GLIM criteria for the diagnosis of malnutrition - A consensus report from the global clinical nutrition community.

RATIONALE: This initiative is focused on building a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings. METHODS: In January 2016, the Global Leadership Initiative on Malnutrition (GLIM) was convened by several of the major global clinical nutrition societies. GLIM appointed a core leadership committee and a supporting working group with representatives bringing additional global diversity and expertise. Empirical consensus was reached through a series of face-to-face meetings, telephone conferences, and e-mail communications. RESULTS: A two-step approach for the malnutrition diagnosis was selected, i.e., first screening to identify "at risk" status by the use of any validated screening tool, and second, assessment for diagnosis and grading the severity of malnutrition. The malnutrition criteria for consideration were retrieved from existing approaches for screening and assessment. Potential criteria were subjected to a ballot among the GLIM core and supporting working group members. The top five ranked criteria included three phenotypic criteria (weight loss, low body mass index, and reduced muscle mass) and two etiologic criteria (reduced food intake or assimilation, and inflammation or disease burden). To diagnose malnutrition at least one phenotypic criterion and one etiologic criterion should be present. Phenotypic metrics for grading severity as Stage 1 (moderate) and Stage 2 (severe) malnutrition are proposed. It is recommended that the etiologic criteria be used to guide intervention and anticipated outcomes. The recommended approach supports classification of malnutrition into four etiology-related diagnosis categories. CONCLUSION: A consensus scheme for diagnosing malnutrition in adults in clinical settings on a global scale is proposed. Next steps are to secure further collaboration and endorsements from leading nutrition professional societies, to identify overlaps with syndromes like cachexia and sarcopenia, and to promote dissemination, validation studies, and feedback. The diagnostic construct should be re-considered every 3-5 years.

GLIM criteria for the diagnosis of malnutrition - A consensus report from the global clinical nutrition community.

RATIONALE: This initiative is focused on building a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings. METHODS: In January 2016, the Global Leadership Initiative on Malnutrition (GLIM) was convened by several of the major global clinical nutrition societies. GLIM appointed a core leadership committee and a supporting working group with representatives bringing additional global diversity and expertise. Empirical consensus was reached through a series of face-to-face meetings, telephone conferences, and e-mail communications. RESULTS: A two-step approach for the malnutrition diagnosis was selected, i.e., first screening to identify "at risk" status by the use of any validated screening tool, and second, assessment for diagnosis and grading the severity of malnutrition. The malnutrition criteria for consideration were retrieved from existing approaches for screening and assessment. Potential criteria were subjected to a ballot among the GLIM core and supporting working group members. The top five ranked criteria included three phenotypic criteria (non-volitional weight loss, low body mass index, and reduced muscle mass) and two etiologic criteria (reduced food intake or assimilation, and inflammation or disease burden). To diagnose malnutrition at least one phenotypic criterion and one etiologic criterion should be present. Phenotypic metrics for grading severity as Stage 1 (moderate) and Stage 2 (severe) malnutrition are proposed. It is recommended that the etiologic criteria be used to guide intervention and anticipated outcomes. The recommended approach supports classification of malnutrition into four etiology-related diagnosis categories. CONCLUSION: A consensus scheme for diagnosing malnutrition in adults in clinical settings on a global scale is proposed. Next steps are to secure further collaboration and endorsements from leading nutrition professional societies, to identify overlaps with syndromes like cachexia and sarcopenia, and to promote dissemination, validation studies, and feedback. The diagnostic construct should be re-considered every 3-5 years.

Dietary lipids alter the effect of steroids on the transport of fructose following intestinal resection in rats.

