Pathophysiology of short bowel syndrome

INTRODUCTION — Short bowel syndrome (SBS) is a malabsorptive condition most often caused by massive resection of the small intestine [1]. Clinical disease is only modestly correlated with the amount of intestine that is resected because of the highly variable length of the human small bowel and the remarkable ability of the bowel to compensate for bowel resection.

The pathophysiology of SBS and intestinal adaptation during recovery will be reviewed here. The complications of SBS and the management of this disorder are discussed separately:

●(See "Management of short bowel syndrome in children".)

●(See "Chronic complications of short bowel syndrome in children".)

●(See "Management of short bowel syndrome in adults".)

●(See "Chronic complications of the short bowel syndrome in adults".)

BACKGROUND

Definitions

●Intestinal failure – Intestinal failure describes the state when an individual's gastrointestinal function is inadequate to maintain his or her nutrient and hydration status without intravenous or enteral supplementation [2,3]. Functionally, intestinal failure may be classified by duration as acute (type I), prolonged acute (type II), or chronic (type III).

●Short bowel syndrome (SBS) – SBS describes intestinal failure that is caused by reduced small intestine absorptive area due to massive resection, a congenital defect, or disease-associated loss of absorption. SBS is by far the most common cause of chronic intestinal failure in all age groups, including approximately 60 percent of cases in adults [2].

For adults, an anatomic definition of SBS is residual small bowel length <200 cm, measured from the duodenojejunal flexure, with or without colon. For children (<18 years), the corresponding definition is small intestinal length <25 percent of the normal length of small intestine for the child's age. The term "functional SBS" is sometimes used to describe patients with a residual small bowel >200 cm but with impaired function due to factors such as the presence of a disease (eg, Crohn disease) or rapid intestinal transit [2].

●Adaptation – Adaptation is the process following intestinal resection, usually extensive, whereby the remaining bowel undergoes a range of morphologic and functional changes that increase its relative absorptive capacity. Adaptation is a critical step in achieving enteral autonomy.

Epidemiology — Challenges to estimating the prevalence of SBS include its multifactorial etiology, varying definitions, and difficulty in estimating intestinal length. Furthermore, there are no data available on the epidemiology of the total SBS population, including both SBS with intestinal failure (ie, those requiring parenteral support) and SBS not requiring parenteral support (ie, those successfully weaned or who never required). Therefore, estimates of the incidence and prevalence of SBS are based on data from registries of patients on home PN, for which SBS is the most common indication. One such study reported that the annual prevalence of home PN in the United States is approximately 120 per million population, of whom approximately 25 percent have SBS; this amounted to approximately 10,000 individuals in 1992 [4]. In some countries and regions that report a low prevalence of SBS [5], it is possible that this is related to an inability to care for these patients in the acute or chronic postsurgical setting, with contributing financial or logistical factors, or a lack of awareness that a life without a bowel is possible if PN is provided. (See "Management of short bowel syndrome in children", section on 'Epidemiology'.)

Causes — SBS is the most common cause of chronic intestinal failure in all age groups. Other causes of intestinal failure include congenital defects that cause severe malabsorption, bowel obstruction, and dysmotility (eg, pseudo-obstruction).

Causes of SBS vary with age:

●Adults – SBS in adults usually results from surgical resection of the small intestine for Crohn disease, trauma, malignancy, radiation, or mesenteric ischemia. In addition, SBS caused by postoperative vascular and obstructive catastrophes requiring massive intestinal resection seems to be increasing in incidence. Advances in the treatment of Crohn disease may lead to a reduction in SBS [6]; however, these improvements do not yet appear to have led to a reduction in the number of patients requiring home parenteral nutrition (PN) [7]. In an international survey of 1880 adults with SBS, the most common causes of SBS were Crohn disease (27 percent) and mesenteric ischemia (27 percent), followed by surgical complications (17 percent) and radiation enteritis (6 percent) [8].

●Children – SBS in infants and small children is usually caused by necrotizing enterocolitis and congenital intestinal anomalies, such as mid-gut volvulus, atresias, or gastroschisis.

INITIAL DETERMINANTS OF INTESTINAL FUNCTION — The main determinants of intestinal dysfunction in the initial phases after bowel resection are:

●Length of the intestinal resection (relative to age or body size)

●Loss of the ileum and ileocecal valve

●Loss of all or part of the colon

●Continuity versus incontinuity of the intestines

Intestinal function is often further disrupted by gastric hypersecretion, which interferes with function of pancreatic enzymes, by altered gastrointestinal motility, and by any mucosal disease in the remaining intestine. Each of these factors will be discussed in detail in the following sections.

