movement in the intestine occurs by osmosis across the semipermeable barrier formed by the lining epithelial cells, similar to other fluid-transporting surfaces in the body. Diarrhea occurs when excessive amounts of fluid remain within the lumen of the intestine (figure 3). This can occur because of increased secretion into the intestinal lumen or reduced absorption of water from the lumen to the body. In either case, there is an increased concentration of osmotically active particles (nutrients and/or electrolytes) within the lumen of the intestine, resulting in a net increase in the water content of the intestinal contents. Increased concentrations of osmotically active particles within the lumen occur through three primary mechanisms:

●Loss of nutrient absorption or the presence of nonabsorbable solutes in the intestinal lumen ( (figure 3), panel B). Examples include the loss of nutrient absorption seen in celiac disease or in inflammation, and diarrhea caused by laxatives such as polyethylene glycol 3350 (PEG 3350). This mechanism underlies diet-induced (previously classified as osmotic) diarrhea, which improves with fasting. (See 'Diet-induced (osmotic)' below.)

●Increased secretion or reduced absorption of electrolytes (Na⁺, Cl^-, K⁺, HCO₃^-) across the epithelium ( (figure 3), panel C). Examples include diarrhea secondary to infection with Vibrio cholerae, which causes excessive secretion of chloride and loss of electroneutral sodium absorption. This mechanism underlies electrolyte transport-related (previously classified as secretory) diarrhea, which fails to improve with fasting. (See 'Mechanisms of altered fluid transport in diarrheal diseases' below and 'Electrolyte transport-related (secretory)' below.)

●Rapid intestinal transit resulting in reduced time for fluid absorption ( (figure 3), panel D). Examples include a variety of conditions that cause hypermotility of the intestine, including the functional diarrhea seen in infants and toddlers (sometimes termed "toddler's diarrhea"). (See 'Motility-related' below and "Overview of the causes of chronic diarrhea in children in resource-abundant settings", section on 'Functional diarrhea in young children'.)

Many of the underlying etiologies of diarrhea in children cause diarrhea through a combination of these primary mechanisms. For example, in inflammatory bowel disease, inflammation causes a loss of absorptive surface area and capacity, causing loss of nutrient transport as well as increasing active Cl^- secretion and intestinal motility.

Mechanisms of altered fluid transport in diarrheal diseases — Alterations in fluid transport between the intestinal lumen and the body underlie many of the causes of diarrheal illness.

Several common diarrheal conditions are characterized by loss of nutrient-driven electrolyte transport. As an example, patients with lactase deficiency are unable to hydrolyze lactose into glucose and galactose. This leads to loss of fluid absorption driven by the Na⁺/glucose co-transporter (SGLT1) and increased osmolality in the intestinal lumen. Lactase deficiency can be either acquired (eg, due to mucosal injury from enteric injury from infection or celiac disease), congenital (loss-of-function mutation in the lactase gene), or genetically driven, age-dependent acquired deficiency (hypolactasia). (See "Lactose intolerance and malabsorption: Clinical manifestations, diagnosis, and management", section on 'Primary lactose malabsorption'.)

Certain enterotoxigenic pathogens cause diarrhea by stimulating fluid secretion. As examples, V. cholerae and enterotoxigenic Escherichia coli release bacterial enterotoxins (cholera toxin, heat-stable enterotoxin), which alter the intracellular levels of second messenger molecules such as cAMP, cGMP, and Ca²⁺ (figure 4) [15]. These signal to the key channels that drive fluid absorption and secretion. Cholera toxin induces elevations in cAMP, leading to activation of the chloride channel CFTR and inhibition of Na⁺ exchanger NHE3, resulting in massive secretory diarrhea. Bacteria can also increase various humoral agonists, neurotransmitters, or neuropeptide receptors such as 5-hydroxytryptamine, vasoactive intestinal peptides and the galanin receptor type 1, also activating Cl^– secretion and inhibiting Na⁺ absorption. Similarly, diarrhea caused by viruses is partly due to the action of viral enterotoxins such as rotavirus NSP4, resulting in intracellular Ca²⁺ elevation, inhibition of Na⁺ absorption, and increased Cl^- secretion (figure 4) [16]. (See "Clinical manifestations and diagnosis of rotavirus infection", section on 'Pathogenesis and histopathology'.)