BACKGROUND: Glucocorticosteroids alter intestinal morphology and transport. We tested the hypothesis that the desired intestinal adaptive response following intestinal resection may be enhanced further by the locally active steroid budesonide, and by feeding a saturated as compared with a polyunsaturated fatty acid diet. METHODS: An in-vitro uptake method was used to assess intestinal fructose uptake by rats of semisynthetic diets enriched in saturated or polyunsaturated fatty acids, and injected with budesonide or control solution. RESULTS: Budesonide increased ileal fructose uptake in chow and PUFA-fed animals, but reduced jejunal fructose uptake in rats fed SFA. GLUT5 and GLUT2 protein and mRNA did not correlate with changes in fructose uptake. Steroids reduced jejunal proglucagon expression in animals fed chow. Animals fed SFA and given budesonide had a reduction in jejunal ODC mRNA compared with those fed PUFA or chow. CONCLUSIONS: (1) budesonide increases ileal fructose uptake following intestinal resection, and this beneficial effect is prevented by feeding SFA rather than PUFA; (2) fructose uptake does not correlate with GLUT5 and GLUT2 protein and mRNA; (3) ODC and proglucagon may be involved in this adaptive response.

Changes in small intestinal nutrient transport and barrier function after lipopolysaccharide exposure in two pig breeds.

Specific pig breeds with unique characteristics have been developed, and the current study sought to characterize some of these differences. Using modified Ussing chambers, electrophysiological mucosal transport of D-glucose, L-Gln, L-Pro, L-Arg, L-Thr, and glycylsarcosine was assessed in small intestinal tissues (duodenum, jejunum, ileum) taken from Yorkshire-based hybrid (BW = 142.4 +/- 2.0 kg; mean age = 8 mo) and Meishan (BW = 65.8 +/- 0.8 kg; mean age = 6 mo) female pigs after 4 h of lipopolysaccharide (LPS) exposure. Gilts were randomly assigned to control (saline infusion; n = 6 Yorkshires, n = 5 Meishans) or LPS (n = 7 Yorkshires, n = 5 Meishans) groups. Therefore, treatments were arranged in a 2 (breed) x 2 (LPS infusion) factorial. Four hours after infusions, pigs were euthanized, and intestinal segment samples were removed. Glucose transport in the ileum was decreased (P < 0.001) in Yorkshires with LPS but was increased (P < 0.001) by over 2-fold in Meishans with LPS. After LPS infusion, Pro transport was increased in duodenum (over 5-fold; P = 0.04) and ileum (over 10-fold; P < 0.001) of Meishans but was unaffected in Yorkshires. Arginine transport in the ileum of control Meishans was greater (P = 0.05) than Arg transport in control Yorkshires. Glycylsarcosine transport was greater (P = 0.02) in Meishans than Yorkshires (nearly 2-fold), regardless of LPS provision. Glycylsarcosine transport was increased (P = 0.003) over 2-fold by LPS, regardless of pig breed. Resistance (barrier function) was increased (P = 0.03) by LPS in Yorkshires but was unaffected in Meishans. The current study indicates that small intestinal function responded differently to LPS in Yorkshire and Meishan gilts and that these effects were nutrient- and segment-dependent.

Glucagon-like peptide 2 stimulates intestinal nutrient absorption in parenterally fed newborn pigs.

OBJECTIVES: Parenteral nutrition is a critically important intervention for children with intestinal dysfunctions. However, total parenteral nutrition (TPN) with no enteral feeding is associated with small intestine atrophy and malabsorption, which complicate the transition to enteral nutrition. The objective of the present study was to evaluate the therapeutic potential of the intestinotrophic peptide glucagon-like peptide 2 (GLP-2), which reduces TPN-associated atrophy and maintains nutrient absorption in adult rats, for preventing nutrient malabsorption in neonates receiving TPN. METHODS: Term pigs obtained by cesarean delivery received from birth TPN alone (TPN; n = 7) or TPN with GLP-2 (25 nmol . kg(-1) . d(-1); GLP-2; n = 8) or were fed sow milk enterally (n = 7). The small intestine was removed on postnatal day 6 to measure morphological responses and absorption of glucose, leucine, lysine and proline by intact tissues and brush border membrane vesicles and to quantify the abundances of mRNA and protein for enterocyte glucose transporters (SGLT-1 and GLUT2). RESULTS: Relative to TPN alone, administration of GLP-2 resulted in small intestines that were larger (P < 0.01), had greater abundances of mRNA and protein for SGLT-1, but not for GLUT2, and had higher capacities to absorb nutrients (P < 0.01). Moreover, the intestines of GLP-2 pigs were comparable in size and absorptive capacities with those of pigs fed sow milk enterally. CONCLUSIONS: Providing GLP-2 to neonates receiving TPN prevents small intestine atrophy, results in small intestine absorptive capacities that are comparable to when nutrients are provided enterally and may accelerate the transition from TPN to enteral nutrition.