Small intestine length — The length of the small intestine remaining after surgical resection is one determinant of intestinal function and prognosis for eventual freedom from parenteral nutrition (PN) or parenteral fluid support. However, it may be difficult to establish an accurate estimate of bowel length. The best information comes from the operative report, and it is important for surgeons to record the length and segment of bowel remaining, not just the length removed. The appearance of the remaining bowel (pink, necrotic, or matted) should also be noted given its implications for the short-term prognosis. Alternatively, barium contrast radiography or computed tomography (CT) can be used to estimate small bowel length; such studies may also delineate other structural features that may be relevant to intestinal function and prognosis, such as the presence of a stricture or bowel dilatation.

Estimated bowel length is modestly correlated with outcomes:

●Based on measurements from living infants undergoing surgery, the normal length of the small intestine is approximately 100 cm at the start of the third trimester of gestation and 160 cm at term [9]. Infants with residual small intestine length of less than 75 cm are at risk for developing SBS [10]. In one series of infants with SBS due to surgical resection during the neonatal period, the likelihood of achieving independence from PN was more than 60 percent for infants with residual small intestine length >38 cm, as compared with 7 percent in those with residual small intestine length <15 cm [11]. In a separate series from a center with expertise in intestinal rehabilitation, the probability of weaning from PN for infants with at least 50 cm of small intestine was 88 percent after 12 months and 96 percent after 24 months [12]. For infants with less than 50 cm of small intestine, the probability of weaning was 23 percent after 12 months, 38 percent after 24 months, and 71 percent after 57 months.

●In adults, the normal length of the small intestine is approximately 480 cm, but ranges widely from 300 cm to 800 cm depending, in part, upon the measurement technique used (ie, at time of surgery versus radiographic versus postmortem) and the individual's height. Adults with residual small intestine of less than 180 cm are at risk for developing SBS [10]. The presence of the colon helps to mitigate functional impairment in SBS, such that presence of at least one-half of the colon is approximately equivalent to having an additional 50 cm of small bowel. Similarly, loss of the ileum and ileocecal valve causes more intestinal dysfunction than loss of a similar amount of jejunum [13,14]. (See 'Site of intestinal resection' below and 'Loss of the colon' below.)

Site of intestinal resection — The jejunum occupies the proximal two-fifths of the small intestine, and the ileum consists of the distal three-fifths. The symptoms associated with bowel resection and eventual independence from PN or parenteral fluid support are highly dependent upon the physiology of the remaining small bowel because each bowel segment has unique characteristics for absorption (figure 1). In addition, the ileum is better able to adapt after intestinal resection compared with the jejunum [15-17] (see 'Ileal versus jejunal adaptation' below). The duodenum and proximal jejunum are uncommon sites of resection in SBS, at least in adults, due to the different causes of the SBS and the blood supply to this section of the gut. Nevertheless, when these sections of the intestine are involved, their resection typically results in more pronounced hypergastrinemia and gastric hypersecretion, and deficiencies in certain micronutrients including iron and folate (figure 1). (See 'Influence of SBS on gastric and pancreatic function' below.)

Based on the remaining bowel anatomy, SBS may be classified into three anatomical types (types 1 to 3) and this has implications for prognosis:

●End-jejunostomy (type 1) – This is the result after resection of the entire ileum and colon (or colon present but disconnected); this anatomy generally has the worst prognosis.

●Jejuno-colic anastomosis (type 2) – This is the result after resection of the entire ileum, ileocecal valve, part of the colon, and variable amounts of the jejunum. This is the most common anatomy in SBS with a prognosis that depends upon the length of remaining jejunum.

●Jejuno-ileocolonic anastomosis (type 3) – This is the result after resection of a portion of the ileum with retention of the ileocecal valve and the entire colon; this anatomy generally has the best prognosis.

The reasons for these differences in prognosis are detailed in the following sections.

