Fat Malabsorption in Short Bowel Syndrome: A Review of Pathophysiology and Management

Abstract

Fat malabsorption is central to the pathophysiology of short bowel syndrome (SBS). It occurs in patients with insufficient intestinal surface area and/or function, to maintain metabolic and growth demands. Rapid intestinal transit and impaired bile acid recycling further contribute to fat malabsorption. A significant portion of patients require parenteral nutrition (PN) for their survival, but may develop sepsis and liver dysfunction as a result. Despite advancements in the treatment of SBS, fat malabsorption remains a chronic issue for this vulnerable patient population. Peer-reviewed literature was assessed on the topic of fat malabsorption in SBS. Current management of patients with SBS involves dietary considerations, PN management, antidiarrheals, glucagon-like peptide 2 agonists, and multidisciplinary teams. Clinical trials have focused on improving intestinal fat absorption by facilitating fat digestion with pancreatic enzymes. Targeting fat malabsorption in SBS is a potential pathway to improving lifestyle and reducing morbidity and mortality in this rare disease.

Introduction

Short bowel syndrome (SBS) occurs after critical loss of intestinal surface area leading to intestinal failure (IF), characterized by inadequate bowel length and/or function to absorb the nutrients necessary to meet metabolic needs (Table 1). The most common etiology of SBS in children is necrotizing enterocolitis. Others include malrotation with midgut volvulus, intestinal atresias, and gastroschisis. Adults may require intestinal resections and develop SBS after complications of irradiation/cancer, mesenteric vascular accidents, or inflammatory bowel disease. The prevalence of SBS in the US is 3-4 million, with approximately 25,000 patients requiring home parenteral nutrition (PN)^1-3.

Table 1.

Key Points

Fat absorption requires pancreatic enzymes, bile salts, enterocyte apical membrane protein receptors, absorptive surface area and intact intestinal motility.

Medium chain triglycerides are absorbed directly into the portal venous system, rather than requiring chylomicrons, and may be a better energy source for patients with short bowel syndrome.

Surgical short bowel syndrome models in pigs have played a significant role in understanding the disease process and identifying management strategies.

Multidisciplinary care is critical for identifying micronutrient deficiencies in patients with short bowel syndrome and supplementing when necessary to prevent sequelae of fat malabsorption.

While oral pancreatic enzyme replacement was studied in clinical trials and not effective in short bowel syndrome, current studies are focused on glucagon-like peptide 2 agonists for weaning PN and alternative strategies, such as lipase cartridges, for facilitating fat absorption.

Management of SBS focuses on supporting normal growth and development in children through a combination of oral, enteral, and parenteral nutrition. The objective in treating SBS is to achieve enteral autonomy, whereby patients are able to meet fluid and metabolic needs without parenteral support. An important limitation in achieving enteral autonomy is malabsorption of fat and fat-soluble vitamins, resulting in steatorrhea, electrolyte disturbances, and nutritional deficiencies. Multidisciplinary intestinal rehabilitation programs have significantly improved the care of patients with SBS⁴. Despite advancement in the management of patients with SBS, treatment with long-term PN still poses a significant risk for complications, including central line-associated blood stream infections (CLABSIs), progressive liver disease, electrolyte/fluid disturbances, renal disease, growth failure and metabolic disease⁵. Indeed, it has been shown that adults with SBS receiving PN who have sepsis and liver dysfunction have a 2-3 fold increase in mortality compared to the same population without sepsis or liver disease ⁶.

Fat malabsorption is a pivotal factor involved in both the pathogenesis and complications related to SBS. In this review, we discuss the relevant pathophysiology, existing preclinical animal models, and clinical implications of fat malabsorption in SBS. We also provide an overview of ongoing clinical trials and therapeutic developments that specifically target fat malabsorption.

Pathophysiology of Fat Malabsorption in SBS

In a typical Western diet, 40% of energy intake is derived from dietary fat⁷. Dietary fat is comprised of triacylglycerol (TAG), phospholipids, and sterols, with 90-95% of energy sourced from TAG⁸. The building blocks of TAG are three fatty acids acetylated to one of three positions on a glycerol backbone. Variation in TAG is determined by fatty acid chain length, position, and double bond composition.

