Targeted inhibition of thrombin attenuates murine neonatal necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is an inflammatory bowel necrosis of premature infants and an orphan disease with no specific treatment. Most patients with confirmed NEC develop moderate-severe thrombocytopenia requiring one or more platelet transfusions. Here we used our neonatal murine model of NEC-related thrombocytopenia to investigate mechanisms of platelet depletion associated with this disease [K. Namachivayam, K. MohanKumar, L. Garg, B. A. Torres, A. Maheshwari, Pediatr. Res. 81, 817-824 (2017)]. In this model, enteral administration of immunogen trinitrobenzene sulfonate (TNBS) in 10-d-old mouse pups produces an acute necrotizing ileocolitis resembling human NEC within 24 h, and these mice developed thrombocytopenia at 12 to 15 h. We hypothesized that platelet activation and depletion occur during intestinal injury following exposure to bacterial products translocated across the damaged mucosa. Surprisingly, platelet activation began in our model 3 h after TNBS administration, antedating mucosal injury or endotoxinemia. Platelet activation was triggered by thrombin, which, in turn, was activated by tissue factor released from intestinal macrophages. Compared to adults, neonatal platelets showed enhanced sensitivity to thrombin due to higher expression of several downstream signaling mediators and the deficiency of endogenous thrombin antagonists. The expression of tissue factor in intestinal macrophages was also unique to the neonate. Targeted inhibition of thrombin by a nanomedicine-based approach was protective without increasing interstitial hemorrhages in the inflamed bowel or other organs. In support of these data, we detected increased circulating tissue factor and thrombin-antithrombin complexes in patients with NEC. Our findings show that platelet activation is an important pathophysiological event and a potential therapeutic target in NEC.

Gastroschisis for the Gastroenterologist: Updates on Epidemiology, Management, and Outcomes.

Gastroschisis is a common congenital abdominal wall defect, likely influenced by environmental factors in utero, with increasing prevalence in the United States. Early detection of gastroschisis in utero has become the standard with improved prenatal care and screening. There are multiple surgical management techniques, though sutureless closure is being used more frequently. Postoperative feeding difficulty is common and requires vigilance for complications, such as necrotizing enterocolitis. Infants with simple gastroschisis are expected to have eventual catch-up growth and normal development, while those with complex gastroschisis have higher morbidity and mortality. Management requires collaboration amongst several perinatal disciplines, including obstetrics, maternal fetal medicine, neonatology, pediatric surgery, and pediatric gastroenterology for optimal care and long-term outcomes.

Galectin-4 as a Novel Biomarker of Neonatal Intestinal Injury.

BACKGROUND: Neonates are at risk of gastrointestinal emergencies including necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP). Identifying biomarkers to aid in diagnosis is imperative. We hypothesized that circulating intestinal-specific protein concentrations would distinguish infants with intestinal injury from controls. AIMS: To identify serum concentrations of intestinal-specific protein(s) in infants with intestinal injury and controls. METHODS: We used an in silico approach to identify intestinal-specific proteins. We collected serum from control infants and infants with NEC or SIP and measured protein concentrations using ELISA. If baseline concentrations were near the detection limit in initial control assays, we proceeded to assess concentrations in a larger cohort of controls and infants with injury. Control infants were frequency matched to infants with injury and compared with nonparametric and mixed-effects models analysis. RESULTS: We evaluated four proteins with high intestinal expression: Galectin-4 (Gal-4), S100G, Trefoil Factor-3, and alanyl aminopeptidase. Only Gal-4 demonstrated consistent results near the lower limit of quantification in controls and was studied in the larger cohorts. Gal-4 concentration was low in 111 control infants (median 0.012 ng/ml). By contrast, Gal-4 was significantly increased at diagnosis in infants with surgical NEC and SIP (n = 14, p ≤ 0.001 and n = 8, p = 0.031) compared to matched controls, but not in infants with medical NEC (n = 32, p = 0.10). CONCLUSIONS: Of the intestinal-specific proteins evaluated, circulating Gal-4 concentrations were at the assay detection limit in control infants. Gal-4 concentrations were significantly elevated in infants with surgical NEC or SIP, suggesting that Gal-4 may serve as a biomarker for neonatal intestinal injury.

Intestinal dysbiosis and necrotizing enterocolitis: assessment for causality using Bradford Hill criteria.