Jejunal resection — The jejunum, with its long villi, large absorptive surface, highly concentrated digestive enzymes, and many transport carrier proteins, is the primary digestive and absorptive site for most macro- and micronutrients. Indeed, most macronutrient absorption occurs within the proximal 150 cm of small intestine. Thus, when the jejunum is resected, a temporary reduction in absorption of most nutrients occurs. The jejunum exhibits modest adaptive changes in response to intestinal resection, and most of these changes are functional (changes in transport and enzyme activity) rather than structural (changes in absorptive area) [18]. (See 'Intestinal adaptation' below.)

Fluid absorption is another important role of the small intestine. The gastrointestinal tract in healthy adults without SBS secretes approximately 4 L of fluid (0.5 L saliva, 2 L gastric acid, and 1.5 L pancreaticobiliary secretions) in response to the 2 to 3 L of food and drink consumed each day. Water absorption is a passive process resulting from the transport of nutrients and electrolytes; sodium transport creates an electrochemical gradient that drives the uptake of nutrients across the intestinal epithelium. In the jejunum, the junctions between the epithelial cells are relatively large compared with other areas of the bowel, resulting in a rapid flux of fluids and nutrients and inefficient fluid absorption. Because of these "leaky" intercellular junctions, the jejunal mucosa is unable to concentrate the luminal contents and sodium diffuses freely into the lumen. Notably, sodium absorption in the jejunum occurs against a concentration gradient, is dependent upon water fluxes, and is coupled to the absorption of glucose [19]. The composition of oral rehydration solutions, and particularly the sodium and glucose concentrations, is designed to take advantage of cotransport of glucose and sodium to optimize jejunal absorption. (See "Oral rehydration therapy".)

Ileal resection — Having residual ileum is advantageous because of its specialized functions:

●Vitamin B12 absorption – The distal 50 to 60 cm of ileum is the primary site for absorption of vitamin B12, bound to intrinsic factor (figure 1). Resection of the terminal ileum, which is common in SBS, is associated with malabsorption of vitamin B12 and can lead to clinical deficiency unless supplemented. The length of ileal resection that causes such consequences in infants is not well-defined. Life-long monitoring and supplementation of vitamin B12 is important in all SBS patients, particularly in those who lack a terminal ileum. (See "Management of short bowel syndrome in children", section on 'Vitamin and mineral supplementation' and "Treatment of vitamin B12 and folate deficiencies" and "Management of short bowel syndrome in adults", section on 'Weaning parenteral nutrition'.)

●Bile acid absorption – The distal ileum also is the site for selective absorption of bile acids. In adults, resection of >100 cm of terminal ileum leads to disruption of the enterohepatic circulation, eventually resulting in bile acid deficiency because bile acid losses exceed the compensatory increase in hepatic bile acid production [20]. The diminished bile acid pool exacerbates malabsorption of fat and fat-soluble vitamins. In addition, the increased passage of bile acids into the colon may induce a colonic secretomotor diarrhea (choleretic enteropathy). (See "Chronic complications of short bowel syndrome in children", section on 'Chronic diarrhea'.)

Malabsorption of fat also leads to increased absorption of oxalate in the colon, resulting in hyperoxaluria and increasing the risk of oxalate nephrolithiasis and chronic kidney disease. (See "Chronic complications of the short bowel syndrome in adults" and "Chronic complications of short bowel syndrome in children", section on 'Hyperoxaluria and kidney stones'.)

●"Ileal brake" – Unabsorbed lipids reaching the ileum cause a delay in gastric emptying (the "ileal brake"), which is beneficial in the setting of SBS because it facilitates absorption of nutrients within the small intestine. This effect is mediated by several hormones secreted by the ileum, the most important of which are glucagon-like peptide-1 and peptide YY [21,22]. Patients with SBS lacking ileum lose the beneficial effects of the ileal brake, resulting in rapid transit and decreased absorption of nutrients in small intestine. (See 'Gut hormones' below.)

●Fluid absorption – Compared with the jejunum, the ileum has tighter intercellular junctions, resulting in less water and sodium flux [19]. The ileum also has active transport of sodium chloride, so that it is able to reabsorb substantial amounts of fluid and concentrate the ileal contents. As a result, the ileum normally reabsorbs a large portion of the fluid secreted by the jejunum during the digestive process, which is particularly important with the large amounts of fluids that enter the lumen in response to hypertonic feedings [19,23]. Thus, patients who lose a substantial portion of the ileum have a limited ability to absorb fluids and electrolytes. Such patients often cannot tolerate large bolus feedings or those with high osmolarity, such as high concentrations of simple carbohydrates.