Dietary fatty acids range up to 24-carbons in length and vary in the arrangement of their carbon-carbon bonds. Saturated fatty acids have no double bonds, thus each carbon in the chain is saturated with hydrogen atoms. Unsaturated fatty acids have one or more carbon-to-carbon double bond. There are two categories of unsaturated fatty acids: monounsaturated fats have one double bond and polyunsaturated fats have two or more double bonds. The majority of dietary TAGs contain chains of over 14 carbons in length, termed long chain triglycerides (LCTs). Medium chain triglycerides (MCTs) are made up of chains between 6-12 carbons in length and short chain fatty acids (SCFAs) have fewer than 6 carbons⁹. Sources of dietary fats include oils that originate from fruits and seeds, such as palm oil, olive oil and soybean oil, and animal sources.

The critical components required for fat digestion and absorption in humans include pancreatic enzymes, bile salts, enterocyte apical membrane protein receptors, sufficient absorptive surface area and intact intestinal motility. A functioning pancreas is required for the secretion of pancreatic lipase, which hydrolyzes up to 70% of total dietary fat, breaking TAGs into the glycerol backbone and free fatty acids (FFAs)¹⁰. The role of bile salts is complex. They are synthesized from cholesterol in the liver and secreted into the intestine along with phospholipids and cholesterol where they form micelles, spherical aggregates of hydrophobic molecules arranged with an outward facing hydrophilic shell, facilitating the digestion and absorption of dietary lipids. The majority (~95%) of bile salts are reabsorbed in the distal ileum and recycled via the enterohepatic circulation¹¹.

Intestinal surface area and motility are fundamental for fat absorption. Upon entering the duodenum, the fat droplets mix with bile salts and pancreatic lipase, which emulsify and hydrolyze TAG. Emulsification puts enzymes in contact with TAG so that digestion can occur (Figure 1). While the initial mixing of pancreatic lipase and TAG occurs in the duodenum, the majority of fat digestion takes place in the upper segment of the jejunum^{12, 13}. After digestion, glycerol and FFAs are absorbed into the enterocytes via key transport proteins such as FAT/CD36^{14, 15}. The majority of FFAs are resynthesized into TAGs in the rough endoplasmic reticulum, which combine with apolipoproteins to form chylomicrons and pass into the lymphatics.

Figure 1.

Physiology of intestinal fat digestion and absorption.

Not all dietary fat undergoes the same pathway for digestion and absorption. Dietary phospholipids and sterols, such as cholesterol, form mixed micelles when they interact with bile salts. Unlike chylomicrons, micelles are formed in the intestine rather than the enterocytes and do not have any associated apolipoproteins. MCTs have a different pathway than TAG composed of LCTs. Rather than requiring chylomicrons and passing into the lymphatics, MCTs pass through the enterocytes and are absorbed directly into the portal venous system⁹.

Fat digestion and absorption are both altered in patients with SBS. First, inadequate small intestinal surface area decreases transit time, limiting the interaction between pancreatic lipase and lipid droplets, thus preventing the hydrolysis of TAG into FFAs that are absorbable. Furthermore, gastric acid hypersecretion, which occurs as a result of hormonal imbalances after intestinal resection, increases the acidity in the upper gastrointestinal tract, denaturing pancreatic enzymes and bile salts¹⁶. Many patients with SBS have decreased jejunal surface area, a key region for fat digestion and absorption (Figure 2). More distally, loss of ileum is also problematic given both decreased absorptive surface area and impaired reabsorption of bile salts, leading to bile acid deficiencies. An inadequate supply of bile acids compromises the ability to form micelles, further impairing dietary fat absorption (Table 2).

Figure 2.

Intestinal alterations in short bowel syndrome.

Table 2.

Mechanisms contributing to fat malabsorption in short bowel syndrome

Contributor	Management
Rapid gastrointestinal transit	Preservation of intestinal length; SIBO management to preserve motility
Decreased surface area	Preservation of intestinal length; Pre-clinical intestinal lengthening efforts and clinical trials on lipase cartridge use
Impaired bile acid recycling	Intravenous lipid emulsions and/or medium chain triglyceride supplementation; bile acid replacement not recommended
Impaired bile acid signaling	Farsenoid X Receptor agnoist

Bile acids were also found to have key roles in hormonal regulation and metabolism via signaling through the Farsenoid X Receptor (FXR)^17-19. Activation of the nuclear receptor, FXR controls metabolism of fatty acids and glucose, and confers a hepatoprotective effect. Impaired recycling of bile acids in patients with SBS impairs signaling through the FXR pathway and contributes to cholestatic liver diseases, such as primary sclerosing cholangitis, primary biliary cholangitis and intestinal failure-associated liver disease (IFALD)^20-23.