Urokinase induced fibrinolysis in thromboelastography: a model for studying fibrinolysis and coagulation in whole blood.

BACKGROUND: The contact system (CS) proteins, factor XII and prekallikrein are thought to have roles in blood coagulation and fibrinolysis. Recent research has suggested that the CS proteins might be more important in fibrinolysis and cell function than in coagulation. Most studies on fibrinolysis have used plasma or euglobulin assays, ignoring the influence of cellular elements of blood on the fibrinolytic process. OBJECTIVE AND METHODS: In order to study both coagulation and fibrinolysis in whole blood (WB), we have developed a thromboelastography (TEG) assay to investigate both coagulation and fibrinolysis in the same blood sample. In this assay, named urokinase (UK) induced fibrinolysis in thromboelastography (UKIFTEG), TEG is performed on recalcified citrated WB in the presence of UK. Large variations in Ly60 (percentage lysis 60 min after clot formation) were obtained between different donors with the same UK concentration. The UKIFTEG assay was therefore performed using UK concentrations that gave Ly60 values in the approximate range of 20-40%. RESULTS: The effect of CS activation was investigated in the presence or absence of celite (10 mg mL(-1) blood). Celite shortened the clotting time (CT), and increased Ly60 values. Factor XIIa (FXIIa) and plasma kallikrein (KK) produced concentration dependent reductions in CT (significant at concentrations of 1303 and 2600 ng mL(-1) blood, respectively) and increased Ly60 values (significant at concentrations of 652 and 1300 ng mL(-1) blood, respectively). CONCLUSIONS: Our results show that CS activation and both FXIIa and KK produce reductions in clotting time and enhanced fibrinolysis in UKIFTEG.

Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients.

BACKGROUND AND AIMS: Glucagon-like peptide 2 (GLP-2) may improve intestinal absorption in short bowel syndrome (SBS) patients with an end jejunostomy. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant GLP-2 analogue, prolongs the intestinotrophic properties of GLP-2 in animal models. The safety and effect of teduglutide were investigated in SBS patients with and without a colon in continuity. METHODS: Teduglutide was given subcutaneously for 21 days once or twice daily to 16 SBS patients in the per protocol investigational group, 10 with end jejunostomy (doses of 0.03 (n = 2), 0.10 (n = 5), or 0.15 (n = 3) mg/kg/day), one with <50% colon in continuity (dose 0.03 mg/kg/day), and five with > or = 50% colon in continuity (dose 0.10 mg/kg/day). Nutrient balance studies, D-xylose tests, and intestinal mucosa biopsies were performed at baseline, on the last three days of treatment, and after three weeks of follow up. Pre-study fasting native GLP-2 levels were determined for the five patients with > or = 50% colon in continuity. RESULTS: Pooled across groups and compared with baseline, teduglutide increased absolute (+743 (477) g/day; p<0.001) and relative (+22 (16)%; p<0.001) wet weight absorption, urine weight (+555 (485) g/day; p<0.001), and urine sodium excretion (+53 (40) mmol/day; p<0.001). Teduglutide decreased faecal wet weight (-711 (734) g/day; p = 0.001) and faecal energy excretion (-808 (1453) kJ/day (-193 (347) kcal/day); p = 0.040). In SBS patients with end jejunostomy, teduglutide significantly increased villus height (+38 (45)%; p = 0.030), crypt depth (+22 (18)%; p = 0.010), and mitotic index (+115 (108)%; p = 0.010). Crypt depth and mitotic index did not change in colonic biopsies from SBS patients with colon in continuity. The most common side effects were enlargement of the stoma nipple and mild lower leg oedema. The improvements in intestinal absorption and decreases in faecal excretion noted after treatment had reversed after the drug free follow up period. A controlled study with a more robust design is ongoing in order to determine the optimal dosage of teduglutide for SBS patients to achieve the maximal effect and utility of this drug in clinical practice. CONCLUSION: Teduglutide, at three dose levels for 21 days, was safe and well tolerated, intestinotrophic, and significantly increased intestinal wet weight absorption in SBS patients with an end jejunostomy or a colon in continuity.