Other bacteria cause diarrhea through an inflammatory mechanism. Invasive bacteria such as Salmonella and Shigella cause a tissue inflammatory response involving recruitment of immune cells and release of cytokines, resulting in intracellular Ca²⁺ signaling. Enteropathogenic and invasive bacteria also result in alterations in channel protein expression, with consequent impaired Na⁺ and Cl^– absorption. (See "Pathogenic Escherichia coli associated with diarrhea", section on 'Enterotoxigenic E. coli' and "Shigella infection: Epidemiology, clinical manifestations, and diagnosis" and "Cholera: Treatment and prevention", section on 'Introduction'.)

Role of the colon — Because the bulk of daily fluid absorption is carried out in the small intestine, any disease that significantly affects the small intestine (eg, celiac disease, short bowel syndrome, enteric infections) can result in clinically significant diarrhea. However, fluid absorption in the colon can often compensate for moderate loss of small intestinal absorptive function.

Although the colon absorbs a much smaller volume of fluid than the small intestine, it is critical for the generation of formed (dehydrated) feces [17]. Therefore, any condition that alters colonic fluid transport or increases colonic motility tends to result in abnormally watery stool and therefore diarrhea.

The colonic microbiome also plays an important role in driving fluid absorption in the colon. Colonic bacteria participate in the fermentation of dietary carbohydrates unabsorbed by the small intestine to produce short-chain fatty acids such as acetate, propionate, and butyrate. These are rapidly absorbed in the colon, enhancing absorption of Na⁺ and water, and secretion of HCO₃^-. Disruption of short-chain fatty acid production may therefore play a role in antibiotic-associated diarrhea. Conversely, stabilization of the colonic microbiome through the administration of probiotics can reduce diarrhea associated with antibiotic use. Alterations to commensal bacteria in the colon after antibiotic administration allows opportunistic pathogens such as Clostridioides difficile to displace the normal flora and can result in toxin-mediated inflammation and diarrhea. (See "Diagnostic approach to diarrhea in children in resource-abundant settings", section on 'Antibiotic-associated diarrhea'.)

The presence of excessive bile acids in the colon as occurs in ileal resection or disease (eg, Crohn disease) leads to activation of colonic Cl^- secretion resulting in bile-acid diarrhea (see "Chronic complications of short bowel syndrome in children", section on 'Chronic diarrhea'). A bile acid-enriched state is thought to occur in a subset of patients with diarrhea-predominant irritable bowel syndrome, inducing fluid secretion as well as reducing the transit time through the colon, resulting in incomplete fecal dehydration and diarrhea. (See "Treatment of irritable bowel syndrome in adults", section on 'Bile acid sequestrants'.)

DIARRHEA CLASSIFICATION

Terminology — Previous classifications have divided diarrhea into osmotic, secretory, inflammatory, and motility-related categories, but these terms can be misleading for the following reasons:

●Osmotic diarrhea – The term "osmotic diarrhea" is traditionally used to refer to diarrhea resulting from unabsorbed solutes or nutrients (figure 3), but this use is misleading since all diarrhea involves osmotic forces. We prefer to use the more precise term "diet-induced diarrhea" (or "substrate-induced diarrhea").

●Secretory diarrhea – The term "secretory diarrhea" is also problematic because it has different definitions that are often used interchangeably. Some authors use the term to refer to diarrhea caused by active ion secretion into the intestine; this definition is problematic because it does not include watery diarrhea caused by defects in intestinal sodium absorption (eg, due to some causes of congenital sodium diarrhea and in viral infections). Others use the term to describe diarrhea with a low stool osmotic gap (see "Approach to the adult with chronic diarrhea in resource-abundant settings", section on 'Characterizing the diarrhea type'). This definition is also problematic because a low stool osmotic gap generally results from a combination of anion-driven fluid secretion and loss of Na⁺-driven fluid absorption. Referring to this type of diarrhea as only "secretory" is therefore somewhat misleading. Because of these definitional issues, we prefer to use the more precise term "electrolyte transport-related diarrhea" rather than "secretory diarrhea."