●Intestinal adaptation – The ileum has a greater capacity for intestinal adaptation compared with the jejunum [24]. (See 'Ileal versus jejunal adaptation' below.)

Loss of the ileocecal valve — The ileocecal valve acts as a barrier to reflux of colonic material from the colon into the small intestine and helps to regulate the passage of fluid and nutrients from the ileum into the colon (figure 1).

In children with SBS, loss of the ileocecal valve tends to be a negative predictor of the ability to wean a patient from PN. As examples, absence of the ileocecal valve typically is associated with a longer duration of PN when resection occurs in childhood [25]. Similarly, infants lacking the ileocecal valve are less likely to be weaned from PN, especially if more than one-half of their small bowel has also been resected [26]. These effects are thought to be due to reduction of small intestinal transit time, which impairs nutrient absorption. In addition, loss of the ileocecal valve promotes small intestinal bacterial overgrowth (SIBO), which may result in reduction in vitamin B12 and deconjugation of bile acids, further contributing to fat malabsorption and diarrhea [27]. More severe complications of SIBO, including bacterial translocation, liver injury, D-lactic acidosis, arthritis, and colitis, can also occur [27,28]. (See 'The microbiome of SBS and pathophysiology of bacterial overgrowth' below.)

However, at least in adults, it has been suggested that the ileocecal valve does not independently affect small bowel transit, the risk of SIBO, or the likelihood of weaning from PN [29]. Instead, the increased risk for SIBO may be related to reduced ileal length and peristalsis and these factors may be the primary predictors of the likelihood of weaning from PN, rather than the presence of the ileocecal valve itself. Therefore, the ileocecal valve may be less relevant to outcomes of SBS in adults.

Loss of the colon — The colon has an important role in absorption of water, electrolytes, and short-chain fatty acids (figure 1). Compared with the jejunum and ileum, the colon has the slowest transit, tightest intercellular junctions, and greatest efficiency of water and sodium absorption. In healthy adults, approximately 1 to 1.5 L of fluid enters the colon each day and all but 150 mL is reabsorbed. In patients with extensive small bowel resection, substantially more fluid exits from the distal small intestine. If the colon is present, it can absorb up to 6 L of this excess fluid each day, which mitigates the fluid loss [30]. Conversely, patients with extensive small bowel resection and without a colon (ie, those with an end-jejunostomy) are at high risk for dehydration and electrolyte depletion. Such patients usually require long-term PN or parenteral fluid support.

In addition to absorbing fluid, the colon is capable of absorbing some nutrients, primarily in the form of fermented malabsorbed carbohydrates. In healthy adults, the colon absorbs up to 15 percent of daily energy requirements. In patients with SBS on a high-carbohydrate diet, the colon can absorb as much as 50 percent of energy requirements [31-33]. Thus, in an adult patient with SBS and a colon, a diet that is high in complex carbohydrates is advantageous. However, such a diet may be disadvantageous for patients without a colon and for infants and young children because concentrated carbohydrates have high osmolarity, which can lead to diarrhea. (See "Management of short bowel syndrome in children", section on 'Advancement of enteral feeds'.)

The colon also helps to slow intestinal transit and stimulate intestinal adaptation. The retained colon undergoes adaptation after small bowel resection, with gradual increases in enterocytes and other cells and in gut hormones including glucagon-like peptide-1 (GLP-1) and peptide YY [34]. (See 'Gut hormones' below.)

For all of the above reasons, patients who retain their colon are more likely to tolerate an extensive small intestinal resection. Indeed, intestinal function in adult patients with little or no colon is similar to that in patients with at least one-half the colon but whose small intestine is 50 cm shorter [35]. Adults with little or no colon and less than 50 to 100 cm of jejunum are likely to require permanent PN [16,36]. Studies in infants and children have reached inconsistent conclusions about whether or not the presence of the colon is an important predictor of weaning from PN [26,29,37,38]. Thus, the presence of a colon may be a less important predictor of survival off of PN in infants compared with adults.