In recent years, several studies have shown that premature infants who develop NEC frequently display enteric dysbiosis with increased Gram-negative bacteria for several days to weeks prior to NEC onset. The importance of these findings, for the possibility of a causal role of these bacteria in NEC pathogenesis, and for potential value of gut dysbiosis as a biomarker of NEC, is well-recognized. In this review, we present current evidence supporting the association between NEC in premature infants and enteric dysbiosis, and its evaluation using the Bradford Hill criteria for causality. To provide an objective appraisal, we developed a novel scoring system for causal inference. Despite important methodological and statistical limitations, there is support for the association from several large studies and a meta-analysis. The association draws strength from strong biological plausibility of a role of Gram-negative bacteria in NEC and from evidence for temporality, that dysbiosis may antedate NEC onset. The weakness of the association is in the low level of consistency across studies, and the lack of specificity of effect. There is a need for an improved definition of dysbiosis, either based on a critical threshold of relative abundances or at higher levels of taxonomic resolution.

Cost-effectiveness Analysis of Feeding Guidelines for Infants Following Intestinal Surgery.

OBJECTIVE: The aim of the study was to determine the cost-effectiveness of postoperative feeding guidelines to reduce complications in infants with intestinal surgery compared to standard feeding practices. METHODS: Using outcomes from a cohort study, Markov models from health care and societal perspectives simulated costs per hospitalization among infants fed via guidelines versus standard practice. Short-term outcomes included intestinal failure-associated liver disease, necrotizing enterocolitis after feeding, sepsis, and mortality. Effectiveness was measured as length of stay. The incremental cost-effectiveness ratios (ICER) compared cost over length of stay. Univariate and multivariate probabilistic sensitivity analyses with 10,000 Monte Carlo Simulations were performed. A second decision tree model captured the cost per quality-adjusted life years (QALYs) using utilities associated with long-term outcomes (liver cirrhosis and transplantation). RESULTS: In the hospital perspective, standard feeding had a cost of $31,258,902 and 8296 hospital days, and the feeding guidelines had a cost of $29,295,553 and 8096 hospital days. The ICER was $-9832 per hospital stay with guideline use. More than 90% of the ICERs were in the dominant quadrant. Results were similar for the societal perspective. Long-term costs and utilities in the guideline group were $2830 and 0.91, respectively, versus $4030 and 0.90, resulting in an ICER of $-91,756/QALY. CONCLUSION: In our models, feeding guideline use resulted in cost savings and reduction in hospital stay in the short-term and cost savings and an increase in QALYs in the long-term. Using a systematic approach to feed surgical infants appears to reduce costly complications, but further data from a larger cohort are needed.

Normative values for circulating intestinal fatty acid binding protein and calprotectin across gestational ages.

BACKGROUND: Necrotizing enterocolitis (NEC) is associated with significant morbidity and mortality. Serum biomarkers to aid diagnosis, such as intestinal fatty acid binding protein (IFABP) and calprotectin, are actively being investigated; however, the normative values of these markers among healthy premature and term infants remains unknown. We sought to identify normative values for the serum concentrations of IFABP and calprotectin across gestational (GA) and post-menstrual age. METHODS: We collected serum from infants (24-40 weeks GA) in the first week of life and at multiple time points in a sub-cohort of premature infants (24-29 weeks GA), excluding sepsis or known intestinal disease. IFABP and calprotectin were measured using ELISA. Groups were compared with descriptive statistics and mixed effects linear regression. RESULTS: One hundred twelve infants had specimens in the first week of life, and 19 premature infants had longitudinal specimens. IFABP concentration in the first week of life was low and did not differ across gestational ages. Longitudinally, IFABP increased 4% per day (P < 0.001). Calprotectin concentration in the first week of life was more variable. An inverse relationship between day of life and calprotectin level was found in the longitudinal cohort (P < 0.001). CONCLUSIONS: Serum IFABP and calprotectin fluctuate over time. Infants had low levels of IFABP during the first week of life, independent of gestational age, and levels increased longitudinally in premature infants. Calprotectin levels generally declined over time. Normative data for infants is necessary to establish meaningful cut-off levels for clinical use.

Helicobacter pylori in Pediatric Patients.