The locally acting glucocorticosteroid budesonide enhances intestinal sugar uptake following intestinal resection in rats.

BACKGROUND AND AIMS: Locally and systemically acting corticosteroids alter the morphology and transport function of the intestine. This study was undertaken to assess the effect of budesonide, prednisone, and dexamethasone on sugar uptake. METHODS: Adult male Sprague Dawley rats underwent transection or resection of 50% of the middle portion of the small intestine, and in vitro uptake of sugars was measured. RESULTS: The 50% enterectomy did not alter jejunal or ileal uptake of glucose or fructose. Prednisone had no effect on the uptake of glucose or fructose in resected animals. In contrast, in resected rats budesonide increased by over 120% the value of the jejunal maximal transport rate for the uptake of glucose, and increased by over 150% ileal uptake of fructose. Protein abundance and mRNA expression of the sodium dependent glucose transporter in brush border membrane (SGLT1), sodium independent fructose transporter in the brush border membrane (GLUT5), sodium independent glucose and fructose transporter in the basolateral and brush border membranes (GLUT2), and Na(+)/K(+) ATPase alpha1 and beta1 did not explain the enhancing effect of budesonide on glucose or fructose uptake. Budesonide, prednisone, and dexamethasone reduced jejunal expression of the early response gene c-jun. In resected animals, expression of the mRNA of ornithine decarboxylase (ODC) in the jejunum was reduced, and corticosteroids reduced jejunal expression of the mRNA of proglucagon. CONCLUSIONS: These data suggest that the influence of corticosteroids on sugar uptake in resected animals may be achieved by post translational processes involving signalling with c-jun, ODC, and proglucagon, or other as yet unknown signals. It remains to be determined whether budesonide may be useful to stimulate the absorption of sugars following intestinal resection in humans.

Intestinal resection- and steroid-associated alterations in gene expression were not accompanied by changes in lipid uptake.

BACKGROUND/AIMS: Glucocorticosteroids alter the morphology and transport function of the intestine of adult rats. This study was undertaken to assess the possible effect on intestinal lipid uptake of the locally acting steroid budesonide, or the systemically active prednisone or dexamethasone. METHODS: Sprague-Dawley rats underwent intestinal transection or 50% intestinal resection. Budesonide, prednisone, dexamethasone, or control vehicle was given for 2 weeks from the time of surgery. Uptake was measured using ring uptake technique. RESULTS: Resection had no effect on the mRNA expression for the early response genes, for proglucagon, or for the ileal lipid binding protein (ILBP), but was associated with reduced jejunal ornithine decarboxylase (ODC) mRNA and with reduced jejunal mRNA for the liver fatty acid binding protein (L-FABP). All three steroids reduced jejunal mRNA for proglucagon and c-jun, and did not affect the mRNA for L-FABP or for ILBP. These resection- and steroid-associated changes in gene expression were not associated with alterations in the intestinal uptake of long chain fatty acids or cholesterol. CONCLUSIONS: The resection-associated alterations in the RNA expression of ODC and L-FABP and the steroid-associated changes in mRNA expression of c-jun and proglucagon were not accompanied by variations in lipid uptake.