Influence of SBS on gastric and pancreatic function — Large resections of the small intestine tend to trigger gastric hypergastrinemia and hypersecretion (unless the stomach has also been resected, which is unusual), probably because the negative feedback mechanism for inhibiting gastrin secretion and reducing gastric acid production has been removed [39]. Although resections involving the duodenum and proximal jejunum are uncommon in SBS, particularly in adults, those who have undergone resections of these bowel segments seem to be at even higher risk of severe hypergastrinemia with voluminous gastric secretions. This increases the volume of secretions entering the small bowel and lowers the pH of the secretions in the proximal gut, potentially aggravating fluid losses and leading to peptic complications and impairment in the function of digestive enzymes. The gastric hypersecretion may lead to very high stool or ostomy output and may last for up to 12 months postoperatively; management includes vigorous fluid replacement and acid blockade. (See "Management of short bowel syndrome in children", section on 'Early management' and "Management of short bowel syndrome in adults", section on 'Management of acute phase'.)

Most SBS patients who are not at complete bowel rest demonstrate normal pancreatic enzyme and bilirubin secretion. An exception is the rare patient with extensive proximal small bowel resection, which may result in loss of sites of secretin and cholecystokinin-pancreozymin (CCK-PZ) synthesis and decreased pancreatic and biliary secretions [40].

INTESTINAL ADAPTATION — Intestinal adaptation is the process following intestinal resection whereby the remaining bowel undergoes macroscopic and microscopic changes that serve to increase its absorptive ability. Adaptation is characterized by improved intestinal absorption, increased gut hormonal secretion, development of hyperphagia, and changes in gut microbiota. Adaptation is highly variable and usually occurs during the first two years following intestinal resection in adults and for longer and perhaps more vigorously in children. Adaptive changes are usually most prominent in the ileum and, to a lesser extent, in the jejunum and colon. These changes are mediated by a variety of internal and external stimuli including nutrients, gastrointestinal secretions, hormones, and growth factors and other genetic and biochemical factors. In particular, adaptation depends upon the nutrient components of the diet and on influences from the remaining segments of the intestine.

Both structural and functional changes can occur:

●Structural adaptive changes include dilation and elongation of the remnant bowel, an increase in intestinal wet weight, protein and DNA content, villus lengthening, expansion in microvilli, and an increase in crypt depth and enterocyte number. These morphologic changes in the mucosa are driven by a proliferative stimulus that affects cellular progression along the crypt-villus axis, resulting in an increase in mucosal weight and enlargement in mucosal folds. Adaptation of the gut muscle layers also takes place, leading to an increase in muscle thickness, circumference, and length.

●Functional adaptive changes occurring include modifications of the brush border membrane enzyme activity, fluidity and permeability, up- or downregulation of carrier-mediated transport (eg, upregulation of Na+/glucose cotransporters, Na+/H+ exchangers, and other enzymes involved in digestion and absorption) and a slowing in the rate of transit, allowing more time for absorption to occur [17,41]. Adaptive changes in gut microbiota [42], motor activity [43], and barrier and immune functions after massive intestinal resection are poorly understood.

Animal models of SBS provide insight into the adaptive process. After bowel resection, epithelial hyperplasia is seen within 24 to 48 hours [44-49]. The length of villi and intestinal absorptive area increases and digestive and absorptive function gradually improve. These morphologic changes are associated with changes in expression of a variety of genes [50-52], some of which are known mediators of intestinal growth. Some of these effects may be mediated by microRNAs, which are short noncoding RNAs that are able to silence numerous genes [53]. Other observed changes, such as upregulation of genes associated with intestinal angiogenesis and new blood vessel growth, appear to be a result rather than a cause of the adaptive process [54]. These adaptive changes are more apparent in the animal models compared with humans with SBS [47,48,54]. Furthermore, most studies investigating the process of adaptation have utilized animal models with a jejuno-ileocolonic anastomosis, a relatively uncommon bowel anatomy in humans with SBS. Thus, the physiologic and structural changes that occur in the animal models are of unclear clinical relevance.

Ileal versus jejunal adaptation — The ileum is capable of undergoing marked adaptation after small bowel resection, with significant growth in villus surface area, as well as increases in intestinal length, diameter, and motor function [55,56]. These structural changes are primarily responsible for enhancement of nutrient uptake in a given segment of bowel [57]. However, there is also some evidence for functional improvement of absorption through upregulation of transporters and of brush border enzymes [15]. These adaptive changes lead to a gradual improvement in macronutrient absorption during the first one to three years after jejunal resection [11,58].