Helicobacter pylori causes one of the most common chronic bacterial infections. Clinical manifestations include asymptomatic chronic gastritis, gastric and duodenal ulcers, adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma in adults. In children, most H pylori infections are asymptomatic despite being associated with microscopic gastric inflammation, and children rarely develop complications associated with infection. Due to rising resistance and lack of symptomatic improvement in the absence of peptic ulcer disease, testing and eradication therapy are recommended only for the subset of patients in whom there is a high suspicion of peptic ulcer disease. Studies do not support the role of H pylori infection in functional disorders such as recurrent abdominal pain. A variety of diagnostic modalities exist; therefore, it is important to understand the appropriate approach to diagnosing H pylori infection. The joint European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines were updated in 2016. Antibiotic and proton pump inhibitor weight-based dosing guidelines have changed to prevent ineffective treatment from increasing antimicrobial resistance. Treatment can also be guided by antibiotic sensitivities obtained from H pylori culture. Patients should be tested again after treatment to confirm eradication.

Use of Breast Milk and Other Feeding Practices Following Gastrointestinal Surgery in Infants.

OBJECTIVES: The aim of the study was to characterize the enteral feeding practices in infants after gastrointestinal surgery. METHODS: We performed a retrospective analysis of infants who underwent intestinal surgery at age <6 months who survived to be fed enterally between January 2012 and June 2017. Demographics, surgical characteristics, feeding practices, and growth-related outcomes during hospitalization, discharge, and follow-up (3, 6, and 12 months) were obtained from the electronic medical records. Descriptive statistics compared infants by their initial diagnosis. RESULTS: We reviewed 111 infants: necrotizing enterocolitis (NEC) = 21, gastroschisis = 28, atresia = 27, spontaneous intestinal perforation (SIP) = 18, and other diagnoses = 17. Most infants (77%) received mother's milk (MM) as the first postoperative feed, but this differed by diagnosis (P = 0.004). Donor milk was used in 11%, most commonly in infants with NEC and SIP. Infants with NEC were least likely to continue MM in the hospital (7%, P = 0.0014) and were more likely to receive elemental formula. Only 44% of infants received MM at discharge. After 1 year, 25% were fed MM. The majority of infants were discharged with feeding tubes (nasogastric: 35%, gastric: 23%). Although all groups had acceptable weights at discharge, infants with NEC (z score: -1.8) and SIP (z score: -1.1) showed growth failure at 3 months (z scores: -3.3, -3.2, respectively, P < 0.0001), but had appropriate gain by 1 year (z scores: -1.1, -1.7, respectively). CONCLUSIONS: Despite most infants receiving MM in the early postoperative period, <50% at discharge and only 33% at 1-year still received MM. Weight gain after discharge in infants with NEC and SIP warrants close monitoring.

Utilizing Information Technology to Improve Influenza Vaccination in Pediatric Patients With Inflammatory Bowel Disease.

Pediatric patients with inflammatory bowel disease are undervaccinated against influenza. Gastroenterology nurses are ideally situated to assist in improving vaccination in this population. The objective of this quality improvement project was to evaluate the implementation of information technology prompts within the electronic medical record to improve influenza vaccination during specialty clinic visits. The proportion of patients with yearly influenza vaccination was evaluated at baseline, Year 1, and Year 2 following implementation. At baseline, only 10% of a random sample had documented influenza vaccination. Vaccination documentation improved to 39% (96/246) by Year 1 and to 61% (175/287) by Year 2 (p < .001). Vaccine counseling improved from 27% to 77% by Year 2 for unvaccinated patients (p < .001). Among patients seen by gastroenterology nurses, the proportion of patients with either documented vaccination or counseling was 94% by Year 2 compared with 70% if seen only by a physician (p < .001). Documentation of influenza vaccination improved with the use of customized prompts. Patients seen by a gastroenterology nurse had higher vaccination documentation and vaccine counseling than those who were seen by a physician alone.

Postoperative Enteral Nutrition Guidelines Reduce the Risk of Intestinal Failure-Associated Liver Disease in Surgical Infants.

OBJECTIVE: To assess the effectiveness of postoperative feeding guidelines in reducing the incidence and severity of intestinal failure-associated liver disease (IFALD) among infants. STUDY DESIGN: Two cohorts of infants <6 months old undergoing intestinal surgery were compared: preguideline (retrospective data from 2007 to 2013; n = 83) and postguideline (prospective data from 2013 to 2016; n = 81). The guidelines included greater initial enteral nutrition volumes of 20 mL/kg/d and daily feeding advancement if tolerated. The primary outcomes were incidence of IFALD (peak direct bilirubin [DB] >2 mg/dL) and severity (DB >5 mg/dL for moderate-severe). Multiple logistic regression was used to determine the odds of developing IFALD. Other outcomes were time to reach 50% and 100% goal calories from enteral nutrition and the incidence of necrotizing enterocolitis after feeding. RESULTS: The incidence of IFALD decreased from 71% to 51% (P = .031), and median peak DB decreased from 5.7 to 2.4 mg/dL (P = .001). After adjusting for diagnosis and prematurity, the odds of developing IFALD of any severity were reduced by 60% (OR 0.40, 95% CI 0.20-0.85), and the odds of developing moderate-to-severe IFALD were reduced by 72% (OR 0.28, 95% CI 0.13-0.58) with guideline use. Time to reach 50% enteral nutrition decreased from a median of 10 to 6 days (P = .020) and time to reach 100% enteral nutrition decreased from 35 to 21 days (P = .035) with guideline use. The incidence of necrotizing enterocolitis after initiating enteral nutrition did not change (5% vs 9%, P = .346). CONCLUSIONS: Implementation of feeding guidelines reduced time to reach feeding goals, significantly reducing IFALD incidence and severity.