Effects of short-chain fatty acid-supplemented total parenteral nutrition on intestinal pro-inflammatory cytokine abundance.

We examined the effect of short-chain fatty acid-supplemented total parenteral nutrition on proinflammatory cytokine levels in piglets. Piglets (N = 22) received either standard total parenteral nutrition or total parenteral nutrition supplemented with short-chain fatty acids. After seven days of continuous nutrient infusion, proinflammatory cytokine (TNF-alpha, IL-1beta, IL-6) abundance in plasma, jejunal, and ileal samples and small intestinal myeloperoxidase was determined using western blotting. No differences were seen in TNF-alpha small intestinal abundance. IL-1beta was higher in the small intestine of the short-chain fatty acid group (P < 0.05). IL-6 was higher in intestinal samples of the short-chain fatty acid group (P = 0.05), with the ileum having a greater abundance of IL-6 than the jejunum (P < 0.005). No differences in proinflammatory cytokine abundance in the plasma or tissue myeloperoxidase were seen. These results indicate short-chain fatty acids beneficially increase small intestinal abundance of IL-1beta and IL-6 during total parenteral nutrition administration, while not affecting systemic production of these cytokines or intestinal inflammation.

Acidomucin goblet cell expansion induced by parenteral nutrition in the small intestine of piglets.

Total parenteral nutrition (TPN) impairs small intestine development and is associated with barrier failure, inflammation, and acidomucin goblet cell expansion in neonatal piglets. We examined the relationship between intestinal goblet cell expansion and molecular and cellular indices of inflammation in neonatal piglets receiving TPN, 80% parenteral + 20% enteral nutrition (PEN), or 100% enteral nutrition (control) for 3 or 7 days. Epithelial permeability, T cell numbers, TNF-alpha and IFN-gamma mRNA expression, and epithelial proliferation and apoptosis were compared with goblet cell numbers over time. Epithelial permeability was similar to control in the TPN and PEN jejunum at day 3 but increased in the TPN jejunum by day 7. By day 3, intestinal T cell numbers were increased in TPN but not in PEN piglets. However, goblet cell expansion was established by day 3 in both the TPN and PEN ileum. Neither TNF-alpha nor IFN-gamma mRNA expression in the TPN and PEN ileum correlated with goblet cell expansion. Thus goblet cell expansion occurred independently of overt inflammation but in association with parenteral feeding. These data support the hypothesis that goblet cell expansion represents an initial defense triggered by reduced epithelial renewal to prevent intestinal barrier failure.

Hypoxia differentially regulates nutrient transport in rat jejunum regardless of luminal nutrient present.

Aggressive enteral nutrition and poor intestinal perfusion are hypothesized to play an important pathogenic role in nonocclusive small bowel necrosis. This study tests the hypothesis that glucose and glutamine transport are differentially regulated during hypoxia regardless of the luminal nutrient present. Sprague-Dawley rats (247 +/- 3 g; n = 16) were randomized to receive 1 h of intestinal hypoxia or serve as normoxic controls. During this hour, jejunal loops were randomized to receive in situ perfusions of mannitol, glucose, or glutamine. When compared with normoxic groups, glucose but not glutamine transport was impaired (P < 0.001) during hypoxia. Messenger RNA abundance of the sodium glucose cotransporter sodium-dependent glucose cotransporter-1 (SGLT-1) and neutral basic amino acid transporter B(o) did not differ with hypoxia or nutrient perfused. Jejunal brush-border SGLT-1 abundance was decreased (P = 0.039) with hypoxia; however, total cellular SGLT-1 protein abundance did not differ among treatment groups. These data indicate that SGLT-1 activity is regulated during hypoxia at the posttranslational level. Additional information regarding the mechanisms regulating nutrient transport in the hypoperfused intestine is critical for optimizing the composition of enteral nutrient formulas.