The jejunum exhibits more modest adaptive changes in response to intestinal resection, and most of these changes are functional (changes in transport and enzyme activity) rather than structural (changes in absorptive area) [15]. Jejunal adaptation appears to depend on influences from other remaining segments of the bowel; patients with a jejuno-colic anastomosis demonstrate functional small bowel adaptation, whereas those with an end-jejunostomy show little to no adaptation. Despite limited evidence, better adaptation is expected for patients with colon-in-continuity compared with those whose colon remains but is not in continuity, given the lack of nutrient exposure to the excluded colon. This reinforces the importance of the colon in the prognosis of the patient with SBS. (See 'Site of intestinal resection' above.)

Nutrient effects — The best established stimulant of intestinal adaptation is the presence of nutrients in the intestinal lumen [59]. This effect is mediated primarily by growth factors produced by the intestine. Studies of parenterally-fed animal models of SBS have demonstrated that adaptation requires enteral feeding and will not occur with exclusively parenteral feeding [60]. Nutrients requiring digestive processing prior to absorption serve as important stimuli for intestinal adaptation. As such, disaccharides and long-chain fats stimulate adaptation more than monosaccharides and medium-chain fat, respectively [61,62].

The effects of specific nutrients on intestinal adaptation have been studied in animals and, to a lesser extent, in humans. These include the amino acids, arginine and glutamine, and medium- and long-chain triglycerides.

●Arginine or citrulline – Animal studies have demonstrated that parenteral arginine supplementation reduces intestinal permeability [63]. Similar effects are seen with enteral or parenteral supplementation of citrulline, which is metabolized to arginine [64,65]. Studies in animal models suggest that supplementing citrulline in total parenteral nutrition (PN) can enhance intestinal adaptation.

Consistent with a possible role as a growth factor, plasma citrulline levels correlate with enterocyte mass in children with SBS [66], and low levels of plasma citrulline correlate with catheter-related bloodstream infections in children with intestinal failure [67]. Measurement of serum citrulline concentrations (a nonprotein amino acid produced by intestinal mucosa) has been proposed to predict permanent versus transient intestinal failure [68]. The level of serum citrulline associated with permanent dependence on PN varies among several studies but typically is less than 15 micromol/L [69].

●Glutamine – Parenteral supplementation of glutamine reversed intestinal hypoplasia in an animal model [70,71]. Enteral glutamine supplementation in animals yields little or no improvement in intestinal adaptation [72]. Studies in humans have shown that enteral glutamine supplementation provides modest benefit in body weight and fluid and electrolyte balance [73]. However, most patients in these studies were also supplemented with growth hormone. (See "Management of short bowel syndrome in children", section on 'Pharmacologic therapy'.)

●Triglycerides – In animal models, enteral supplementation with long-chain triglycerides appears to be more beneficial than medium-chain triglycerides in promoting intestinal adaptation, although medium-chain triglycerides may be more easily absorbed [74,75]. Human data are limited. One series demonstrated that feedings with relatively high concentrations of long-chain triglycerides (as in breast milk or some amino acid formulas) are associated with improved intestinal adaptation in neonates with SBS, compared with feedings with lower concentrations of long-chain triglycerides [76]. (See "Management of short bowel syndrome in children", section on 'Diet composition and adjustments'.)

●Omega-3 fatty acids – Dietary fish oil, which is rich in omega-3 fatty acids, appears to be beneficial in inducing adaptation in the small intestine and colon. This was shown in an animal model of SBS in which fish oil reduced diarrhea and fecal fat excretion as compared with corn oil [77]. In a separate study, parenteral administration of omega-3 fatty acids also induced intestinal adaptation in rats [78]. In this model, parenteral administration was more effective than enteral administration of the nutrient.

Most of the studies of omega-3 fatty acid supplementation in humans are observational and limited to the pediatric population. However, increasing evidence suggests that parenteral administration of lipids derived from fish oil (rich in omega-3 fatty acids) may reduce serum bilirubin levels and reverse intestinal failure-associated liver disease, compared with conventional soy-based lipids. (See "Intestinal failure-associated liver disease in infants", section on 'Fish oil-based lipid emulsions'.)

Gut hormones — Nutrients probably promote intestinal adaptation by inducing release of one or more trophic gastrointestinal hormones, a stimulus that is mediated primarily by fat. Several enterocyte-derived mediators of the adaptation process have been described.