Conjugated linoleic acid is a preferential substrate for fatty acid nitration.

The oxidation and nitration of unsaturated fatty acids by oxides of nitrogen yield electrophilic derivatives that can modulate protein function via post-translational protein modifications. The biological mechanisms accounting for fatty acid nitration and the specific structural characteristics of products remain to be defined. Herein, conjugated linoleic acid (CLA) is identified as the primary endogenous substrate for fatty acid nitration in vitro and in vivo, yielding up to 10(5) greater extent of nitration products as compared with bis-allylic linoleic acid. Multiple enzymatic and cellular mechanisms account for CLA nitration, including reactions catalyzed by mitochondria, activated macrophages, and gastric acidification. Nitroalkene derivatives of CLA and their metabolites are detected in the plasma of healthy humans and are increased in tissues undergoing episodes of ischemia reperfusion. Dietary CLA and nitrite supplementation in rodents elevates NO(2)-CLA levels in plasma, urine, and tissues, which in turn induces heme oxygenase-1 (HO-1) expression in the colonic epithelium. These results affirm that metabolic and inflammatory reactions yield electrophilic products that can modulate adaptive cell signaling mechanisms.

Contributing factors common to COVID­19 and gastrointestinal cancer.

The devastating complications of coronavirus disease 2019 (COVID­19) result from the dysfunctional immune response of an individual following the initial severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) infection. Multiple toxic stressors and behaviors contribute to underlying immune system dysfunction. SARS­CoV­2 exploits the dysfunctional immune system to trigger a chain of events, ultimately leading to COVID­19. The authors have previously identified a number of contributing factors (CFs) common to myriad chronic diseases. Based on these observations, it was hypothesized that there may be a significant overlap between CFs associated with COVID­19 and gastrointestinal cancer (GIC). Thus, in the present study, a streamlined dot­product approach was used initially to identify potential CFs that affect COVID­19 and GIC directly (i.e., the simultaneous occurrence of CFs and disease in the same article). The nascent character of the COVID­19 core literature (~1­year­old) did not allow sufficient time for the direct effects of numerous CFs on COVID­19 to emerge from laboratory experiments and epidemiological studies. Therefore, a literature­related discovery approach was used to augment the COVID­19 core literature­based 'direct impact' CFs with discovery­based 'indirect impact' CFs [CFs were identified in the non­COVID­19 biomedical literature that had the same biomarker impact pattern (e.g., hyperinflammation, hypercoagulation, hypoxia, etc.) as was shown in the COVID­19 literature]. Approximately 2,250 candidate direct impact CFs in common between GIC and COVID­19 were identified, albeit some being variants of the same concept. As commonality proof of concept, 75 potential CFs that appeared promising were selected, and 63 overlapping COVID­19/GIC potential/candidate CFs were validated with biological plausibility. In total, 42 of the 63 were overlapping direct impact COVID­19/GIC CFs, and the remaining 21 were candidate GIC CFs that overlapped with indirect impact COVID­19 CFs. On the whole, the present study demonstrates that COVID­19 and GIC share a number of common risk/CFs, including behaviors and toxic exposures, that impair immune function. A key component of immune system health is the removal of those factors that contribute to immune system dysfunction in the first place. This requires a paradigm shift from traditional Western medicine, which often focuses on treatment, rather than prevention.

Common contributing factors to COVID-19 and inflammatory bowel disease.