Small intestinal bacterial overgrowth (SIBO) is a sequela of SBS that is poorly understood, attributed to proliferation of select microorganisms in the bowel, and impairs quality of life with symptoms of diarrhea and abdominal pain²⁴. SIBO is often empirically treated with antibiotics. Patients may require periodic (7-14 days per month) or continuous use of antibiotics and intermittent rotation of different antibiotics is often performed to reduce risk of resistance²⁵. Prokinetics and herbal remedies may be effective when antibiotics fail²⁶. Probiotics are not recommended due to the risk of developing probiotic-associated central venous catheter bloodstream infection that may lead to sepsis and increased mortality^{27, 28}. Failure of antibiotics does not definitively rule out SIBO, but may prompt testing for an alternative diagnosis that would require directed treatment. If left untreated, SIBO results in reversible loss of intestinal villi, decreased surface area, and impaired intestinal motility all of which further compromise fat absorption^{29, 30}.

Ultimately, alterations in the physiology of fat absorption in SBS contribute to essential fatty acid deficiency (EFAD), fat-soluble vitamin deficiencies, and IFALD. EFAD presents with growth delay, infertility, dermatitis, and hair loss^31-34. It occurs when there is a deficiency in the omega-6 and omega-3 polyunsaturated fatty acids (PUFAs)³⁵, which are long-chain fatty acids that that must be provided in the diet. During EFAD, altered enzymatic activity results in an increase in the ratio of a triene, omega-9 Mead acid, to the tetraene arachidonic acid, an omega-6 fatty acid, which can be used to monitor EFAD in the clinical setting³⁴.

Vitamins are essential micronutrients that cannot be synthesized endogenously and interact with a range of physiologic processes. The fat-soluble vitamins include A, D, E, and K (Table 3).

Table 3.

Function of fat-soluble vitamins and symptoms of deficiency

Vitamin	Primary Sources	Function	Deficiency
Vitamin A	Milk, cheese butter, spinach, carrots, squash	Differentiation and proliferation of epitheilal cells, production of rhodopsin in the retina	Night blindness, xeropthalmia, Bitot spots
Vitamin D	cow's milk, almond milk, soy milk, salmon, tuna, and skin exposure to sunlight	Increases calcium and phosphate levels for mineralization of the bone osteoid	Osteomalacia, ricketts
Vitamin E	Vegetable oils, seeds, nuts, and whole grains	Antioxidant activity, inhibits generation of reactive oxygen species, inhibts lipid peroxidation	Ataxia, hyporeflexia, upward gaze limitations, and blindness, memory impairment, and arrhythmias in severe cases
VItamin K	green leafy vegetables, cabbage, cauliflower	Activation of clotting factors	Hemorrhagic disease of the newborn, easy bleeding and bruising in adults

IFALD develops more commonly in children compared to adults, occurring in over 1/3 of neonates who require PN³⁶. The etiology is multifactorial with the risk of IFALD increasing in patients receiving intravenous lipid emulsions (ILEs) containing high levels of omega-6 fatty acids and phytosterols, low alpha-tocopherol, and specific patient characteristics, such as lack of an ileocecal valve, prematurity, among others³⁷. Hepatic dysfunction develops, resulting in cholestasis and increased transaminases, and may progress to end stage liver disease, requiring transplantation or leading to death^{38, 39}. Cholestatic IFALD may also be associated with reduced bile excretion which can lead to further exacerbation of fat malabsorption and continued PN dependence.

Preclinical Animal models

Animal models play a pivotal role in understanding lipid digestion, absorption, and metabolism in patients with short bowel syndrome. Early studies used rat models to determine the normal physiology in fat metabolism. For instance, Ricketts et al. administered safflower oil (polyunsaturated fatty acid) vs lard-based (saturated fatty acid) diets to normal rats and determined that lipase activity was 80% higher in the subjects receiving safflower oil compared those receiving lard⁴⁰. Normal rats were also used by Vallot. et al. to determine the impact of chain length on absorption pathway⁴¹. Medium chain fatty acids traveled to the portal blood when administered alone compared to their route to the lymphatics when administered with LCTs⁴¹. Piglets studies confirmed these findings, demonstrating the rapid rise of MCTs in the portal blood after direct infusion into the duodenum⁴².