●Mixed diarrhea – Lastly, diarrhea that is obviously neither "secretory" or "osmotic" or has an intermediate stool osmotic gap has been referred to as "mixed." Although intermediate values for the stool osmotic gap occur frequently, these often reflect the dietary intake at the time of testing. From a diagnostic standpoint, this category is rarely helpful.

Despite the above caveats, the terms "osmotic" and "secretory" diarrhea are widely used clinically and historically, and for the purposes of this topic review, we will refer to both the existing terms and our newer terminology.

Diet-induced (osmotic) — Diet-induced diarrhea occurs when osmotically active substances are present in the intestinal lumen, resulting in water retention. This can occur because of loss of absorption of a dietary solute, such as lactose, or administration of a nonabsorbable solute such as polyethylene glycol 3350 (PEG 3350). Because this form of diarrhea is driven by osmotically active ingested nutrients (eg, carbohydrates) or exogenous substances (eg, osmotic laxative), the diarrhea will abate during fasting. Thus, a trial of fasting (>12 hours) is a useful diagnostic test. This is ideally done in a hospital to carefully monitor both stool output and hydration status but can also be inferred from the history if the diarrhea abates during either deliberate or inadvertent fasting.

Primary lactose intolerance or PEG 3350 ingestion are examples of diarrheas with a purely osmotic mechanism. A diet-induced mechanism can also contribute to diarrhea from a variety of other causes. For example, enteric infections and inflammatory conditions such as Salmonella and inflammatory bowel disease can cause damage to intestinal epithelial cells and loss of absorptive surface area, leading to impaired nutrient absorption and diet-induced diarrhea. (See 'Inflammation-related' below and "Approach to chronic diarrhea in children >6 months in resource-abundant settings", section on 'Warning signs'.)

Electrolyte transport-related (secretory) — This type of diarrhea occurs as a result of alterations in ion transport mechanisms in epithelial cells. The distinguishing clinical characteristic is that this type of diarrhea will persist unabated during fasting because it is independent of ingested osmotically active nutrients. Several types of diarrheal diseases fall into this category:

●Enterotoxigenic bacteria – The classic example of electrolyte transport-related diarrhea (although rarely encountered in resource-abundant settings) is infection with the pathogen V. cholerae, in which the enterotoxin, cholera toxin, causes massive (liters) fluid secretion of Cl^- and water. Other examples of bacterial enterotoxins include the enterotoxins produced by Clostridia perfringens and C. difficile, and the heat-stable enterotoxin of E. coli. (See "Causes of acute infectious diarrhea and other foodborne illnesses in resource-abundant settings", section on 'Clostridium perfringens' and "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology", section on 'Pathophysiology' and "Pathogenic Escherichia coli associated with diarrhea", section on 'Enterotoxigenic E. coli' and "Cholera: Treatment and prevention", section on 'Introduction'.)

●Enterotoxigenic viruses – Viral enterotoxins also may cause secretory diarrhea. As an example, rotavirus produces a viral enterotoxin, the nonstructural glycoprotein (NSP4). NSP4 causes Ca²⁺-dependent transepithelial Cl^- secretion from the crypt cells, resulting in secretory diarrhea. (See "Clinical manifestations and diagnosis of rotavirus infection" and "Acute viral gastroenteritis in children in resource-abundant countries: Clinical features and diagnosis", section on 'Pathogenesis'.)

●Other secretory diarrheas – Noninfectious causes of secretory diarrhea include:

•Diarrheas mediated by gastrointestinal peptides (such as vasoactive intestinal peptide and gastrin) (see "VIPoma: Clinical manifestations, diagnosis, and management" and "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis")

•Certain physiologic substances, such as bile acids, and certain medications (magnesium sulfate, lubiprostone, linaclotide) (see "Approach to the adult with chronic diarrhea in resource-abundant settings", section on 'Post-cholecystectomy diarrhea' and "Chronic complications of short bowel syndrome in children", section on 'Chronic diarrhea')

•Congenital defects (eg, congenital chloride diarrhea) (see "Approach to chronic diarrhea in neonates and young infants (<6 months)", section on 'Evaluation for suspected congenital diarrheas and enteropathies')

Motility-related — Changes in gastrointestinal motility can significantly influence fluid absorption, particularly in the colon. Hypomotility, or the severe impairment of intestinal peristalsis, results in stasis with subsequent bacterial overgrowth and secondary bile acid deconjugation, bile acid malabsorption, and activation of colonic secretion. In contrast, hypermotility, which probably contributes to the pathogenesis of functional diarrhea in infants and toddlers (along with excessive carbohydrate intake), can lead to diarrhea secondary to inadequate time for colonic absorption. Hypermotility also contributes to some cases of diarrhea-predominant irritable bowel syndrome. (See "Overview of the causes of chronic diarrhea in children in resource-abundant settings", section on 'Diarrhea-predominant irritable bowel syndrome'.)