The devastating complications of coronavirus disease 2019 (COVID-19) result from an individual's dysfunctional immune response following the initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Multiple toxic stressors and behaviors contribute to underlying immune system dysfunction. SARS-CoV-2 exploits the dysfunctional immune system to trigger a chain of events ultimately leading to COVID-19. We have previously identified many contributing factors (CFs) (representing toxic exposure, lifestyle factors and psychosocial stressors) common to myriad chronic diseases. We hypothesized significant overlap between CFs associated with COVID-19 and inflammatory bowel disease (IBD), because of the strong role immune dysfunction plays in each disease. A streamlined dot-product approach was used to identify potential CFs to COVID-19 and IBD. Of the fifty CFs to COVID-19 that were validated for demonstration purposes, approximately half had direct impact on COVID-19 (the CF and COVID-19 were mentioned in the same record; i.e., CF---→COVID-19), and the other half had indirect impact. The nascent character of the COVID-19 core literature (∼ one year old) did not allow sufficient time for the direct impacts of many CFs on COVID-19 to be identified. Therefore, an immune system dysfunction (ID) literature directly related to the COVID-19 core literature was used to augment the COVID-19 core literature and provide the remaining CFs that impacted COVID-19 indirectly (i.e., CF---→immune system dysfunction---→COVID-19). Approximately 13000 potential CFs for myriad diseases (obtained from government and university toxic substance lists) served as the starting point for the dot-product identification process. These phrases were intersected (dot-product) with phrases extracted from a PubMed-derived IBD core literature, a nascent COVID-19 core literature, and the COVID-19-related immune system dysfunction (ID) core literature to identify common ID/COVID-19 and IBD CFs. Approximately 3000 potential CFs common to both ID and IBD, almost 2300 potential CFs common to ID and COVID-19, and over 1900 potential CFs common to IBD and COVID-19 were identified. As proof of concept, we validated fifty of these ∼3000 overlapping ID/IBD candidate CFs with biologic plausibility. We further validated 24 of the fifty as common CFs in the IBD and nascent COVID-19 core literatures. This significant finding demonstrated that the CFs indirectly related to COVID-19 -- identified with use of the immune system dysfunction literature -- are strong candidates to emerge eventually as CFs directly related to COVID-19. As discussed in the main text, many more CFs common to all these core literatures could be identified and validated. ID and IBD share many common risk/contributing factors, including behaviors and toxic exposures that impair immune function. A key component to immune system health is removal of those factors that contribute to immune system dysfunction in the first place. This requires a paradigm shift from traditional Western medicine, which often focuses on treatment, rather than prevention.

Postoperative Feeding Guidelines Improve Outcomes in Surgical Infants.

BACKGROUND: Early introduction of enteral nutrition (EN) in postoperative infants improves intestinal adaptation, reducing the risk of intestinal failure-associated liver disease (IFALD). Our objective was to determine whether guideline use reduces feeding variability and improves outcomes in the neonatal intensive care unit (NICU). METHODS: In a cohort study, surgical infants at risk for IFALD were evaluated pre and post implementation of feeding guidelines at 2 NICUs. A total of 167 guideline infants (2013-2018) were compared with 242 historical controls (2007-2013). Adherence was measured with timing and volume of initial postoperative feed. Primary outcomes were IFALD incidence and time to reach 50% and 100% of energy from EN. Secondary outcomes were parenteral nutrition (PN) days, postoperative necrotizing enterocolitis (NEC), central line-associated bloodstream infection (CLABSI), and length of stay (LOS). RESULTS: Moderate IFALD decreased from 32% to 20% (P = .005) in the guideline group. Time to achieve 50% and 100% energy from EN was decreased from medians of 8 to 5 and 28 to 21 days, respectively (P < .001). There was an overall decrease in PN use from 41 to 29 days (P = .002), CLABSI incidence from 25% to 5% (P < .001), and LOS from 70 to 53 days (P = .030). Once stratified by diagnosis, infants with NEC showed greatest improvement and reduction in IFALD from 67% to 42% (P = .045). With no difference in postoperative NEC (P = .464). CONCLUSION: Early standardized postoperative EN guidelines in intestinal-surgery infants was associated with improved outcomes, including faster achievement of feeding goals and reduced IFALD severity, especially in infants with NEC.

Treatment repurposing for inflammatory bowel disease using literature-related discovery and innovation.