Piglet models of SBS following extensive intestinal resection have been used to study the disease pathophysiology and evaluate treatments. Intestinal resection models allowed for the characterization of intestinal adaptation, a process in which morphological changes, such as increased villus height, crypt depth, and hyperplasia, occur as an adaptive response to resection and result in functional improvement. Intestinal adaptation is mediated by glucagon-like peptide 2 (GLP-2) and a mechanism that may be harnessed to facilitate bowel growth and PN weaning in patients with SBS⁴³. One of the first piglet intestinal resection models was performed by Sigalet et al in 1990⁴⁴. Animals underwent transection and reanastomosis of mid-small bowel (control) vs 75% mid-small bowel resection, leaving equal residual lengths of jejunum and ileum. Over the course of the study, resected subjects demonstrated a decrease in weight gain. However, resected animals demonstrated histological signs of intestinal adaptation that resulted in 18% increase in absorptive surface area by week 6 and 33% by week 16. In 2011, Turner et al. developed two different resection models in neonatal piglets, one involving midintestinal resection with jejunoileal anastomosis and a second model involving distal intestinal resection with jejunocolic anastomosis⁴⁵. Both cohorts exhibted signs of malabsorption with growth retardation and impaired fat absorption at study day 15. However, only the subjects with preserved ileum demonstrated improved intestinal adaptation on histology and successfully weaned from PN by the end of the two-week study⁴⁵. The ileum is a reservoir for hormonal cells that produce GLP-2, which explains why the adaptive response is limited to subjects with preserved ileum⁴³.

Investigators have used resection models to evaluate therapeutics. With resepect to fat malabsorption specifically, two recent preclinical studies utilized an immobilized lipase cartridge (Alcresta Therapeutics, Newton, MA) that connects in-line with existing enteral feeding sets, which is designed to digest fats in formula feeds prior to reaching the patient. Use of this cartridge was associated with both improved fat absorption and decreased PN dependence in a preclinical porcine SBS model^{46, 47}.

Piglets are also frequently used to evaluate surgical therapies for SBS. Bowel lengthening operations, such as the Bianchi procedure and serial transverse enteroplasty, were tested in piglets^{48, 49}. Piglets were also used to evaluate devices exerting a mechanical force for lengthening, such as balloons and hydraulically controlled devices⁵⁰. The most recent promising model of distraction enterogenesis employs nitinol coated springs that expand, exerting a mechanical force on the surrounding bowel⁵¹. These devices have resulted in small intestinal lengthening of 1.5-3x in piglets.

Models of IFALD have been developed to successfully evaluate toxins and hepatoprotective therapies. Neonatal piglets, delivered preterm and initiated on PN, have been used to model the effects of FXR agonists and the consequences of certain lipid emulsions. Burrin et al. established a model of IFALD in neonatal piglets receiving PN⁵². Compared to enterally fed piglets, those receiving PN over 17 days developed insulin resistance, hepatic inflammation and steatosis⁵². Neonatal piglets were also used by the group to test new generation lipid emulsions⁵³. This model was also used in a recent study to evaluate a structurally engineered fatty acid that acts through PPARα, activating FXR and preventing hepatic steatosis and cholestasis⁵⁴.

Diagnosis and Evaluation

Fat malabsorption may be suspected clinically in the SBS patient with steatorrhea, weight loss, failure to thrive, fat-soluble vitamin deficiencies, or EFAD. Diagnostic tests for fat malabsorption are primarily based upon those in the cystic fibrosis (CF) and chronic pancreatitis literature for evaluation of pancreatic enzyme insufficiency⁵⁵. As fat malabsorption, by definition, results in increased fecal fat content, measurement of fecal fat is often the initial step. The Sudan stain is an inexpensive, easy, and reasonably sensitive qualitative test of fat malabsorption (Table 4). Spot collected stool is stained with Sudan red and examined microscopically, with 100% sensitivity and 96% specificity. In this test, a stool sample is mixed with thanolic Sudan III and glacial acetic acid and smeared on microscope slide. The slide heated then examined for evidence of fatty acid globules. The number of fat globules present correlates with the quantitative amount of fecal fat. Alternative methods of spot stool fat quantification (acid steatocrit, near-infrared reflectance analysis) are accurate and quick measures of fat content, although not widely available in the United States⁵⁶.