Glucagon-like peptide 2 (GLP-2) is an intestinal growth factor produced by the enteroendocrine L cells of the ileum and proximal colon [79]. In animal models undergoing mid-small bowel resection, plasma concentrations of GLP-2 increase rapidly, and this induces adaptation in the remaining intestine [80]. Further supporting the role of GLP-2 as an intestinotrophic agent, this response does not occur if the GLP-2 producing cells in the ileum and proximal colon are resected. Exogenous administration of GLP-2 induces marked villus hyperplasia of the ileum and jejunum within four days of administration to mice with SBS [81], accompanied by an increase in glucose absorption and a decrease in intestinal permeability [82]. Evidence suggests that teduglutide, a longer-acting GLP-2 analog, promotes intestinal adaptation and absorption and has modest benefits with respect to weaning of PN in adults with SBS [83,84]. (See "Management of short bowel syndrome in children", section on 'Pharmacologic therapy'.)

Growth hormone has also been explored as a possible promoter of intestinal adaptation. Studies in humans with SBS have evaluated the use of growth hormone, with or without glutamine or other growth factors, but results have been conflicting and inconclusive. (See "Management of short bowel syndrome in adults" and "Management of short bowel syndrome in children", section on 'Pharmacologic therapy'.)

Other trophic gastrointestinal hormones, such as enteroglucagon (or fragments or precursors of this molecule), epidermal growth factor, hepatocyte growth factor, trefoil peptides, and insulin-like growth factor 1 (IGF-1), are produced by the ileal mucosa [85,86]. As a result, ileal resection may decrease the potential for adaptation induced by these hormones. In animal models of SBS, epidermal growth factor induces changes in the intestinal smooth muscle and also enhances mucosal integrity [87]. Similarly, IGF-1 delivered via colostrum supplementation positively affects the muscularis mucosa in the intestinal tract [88]. Thus, these substances appear to play a primary role in tissue proliferation, but clinical trials of these hormones in humans with SBS are lacking.

Some hormones have antitrophic effects. Transforming growth factor beta-1 inhibits stem cells, enterocyte proliferation, and adaptation in rat intestinal mucosa [89,90]. Octreotide, the synthetic somatostatin analog, impairs gut structural adaptation by decreasing cell proliferation following massive resection [91]. This inhibitory effect limits the utility of octreotide as a treatment for diarrhea in SBS. In general, octreotide should be avoided during the most critical period of intestinal adaptation. (See "Management of short bowel syndrome in adults" and "Management of short bowel syndrome in children", section on 'Pharmacologic therapy'.)

Gut hormones also can affect the pathophysiology of SBS in ways other than enhancing adaptation:

●Motility – Gastrointestinal motility is regulated by gut hormones, and massive resection of the small bowel may alter various aspects of gut motility, such as gastroduodenal emptying and intestinal transit. Resection of the ileum has particularly important effects on motility.

In individuals without SBS, unabsorbed lipids reaching the distal ileum reduces gastrointestinal motility, known as the "ileal brake." Patients with SBS lacking ileum lose the beneficial effects of the ileal brake. The resulting rapid transit will further reduce the time of contact of nutrients with the mucosal surface, impairing both their absorption and their trophic effect on the small intestine. However, if some ileum is present, the feeding of lipids engages the ileal brake, which might enhance intestinal adaptation by delaying transit through the small bowel, resulting in increased nutrient contact with the epithelium. This mechanism has been supported by animal experiments in which administration of menhaden oil enhanced intestinal adaptation, with an associated increase in peptide YY and delay in gastrointestinal motility [92].

●Gastrin – Hypergastrinemia is present in many patients with SBS [39] (see 'Influence of SBS on gastric and pancreatic function' above). As a result, many patients benefit from acid suppression using a histamine 2 receptor antagonist (H2 blocker) or a proton pump inhibitor, particularly during the early phase of SBS. (See "Management of short bowel syndrome in children", section on 'Early management' and "Management of short bowel syndrome in adults", section on 'Pharmacologic therapy to reduce fluid loss'.)

Prostaglandins — Prostaglandins stimulate intestinal proliferation [93-95]. Inhibition of prostaglandin synthesis with aspirin, nonsteroidal antiinflammatory drugs, or corticosteroids may inhibit the adaptation process.

THE MICROBIOME OF SBS AND PATHOPHYSIOLOGY OF BACTERIAL OVERGROWTH — The microbial population of the intestine is altered in patients with SBS [42,96,97]. In a study of adults with SBS and partial colon resection, bacterial diversity in the colon was reduced and Lactobacillus was overrepresented compared with normal colonic bacteria [42].