Dietary lipids alter the effect of steroids on the uptake of lipids following intestinal resection in rats.

Steroids alter the transport function of the intestine. This study was undertaken to assess the effect of glucocorticosteroids on lipid uptake in rats fed either a saturated (SFA) or a polyunsaturated fatty acid (PUFA) diet. Sprague-Dawley rats underwent transection or 50% resection of the small intestine. The steroids had no effect on the uptake of lipids. However, resection decreased the jejunal uptake of palmitic acid in animals fed SFA and increased the jejunal uptake of palmitic and linoleic acids in those fed PUFA. In animals undergoing intestinal resection, fed SFA, and given control vehicle, there was a reduction in jejunal proglucagon mRNA expression as compared to those fed chow or PUFA. Ornithine decarboxylase (ODC) mRNA expression in the jejunum of resected animals was reduced. In summary, dietary lipids modify the uptake of lipids in resected animals and ODC and proglucagon may be involved in this adaptive response.

Intestinal transport of the lactokinin Ala-Leu-Pro-Met-His-Ile-Arg through a Caco-2 Bbe monolayer.

ACE inhibitory peptides are biologically active peptides that play a role in blood pressure regulation. When derived from food proteins during food processing or gastrointestinal digestion, these peptides could function as efficient agents in treating and preventing hypertension. However, in order to exert an antihypertensive effect by inhibition of the ACE enzyme, they have to reach the bloodstream intact. The aim of this research was to assess if the known ACE inhibitory peptide Ala-Leu-Pro-Met-His-Ile-Arg, derived from a tryptic digest of beta-lactoglobulin, could be absorbed through a Caco-2 Bbe cell monolayer in an Ussing chamber and reach the serosal side undegraded. Samples of the mucosal compartment showed high ACE inhibitory activity. No or only little ACE inhibitory activity was detected in the serosal compartment. However, when the serosal sample was concentrated three-fold, a substantial ACE inhibitory activity was registered. Concomitantly, HPLC and MS clearly showed the presence of Ala-Leu-Pro-Met-His-Ile-Arg in the mucosal compartment, whereas in the serosal compartment only MS was able to detect the heptapeptide. In conclusion. under the observed experimental conditions, the ACE inhibitory peptide Ala-Leu-Pro-Met-His-Ile-Arg was transported intact through the Caco-2 Bbe monolayer, but in concentrations too low to exert an ACE inhibitory activity.

2001 Harry M. Vars Research Award. Enteral nutrients alter enterocyte function within an in vitro model similar to an acute in vivo rat model during hypoxia.

BACKGROUND: Early enteral nutrition in patients following traumatic injury is an important intervention. However, after shock-resuscitation, intestinal hypoperfusion persists despite adequate systemic resuscitation. Our previous in vivo rat studies indicate that hypoperfusion impairs mucosal function in the small intestine. Therefore, the current study sought to improve previous in vitro models by the following means: (1) We used Caco-2 monolayers stably transfected with the brush-border sodium-glucose co-transporter (SGLT-1); and (2) we created an environment that mimicked the physiologic enterocyte environment. We hypothesized that hypoxic alterations of epithelial function in an in vitro model are comparable to those of an in vivo rat model. METHODS: After 21 days, monolayers were randomized to receive 24 hours of incubation in a normoxic or hypoxic environment. Cells were further randomized to receive 1 of 4 nutrient treatments: mannitol (an osmotic control), glucose (uses SGLT-1 and is metabolized), 3-O-methylglucose (3-O-mg; uses SGLT-1 and is not metabolized), or fructose (does not use SGLT-1 but can be metabolized). RESULTS: Transepithelial resistance (p = .007) and short-circuit current (p = .05) were lower in hypoxic groups. When compared with normoxic groups, hypoxic groups had significantly impaired glucose (p < .001) but not glutamine transport, irrespective of nutrient treatment. Additionally, adenosine triphosphate/adenosine diphosphate ratio was reduced (p = .01) and lactate concentration was increased (p < .001) during hypoxia. CONCLUSIONS: In summary, results from this in vitro study using Caco-2BBe cells stably transfected with SGLT-1 correspond to results obtained in the in vivo rat model. Therefore, this is an appropriate in vitro model in which to study cellular alterations caused by the hypoxic small intestine, with the goal of ensuring safe early enteral nutrition following traumatic injury.