Table 4.

Diagnostic Tests for Fat Malabsorption

Test	Normal Range	Pro	Cons
Sudan stain for fecal fat	No value	100% Sensitivity; 96% Specificity	Not quantitative
Coefficient of fat absorption	85% or greater up to 6 months of age; 93% or greater for children older than 6 months and adults	Quantitative test	72 hour stool collection required
Malabsorption blood test	Not yet determined	Can elucidate etiology of malabsorption	Not yet validated
Fecal Elastase	>200 μg/g stool	High sensitivity and specificity	Unable to differentiate pancreatic from non-pancreatic malabsorption

The gold standard test to assess fat malabsorption is the coefficient of fat absorption obtained from a 72-hour stool collection, which measures the percentage of consumed fat that is absorbed. A controlled high-fat diet is administered, and stool is collected for 72 hours. Various protocols are used, ranging from initiation of the high-fat diet three days prior to stool collection, to the use of dye as a colored marker at the start of the diet with stool collection at the first discolored stool, to keeping a detailed dietary record from which the fat intake is calculated for the duration of the stool collection⁵⁷. The coefficient of fat absorption (%) is calculated as the [g fat intake – g fat excretion] / [g fat intake] x 100. Despite its accuracy, a 72-hour stool collection is burdensome for patients and caregivers due to the need for sample refrigeration, and also relies heavily upon patient compliance with the diet and stool collection protocols.

Given the challenges with 72-hour stool collection, the malabsorption blood test has emerged as a measure of fat malabsorption⁵⁸. Following an overnight fast, patients are administered a standardized meal containing pentadecanoic acid or triheptadecanoic acid, two odd-number carbon chain length fatty acids. Plasma samples are obtained over eight hours. Pentadecanoic acid is absorbed without enzymatic digestion, whereas triheptadecanoic acid requires lipase hydrolysis. Thus, differential absorption of the two fatty acids may provide information on the degree of fat malabsorption. Furthermore, unlike the Sudan stain and coefficient of fat absorption, the malabsorption blood test can discriminate the etiology of fat malabsorption, i.e. whether pancreatic exocrine insufficiency is present. The malabsorption blood test has not yet been validated in SBS populations; thus, further studies are needed. An additional noninvasive test of pancreatic insufficiency is measurement of fecal elastase. Elastase is secreted by the exocrine pancreas into the gastrointestinal tract. A low fecal elastase is indicative of exocrine pancreatic insufficiency⁵⁹.

Sequelae of fat malabsorption include fat-soluble vitamin deficiencies and EFAD. While fat-soluble vitamins are often supplemented either enterally or parenterally, fat malabsorption in addition to intestinal loss (particularly of the ileum) may result in an EFAD. The European Society for Parenteral and Enteral Nutrition guidelines for intestinal failure recommend that baseline serum vitamin levels should be measured at least annually⁶⁰. For patients with SBS, however, this is likely inadequate for assessing fat-soluble vitamin status. Similarly, EFAD should be evaluated using the triene:tetraene ratio, with more frequent monitoring in infants and children, in cases of lipid restriction or fat malabsorption.

Management

Initial nutrition management in patients with SBS and related fat malabsorption is focused on intravenous supplementation of fat-soluble vitamins and essential fatty acids. Historically, linoleic acid and α-linolenic acid were considered an essential dietary need to prevent EFAD. However, success using fish oil lipid emulsions (FOLE), which contain minimal linoleic acid and α-linolenic acid , but substantial arachidonic acid and docosahexaenoic acid (downstream products of linoleic acid and arachidonic acid, respectively), to prevent EFAD have expanded our understanding of essential fatty acids³⁵. Thus, ILEs are a necessary component of PN for those unable to tolerate EN but are not risk-free. For example, omega-6 fatty acids are proinflammatory and increase IFALD risk, while children with concern for cholestasis can be maintained on 100% FOLE, which treats cholestatic liver disease in pediatric SBS patients with a history of IFALD^61-65. Plant oil-based ILEs contain phytosterols, which undergo limited absorption when given enterally, but promote liver injury when administered intravenously^{37, 66, 67}.