Gut microbes can have beneficial effects in patients with SBS. In patients with residual colon, colonic bacteria participate in metabolism and salvage of malabsorbed macronutrients, thereby improving energy extraction from the diet. The overrepresentation of Lactobacillus in SBS probably enhances absorption of sugars in the colon since Lactobacillus is a facultative anaerobe, capable of fermenting carbohydrates [98]. (See 'Loss of the colon' above.)

Gut bacteria also can have detrimental effects in patients with SBS. Whereas humans without SBS tend to have only a small population of bacteria in the proximal small intestine (mostly aerobic), those with SBS tend to have more bacteria in the small intestine, including more anaerobes [27]. Invasion of the small intestine with excessive or imbalanced population of bacteria can lead to small intestinal bacterial overgrowth (SIBO), which may exacerbate malabsorption and cause gas and other gastrointestinal symptoms that may reduce oral intake, thereby impeding weaning from parenteral nutrition (PN). The excess bacteria may also exacerbate malabsorption by several mechanisms. First, bacterial deconjugation of bile acids diminishes the intestinal absorption of monoglycerides and fatty acids [27]. Second, the inflammatory response caused by bacterial overgrowth damages the absorptive surface, resulting in further malabsorption, including of carbohydrates and proteins. Third, bacteria within the lumen of the small intestine compete for vitamin B12. (See "Small intestinal bacterial overgrowth: Etiology and pathogenesis", section on 'Pathophysiology'.)

Diagnosis and management of bacterial overgrowth in patients with SBS is discussed in separate topic reviews. (See "Chronic complications of the short bowel syndrome in adults", section on 'Small intestinal bacterial overgrowth' and "Chronic complications of short bowel syndrome in children", section on 'Small intestinal bacterial overgrowth'.)

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: Short bowel syndrome".)

SUMMARY

●Initial determinants of intestinal function

•Ileum – Resection of the ileum has important implications for patients with SBS because of the ileum's special roles in absorbing vitamin B12 and bile acids (figure 1), reducing intestinal motility when stimulated by fat (the "ileal brake"), and undergoing adaptive changes. (See 'Ileal resection' above.)

Loss of the ileocecal valve reduces the likelihood that a pediatric patient will be able to be weaned from parenteral nutrition (PN). This is because of reduced intestinal transit time and promotion of small bacterial overgrowth. The ileocecal valve appears to be less relevant to outcomes of SBS in adults. (See 'Loss of the ileocecal valve' above.)

•Colon – The colon has an important role in absorption of water and electrolytes and the salvage of energy in the form of short-chain fatty acids. The latter can provide a significant portion of energy requirements in patients with SBS, at least in adults. The colon also helps to slow intestinal transit and stimulate intestinal adaptation. (See 'Loss of the colon' above.)

●Intestinal adaptation

•Definition and time course – Intestinal adaptation refers to changes that occur after intestinal resection that increase absorptive capacity. Both structural and functional changes occur. Most intestinal adaptation occurs in the ileum, but some functional adaption may also occur in the jejunum or colon. This process leads to a gradual improvement in macronutrient absorption during the first one to three years after intestinal resection. (See 'Ileal versus jejunal adaptation' above.)

•Mediators – The best established stimulant of intestinal adaptation is the presence of nutrients in the intestinal lumen; as a result, enteral feeding is the cornerstone of treatment for patients with SBS. This effect is mediated by growth factors produced by the intestine and by functional and hormonal effects of biliary and pancreatic secretions. (See 'Nutrient effects' above and 'Gut hormones' above.)

Glucagon-like peptide 2 (GLP-2) is an important mediator of intestinal adaptation. Exogenous administration of GLP-2 promotes adaptation and nutrient absorption in animal models of SBS. Studies in humans suggest that teduglutide, a longer-acting GLP-2 analog, promotes intestinal adaptation and absorption and has benefits in the weaning of PN in patients with SBS. (See 'Gut hormones' above.)

●Implications – Implementation of these pathophysiologic principles into clinical care is discussed in separate topic reviews. (See "Management of short bowel syndrome in adults" and "Management of short bowel syndrome in children".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jon A Vanderhoof, MD, and Rosemary J Pauley-Hunter, NP-C, MS, RN, who contributed to earlier versions of this topic review.