Inflammation-related — Intestinal inflammation leads to diarrhea through multiple mechanisms. The diarrhea can have a diet-induced component because the inflammatory process causes destruction or impairment of epithelial cells, resulting in loss of surface area and transports, resulting in impaired nutrient absorption and increased osmotic load in the intestinal lumen (see 'Diet-induced (osmotic)' above). Inflammation can also cause electrolyte transport-related diarrhea by inducing active Cl^- secretion and a loss of Na⁺ absorption (see 'Electrolyte transport-related (secretory)' above). In addition, the inflammatory process also can lead to the breakdown in intestinal barrier function, resulting in the exudation of mucus, protein, and blood into the gut lumen (eg protein-losing enteropathy).

The most common cause of inflammatory diarrhea is infection. A number of relatively common enteric pathogens (eg, Salmonella, Campylobacter, C. difficile) cause primarily inflammatory responses, resulting in either watery or often bloody diarrhea (dysentery) (see "Diagnostic approach to diarrhea in children in resource-abundant settings", section on 'Causes' and "Approach to the child with acute diarrhea in resource-limited settings", section on 'Infectious causes'). Intestinal inflammation can also be caused by chronic diseases, such as inflammatory bowel disease and celiac disease. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children" and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children".)

RELEVANCE FOR DRUG TREATMENT — A number of interventions are available to treat diarrhea by altering the underlying pathophysiologic processes. These include oral rehydration solutions (ORS) and several classes of drugs; other candidate drugs are in development. Each of these treatments targets a different pathophysiologic cause of diarrhea, as outlined below:

Oral rehydration solution — ORS is an orally ingested solution that stimulates intestinal Na⁺ absorption by Na⁺/glucose cotransporter 1 (SGLT1 [SLC5A1]) and Na⁺-coupled amino acid transporters. The World Health Organization (WHO)-recommended ORS is hypo-osmolar (245 mOsm/L), with optimized glucose-to-Na⁺ ratios to increase water absorption. ORS is a highly effective treatment that relies on the fact that SGLT1 transport is preserved in electrolyte transport-related (secretory) diarrheas such as those caused by bacterial enterotoxins. Beverages commercially marketed for hydration during exercise ("sports" beverages) have much higher concentrations of glucose and higher osmolarity, which reduces fluid absorption; these are less effective for oral rehydration. Alternative ORS solutions including rice starch or amino acids have also been shown to be effective in maintaining hydration during diarrhea [18]. (See "Oral rehydration therapy".)

Antimotility agents — Drugs that inhibit intestinal motility have been used extensively to treat diarrhea. The putative mechanism of action for antimotility drugs is increased Na⁺ and fluid absorption as a result of slow intestinal transit. Loperamide and diphenoxylate and atropine are mu-opioid receptor agonists that are widely used for mild, nonspecific diarrhea. They are not recommended in bacterial diarrheas, primarily owing to the risk of paralytic ileus, and diphenoxylate also has substantial central opioid effects.

Antisecretory agents — Inhibiting intestinal fluid secretion is another mechanism by which some agents reduce diarrhea. Historically, bismuth subsalicylate was shown to have antidiarrheal efficacy, although it is now rarely used. Racecadotril, an enkephalinase inhibitor, or its active metabolite thiorphan, is used in Europe and South America as an antidiarrheal agent, with varying reports of efficacy; it is not approved by the US Food and Drug Administration (FDA) in the United States. It acts via inhibition of the breakdown of endogenous enkephalins that exert antisecretory effects through enkephalin-stimulated activation of epithelial mu-opioid receptors [19]. A natural-product antisecretory agent, crofelemer, has been approved for use in HIV-related diarrhea based on a clinical trial showing efficacy in improving chronic diarrhea in patients with HIV [20]. Crofelemer is a heterogeneous proanthocyanidin oligomer extracted from the bark latex of the South American tree Croton lechleri. Crofelemer acts by inhibiting Cl^– channels in the apical membrane. (See "Evaluation of the patient with HIV and diarrhea", section on 'Empiric therapy'.)