Inflammatory bowel disease (IBD) incidence has been increasing steadily, most dramatically in the Western developed countries. Treatment often includes lifelong immunosuppressive therapy and surgery. There is a critical need to reduce the burden of IBD and to discover medical therapies with better efficacy and fewer potential side-effects. Repurposing of treatments originally studied in other diseases with similar pathogenesis is less costly and time intensive than de novo drug discovery. This study used a treatment repurposing methodology, the literature-related discovery and innovation (LRDI) text mining system, to identify potential treatments (developed for non-IBD diseases) with sufficient promise for extrapolation to treatment of IBD. By searching for desirable patterns of twenty key biomarkers relevant to IBD (e.g., inflammation, reactive oxygen species, autophagy, barrier function), the LRDI-based query retrieved approximately 9500 records from Medline. The most recent 350 records were further analyzed for proof-of-concept. Approximately 18% (64/350) met the criteria for discovery (not previously studied in IBD human or animal models) and relevance for application to IBD treatment. Many of the treatments were compounds derived from herbal remedies, and the majority of treatments were being studied in cancer, diabetes, and central nervous system disease, such as depression and dementia. As further validation of the search strategy, the query identified ten treatments that have just recently begun testing in IBD models in the last three years. Literature-related discovery and innovation text mining contains a unique search strategy with tremendous potential to identify treatments for repurposing. A more comprehensive query with additional key biomarkers would have retrieved many thousands more records, further increasing the yield of IBD treatment repurposing discovery.

Efficacy and Tolerance of Blended Diets in Children Receiving Gastrostomy Feeds.

BACKGROUND: To determine the prevalence of gastrointestinal (GI) symptoms in children receiving a blended diet via a gastrostomy tube. METHODS: This is a single-center, retrospective study of children ages 1-18 years that received a blended diet. We reviewed demographics, anthropometrics, clinical characteristics, and rationale for switching to blended diet. Fixed-effects logistic regression analysis was used to evaluate the changes in patient symptoms over the 12-month follow-up period, and fixed-effects regression was employed to test for changes in anthropometrics. RESULTS: Twenty-three patients (8 female, 15 male) were identified, and data from 89 outpatient visits were analyzed. The most common underlying diagnosis was neurological disorder. Thirty-five percent of patients received commercial whole cow milk formulas, 30% received hydrolysate formulas, and 35% received amino acid-based formulas. After formula switches were made, 65% received homemade blended diets, 17.5% received commercial blended diets, and 17.5% received a combination of both. Median duration of time on a blended diet was 17 months. Ninety-five percent of patients who were previously experiencing upper GI symptoms improved within the first 3 months after blended diet initiation. Twenty-one percent of patients developed mild constipation on the diet, which was managed with increased water intake and/or polyethylene glycol. Only 2 patients discontinued the blended diet, because of inadequate weight gain and worsening of upper GI symptoms. CONCLUSIONS: In our study population, blended diets were well tolerated in gastrostomy-fed children and were associated with clinical improvement of upper GI symptoms.

A Central Role for Lipocalin-2 in the Adaptation to Short-Bowel Syndrome Through Down-Regulation of IL22 in Mice.

BACKGROUND & AIMS: In short-bowel syndrome (SBS), inadequate intestinal adaptation is responsible for the majority of complications, including sepsis, liver failure, and death. In this study, we sought to further delineate the adaptive response to identify potential therapeutic targets. METHODS: We performed a 75% small-bowel resection (SBR) or sham operation on C57Bl/6J wild-type (WT), lipocalin-2 (LCN2)-/-, and interleukin 22 (IL22)-/- mice. Exogenous IL22 was administered to SBR WT mice. Cecal fecal matter from SBR WT and SBR LCN2-/- mice were transplanted into germ-free mice. Intestinal permeability, inflammation, proliferation, and the microbiome were evaluated 1 week after surgery. CD4+IL22+ laminal propria lymphocytes were sorted by flow cytometry. Naïve T cells were polarized to T-helper cells with or without LCN2. RESULTS: A 75% SBR in a mouse re-creates the increased intestinal permeability, enterocyte proliferation, and intestinal dysbiosis seen in SBS. LCN2 expression increases after 75% SBR, and this increase can be abrogated with broad-spectrum antibiotic treatment. LCN2-/- mice have less intestinal inflammation, increased IL22 expression, and greater adaptation as evidenced by less intestinal permeability, increased carbohydrate enzyme expression, less weight loss, and less dysbiosis after 75% SBR than WT mice. The proinflammatory and anti-adaptive effects of LCN2 can be transferred to germ-free mice via a fecal transplant. Administration of exogenous IL22 improves adaptation and restores the normal microbiome after 75% SBR in WT mice. CONCLUSIONS: LCN2 promotes inflammation and slows intestinal adaptation through changes in the microbiome and IL22 inhibition in a mouse SBS model. Strategies to reduce LCN2 may offer novel therapeutic approaches to enhance adaptation in SBS.