Advances in methods to evaluate gastrointestinal transport function.

Malnutrition is a serious problem, and malabsorption of nutrients is believed to be partially responsible for its prevalence. A wide variety of innovative methods have been developed to study gastrointestinal transport function. Some of the first research into gastrointestinal function was conducted in the 1700's with animal and human models. Methodological advancements continue to allow scientists to innovatively assess gastrointestinal function in animal models, cellular preparations and clinical settings. For this update, the methods are divided into in vivo, ex vivo, isolated cells and membranes, and molecular biology approaches. The in vivo methods discussed include animal and human models to measure nutrient disappearance, catheterized animal models, models with isolated intestinal segments, and a new procedure for sampling luminal fluid from patients. The ex vivo approaches discussed obtain measurements with intact tissue, such as the everted sleeves method and Ussing chambers. The utility of novel cellular preparations, membrane fractionation procedures and various molecular biology techniques is included. Various aspects of these methods are evaluated to provide a detailed overview of recent methodological developments.

Luminal nutrients exacerbate intestinal hypoxia in the hypoperfused jejunum.

BACKGROUND: Provision of enteral nutrients shortly after traumatic injury has become the preferred method of nutrition support provided to patients. However, traumatic shock results in splanchnic hypoperfusion, which may cause persistent intestinal hypoxia. This study tested the hypothesis that delivery of enteral nutrients to the hypoperfused jejunum increases oxidative demand beyond that available, thereby exacerbating intestinal hypoxia. METHODS: Wistar-Furth rats (186+/-4 g; n = 24) were randomized to receive intestinal hypoxia (superior mesenteric artery occlusion) or serve as normoxic controls (sham laparotomy). Within the jejunum of each rat, 4 6-cm loops were randomized to receive luminal perfusions with 1 of 4 substrates: mannitol (an osmotic control); glucose (undergoes active transport via the sodium-glucose co-transporter [SGLT-1] and is metabolized); 3-o-methylglucose (3-o-mg; uses SGLT-1 but is not metabolized); or fructose (does not use SGLT-1 but is metabolized). After in situ perfusions, jejunal tissue was removed for analysis of nutrient transport and barrier function in modified Ussing chambers. Tissue homogenate was used to determine concentration of ATP, lactate, pyruvate, and protein. Also, jejunal tissue was stained with hematoxylin and eosin for qualitative analysis of ischemia and necrosis. RESULTS: Transmural resistance was lower (p < .001) in the hypoxia groups, irrespective of substrate, indicating increased mucosal permeability. When compared with the normoxic controls, glucose transport was impaired (p < .001) in the hypoxic groups; however, glutamine transport was unaffected. The degree of intestinal hypoxia, assessed by jejunal lactate concentration, was higher (p < .001) in the glucose and fructose groups, than the control mannitol and 3-o-mg groups. CONCLUSIONS: The observation that 3-o-mg did not differ from the mannitol control indicates that SGLT-1 activation alone does not exacerbate hypoxia. Rather, these results indicate that provision of metabolizable nutrients to the hypoperfused intestine exacerbate hypoxia and potentially lead to intestinal ischemia. Although early enteral nutrition is an important intervention after trauma, care must be taken to ensure intestinal perfusion is adequate to allow for nutrient metabolism and prevent further compromise.