Investigational drugs — A number of investigational or more recently approved drugs target several of the pathophysiologic pathways described above:

●The bile acid analog obeticholic acid has shown efficacy in bile-acid diarrhea (see 'Electrolyte transport-related (secretory)' above and "Overview of the management of primary biliary cholangitis", section on 'Subsequent therapy')

●The opioid receptor agonist eluxadoline is approved for diarrhea-predominant irritable bowel syndrome (see "Treatment of irritable bowel syndrome in adults", section on 'Antidiarrheal agents' and 'Motility-related' above)

●Drugs directly targeting ion channels, such as absorbable inhibitors of the chloride channel CFTR (BPO-27), are under clinical development [13]

SUMMARY

●Definitions – For practical use in a clinical setting, diarrhea is defined as the passage of three or more loose or liquid stools per day, or more frequent passage than is normal for the individual. (See 'Definitions' above.)

●Pathophysiology of fluid transport

•The normal movement of fluid between the intestinal lumen and blood is driven by the active transport of ions (mainly Na⁺, Cl^–, HCO₃^–, and K⁺) and nutrients (mainly glucose) (figure 2). Fluid absorption is driven by the active transport of Na⁺ across the epithelium with parallel Cl^– or HCO₃^– absorption. Fluid secretion is driven by transepithelial Cl^– secretion through basolateral and apical Cl^– channels and transporters. (See 'Molecular mechanisms' above.)

•Diarrhea occurs when there is excessive fluid maintained within the lumen of the intestine. This occurs due to either loss of nutrient absorption or the presence of nonabsorbable solutes in the intestinal lumen, increased secretion or reduced absorption of electrolytes, rapid intestinal transit, or a combination of these factors (figure 3). (See 'Pathophysiology of fluid transport in diarrheal disease' above.)

●Types of diarrhea – The causes of diarrhea can be categorized as diet-induced (osmotic), electrolyte transport-related (secretory), motility-related, or inflammation-related, but multiple mechanisms often are involved.

•Diet-induced (osmotic) diarrhea occurs when there is loss of absorption of a normally absorbed dietary solute, such as lactose, or ingestion of a nonabsorbable solute such as polyethylene glycol 3350 (PEG 3350), resulting in water retention within the intestinal lumen. (See 'Diet-induced (osmotic)' above.)

•Electrolyte transport-related (secretory) diarrheas occur as a result of alterations in ion transport mechanisms in epithelial cells. This can be caused by an infectious process (eg, cholera, rotavirus, and some forms of Escherichia coli), secretion of gastrointestinal peptides (eg, vasoactive intestinal peptide and gastrin), or by the stimulatory effect of bile acids and laxatives. Some rare inherited disorders of intestinal transport, such as congenital chloride diarrhea, also may cause secretory diarrhea. (See 'Electrolyte transport-related (secretory)' above.)

•Disorders associated with reduced intestinal motility can cause diarrhea indirectly by causing intestinal stasis and bacterial overgrowth, which leads to bile acid malabsorption. Disorders with increased intestinal motility can cause diarrhea by reducing intestinal transit time and absorption. Examples of increased motility include functional diarrhea in young children (sometimes termed "toddler's diarrhea") and some cases of diarrhea-predominant irritable bowel syndrome. (See 'Motility-related' above.)

•Inflammatory processes can cause the destruction of epithelial cells and/or loss or dysfunction of electrolyte transporters, leading to diarrhea through both osmotic and secretory mechanisms, as well as exudation of mucus, proteins, and blood into the intestinal lumen. This can be caused by infectious processes (eg, Shigella), inflammatory bowel disease, or immune-mediated processes (eg, celiac disease). (See 'Inflammation-related' above.)

●Relevance for treatment – The appropriate therapeutic intervention depends on the type of diarrhea. Available interventions include oral rehydration solutions (ORS) and a variety of drugs. (See 'Relevance for drug treatment' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Mark A Gilger, MD, who contributed to earlier versions of this topic review.