The ultimate goal of intravenous lipid supplementation is to give the chance for the intestine to adapt and for enteral autonomy to be achieved. With the use of various strategies to improve fat absorption this can be accelerated. Provision of EN to the gut has numerous advantages including enhancement of intestinal adaptation, preservation of hepatic immune function, and improved gut barrier function⁶⁸. Weaning of PN further reduces the risk for IFALD and central line-related complications⁶⁹.

When providing EN, fat absorption depends on the specific intestinal anatomy. In patients with ileal resections, impaired bile acid absorption via the enterohepatic circulation results in fat malabsorption. High fat intake may result in delayed gastric emptying, early satiety and increased water loss from the colon, which must be monitored⁷⁰. Patients with SBS are at high risk for fat malabsorption and steatorrhea, which may significantly worsen when providing EN. The presence of an intact colon also increases the risk for formation of calcium oxalate stones. In SBS, unabsorbed fat in the intestine binds calcium, leading to increased absorption of oxalate, which is normally bound to calcium and excreted. Oxalate is absorbed at higher rates and precipitates with calcium in the kidney, resulting in nephrolithiasis and ureteral obstruction⁷¹. A diet low in oxalate is advised for patients with an intact colon and SBS⁷⁰.

Compared with patients who have a colon in continuity, those with either a jejunostomy or ileostomy may actually be able to tolerate a higher fat diet (30-40% of calories)⁷². For patients with a remnant colon, medium-chain triglyceride (MCT) supplementation may improve overall fat absorption compared to diets consisting of only long-chain triglycerides (LCTs)⁷³. Jeppesen et al. evaluated the impact of MCT supplementation in 19 adult patients, 10 of whom had a colon in continuity. When the colon was in continuity, MCTs increased energy absorption⁷³. However, MCT-based formulas are imperfect. For example, MCT-based formulas must be supplemented with both omega-3 and omega-6 fatty acids to avoid EFAD. In addition, MCTs lack the benefits that short- and long-chain triglycerides provide, including greater trophic effect on the intestine and superior intestinal adaptation⁷⁴.

Medical therapies assist in the management of fat malabsorption-related complications. Antidiarrheals can be used for bowel control to improve the quality of life but may increase the risk of bacterial overgrowth. Bile acid replacement therapy and binding resins, such as cholestyramine, have theoretical advantages, but have not demonstrated clinical benefit and may interfere with medication absorption and worsen steatorrhea and secretory diarrhea,^75,76. Gastric acid hypersecretion is common in patients with SBS. Gastrin degradation is impaired, leading to hypergastrinemia and acid hypersection⁷⁷. Treatment with proton pump inhibitors or H2 blockers is recommended in the first 6-12 months after resection in adult and pediatric patients and may be continued after that time on a case-by-case basis⁷⁸. When SIBO occurs, antibiotic therapy may be initiated to avoid villous blunting, which may further impair absorption. Common treatment modalities include ciprofloxacin and metronidazole²⁴. There is also emerging evidence in favor of probiotics in the management of SIBO^{79, 80}.

Surgical management for SBS is another strategy that is focused on optimizing the function of the remaining intestine. In patients with SBS who require reoperation on the intestinal remnant, resection should be avoided whenever possible so as to preserve the existing intestinal length⁷⁰. Alternative procedures to resection include strictureplasty for benign strictures and serosal patching. If resection is unavoidable, an end-to-end anastomosis is preferred to maximize functional intestinal length and to prevent formation of blind loops.

Therapeutic developments and Clinical Trials

Despite advances in the management of SBS, no single therapeutic targeting fat malabsorption has reliably demonstrated improved PN weaning and decreased mortality. Few studies have or are currently investigating therapeutics for fat malabsorption in SBS. The majority of active clinical trials in patients with SBS are evaluating glucagon-like peptide 2 (GLP-2) agonists such as teduglutide, and have demonstrated improved intestinal adaptation, decrease in fluid requirements, and PN weaning in some cases. Unfortunately, patients may still develop fat-soluble vitamin deficiencies and require endoscopic monitoring for intestinal adenomas⁸¹.