Systemic short-chain fatty acids rapidly alter gastrointestinal structure, function, and expression of early response genes.

Luminal and systemic short chain fatty acids (SCFA) stimulate mucosal proliferation but the mechanism(s) is unclear. This study examined acute effects of systemic SCFAs on gastrointestinal structure and function and signals potentially mediating SCFA-induced mucosal proliferation. Male Sprague-Dawley rats (246+/-2 g) received nutrients as either standard total parenteral nutrition (TPN) or an isoenergetic, isonitrogenous formulation containing SCFAs (TPN + SCFA). Animals were randomized to one of five treatments: standard TPN for 72 hr, TPN + SCFA for 72 hr, or standard TPN followed by TPN + SCFA for the final 6, 12, and 24 hr. SCFAs reduced (P < 0.003) ileal protein within 6 hr. Jejunal GLUT2 expression was increased (P=0.0001) in all SCFA groups and ileal GLUT2 protein in the 6-, 12-, and 24-hr SCFA groups (P < 0.05). SCFAs increased (P < 0.003) ileal proglucagon abundance following 6, 12, and 24 hr, and plasma GLP-2 concentration following 12 hr (P < 0.03). Jejunal c-myc expression was increased (P < 0.001) following 6, 12, and 24 hr of SCFAs. SCFAs increased ileal c-myc, c-jun, and c-fos expression following 24 hr (P < 0.02), 12 hr (P < 0.05) and 6, 12, and 24 hr (P=0.0001), respectively. In conclusion, systemic SCFAs increase plasma GLP-2 and ileal proglucagon mRNA, GLUT2 expression and protein, and c-myc, c-jun, and c-fos expression.

Short-chain fatty acid-supplemented total parenteral nutrition alters intestinal structure, glucose transporter 2 (GLUT2) mRNA and protein, and proglucagon mRNA abundance in normal rats.

Intestinal adaptation is a complex physiologic process that is not completely understood. Intravenous short-chain fatty acids (SCFAs) enhance intestinal adaptation after 80% enterectomy in rats. The purpose of this study was to examine rapid responses to SCFA-supplemented total parenteral nutrition (TPN) in the normal small intestine. After jugular catheterization, 31 Sprague-Dawley rats (weighing 258 +/- 3 g) were randomly assigned to receive standard TPN or an isoenergetic, isonitrogenous TPN solution supplemented with SCFAs (TPN+SCFA). Intestinal samples were obtained after 24 or 72 h of nutrient infusion. TPN+SCFA for 24 h increased (P < 0.05) the ileal RNA concentration (microg RNA/mg ileum) whereas TPN+SCFA for 72 h increased (P < 0.05) the ileal DNA concentration (microg DNA/mg ileum) and decreased (P < 0.05) the ileal protein concentration (microg protein/mg ileum). Ileal proglucagon mRNA abundance was elevated (P < 0.05) after 24 h of TPN+SCFA infusion and returned to levels seen with control TPN by 72 h. Glucose transporter 2 (GLUT2) mRNA was significantly higher (P < 0.05) in the TPN+SCFA groups at both time points when compared with control TPN groups. Ileal GLUT2 protein abundance in the 72-h TPN+SCFA group was significantly higher (P < 0.05) than that of all other groups. Sodium-glucose cotransporter (SGLT-1) mRNA and protein abundance and uptake of D-fructose and D-glucose did not differ between groups. Jejunal uptake of L-glucose and lauric acid was significantly higher (P < 0.05) after 72 h of TPN+SCFA than after 24 h, whereas the 24- and 72-h TPN groups did not differ. In summary, SCFAs led to rapid changes in ileal proglucagon and glucose transporter expression in rats receiving TPN and provide insights into therapeutic management of individuals with short bowel syndrome or intestinal malabsorption syndromes.