Improving fat absorption may decrease micronutrient deficiencies and PN requirements, thus reducing morbidity and mortality. The use of enzymatic modalities to improve fat absorption have been the focus of several recent investigations. Similar to SBS, CF is another condition characterized by fat malabsorption. The benefit of pancreatic enzyme replacement in patients with CF is well established in those with acquired pancreatic insufficiency⁸². A 2020 study investigated the impact of a readily absorbable structured lipid technology on fat absorption among children with CF and pancreatic insufficiency. The structured lipid was administered as an oral supplement powder containing lisophosphatidylcholine, which is water-soluble and designed to facilitate lipid absorption⁸³. This study demonstrated the successful use of this lipid to improve fat absorption, plasma fatty acids, and growth within three months.⁸⁴ However, as the structured lipid requires enteral absorption, its clinical utility may be limited in patients with SBS. Furthermore, unlike in CF, the pathophysiology of fat malabsorption in SBS involves rapid intestinal transit and decreased absorptive surface area. While both CF and SBS involve fat malabsorption, the mechanisms differ and thus may require different treatment approaches.

The effect of orally administered pancreatic enzyme replacement in mostly enterally-fed patients intestinal failure was evaluated in a phase 2 clinical trial⁸⁵ (Table 5). The primary outcome was the coefficient of fat absorption over a 72-hour window. In all 11 subjects, no statistical improvement in enteral fat absorption was observed, although 6 subjects did exhibit an increase in coefficient of fat absorption after using pancreatic enzymes⁸⁵. The conclusion from this trial was that oral pancreatic enzyme replacement therapy is ineffective and not recommended for short bowel syndrome. Additional studies could be pursued given the small sample size, but rapid transit and decreased intestinal length are significant limitations to oral pancreatic enzyme replacement.

Table 5.

Ongoing and completed clinical trials for fat malabsorption in SBS

Investigator	Institution	Number	Year Initiated	Primary Outcomes	Study Design	Intervention	Result
Puder et al.	Boston Children's Hospital	05635747	2022	Change from baseline in PN calories	Prospective exploratory study	Immobilized lipase cartridge	Pending
Puder et al.	Boston Children's Hospital	03530852	2018	Change from baseline in PN calories	Prospective exploratory study	Immobilized lipase cartridge	Pending
Zemel et al.	Children's Hospital of Philadelphia	03097029	2016	Change in Coefficient of Fat Absorption	Prospective exploratory study	Pancrealipase	No benefit

An alternative strategy for improving fat absorption in SBS utilizes an immobilized lipase cartridge (ILC; RELiZORB, Alcresta Therapeutics, Newton, MA) that is connected in-line with enteral tube feeding sets, which improves fat and nutrient absorption by predigesting fats in the enteral formula before it reaches the patient’s body. It is hypothesized that this would bypass the rate limiting steps that impact fat absorption in SBS specifically (i.e. rapid intestinal transit and decreased intestinal surface area). Preclinical studies in a porcine SBS model demonstrated that the ILC improved absorption of fat and fat-soluble vitamins, and reduced PN dependence^{46, 47}. Two clinical trials designed to evaluate the effects of the ILC in pediatric patients with SBS are ongoing (NCT03530852, NCT05635747)⁸⁶.

Discussion

Fat malabsorption is frequently encountered in adult and pediatric patients with SBS and intestinal failure, and may lead to life-limiting complications. Intestinal loss involving the jejunum obviates the primary site of fat absorption and ileal loss results in a deficiency of the bile acids required to absorb fats and fat-soluble vitamins. Sequelae of fat malabsorption include deficiencies in vitamins A, D, E, and K, increasing the risk for night blindness, ataxia, impaired clotting, and osteoporosis. Without sufficient dietary fats, children develop failure to thrive and impaired growth and development. Adult patients may develop metabolic abnormalities, osteomalacia, and osteoporosis. Supplementation of fats via PN is often required and carries the risks associated with indwelling central catheters and ILEs, such as CLABSIs and IFALD, respectively. Dietary modifications, GLP-2 agonists, and surgical treatments delivered through intestinal rehabilitation programs are designed to sustain normal metabolism and strive to improve absorption, offering patients a chance in achieving enteral autonomy. Supplementing the enzymes enterally necessary to facilitate fat absorption is challenging due to limitations attributed to the pathophysiology of SBS namely decreased intestinal surface area, impaired intestinal motility, and bile acid deficiencies. Ongoing clinical trials utilizing an immobilized lipase cartridge avoids stability issues related to predigested formulas and may address the limitations affecting enteral fat absorption thus potentially improving the chance of achieving enteral autonomy. Ultimately, fat malabsorption remains a critical component in the pathophysiology of SBS and an active area of ongoing research.