Growth differentiation factor 15 (GDF15) elevation in children with newly diagnosed cancer.

Background: Growth differentiation factor 15 (GDF15), an inflammatory marker and mediator of adult cancer cachexia, remains largely unexplored in children. GDF15 increases nausea, vomiting, and anorexia in cancer and contributes to malnutrition, with the potential to be a cachexia therapeutic target. No studies have examined GDF15 in children with newly diagnosed cancer. Our pilot study compares GDF15 in children with newly diagnosed cancer to age- and sex-matched controls and correlates levels with anthropometric measurements and quality of life (QOL). Methods: Children with newly diagnosed cancer aged 2-21 years were enrolled with serum GDF15 ELISA, anthropometric measures [height, weight, and mid-upper arm circumference (MUAC)], and QOL assessments (using PedsQL™ Core and Gastrointestinal Modules), which were collected at baseline and repeated 3 months later. Serum GDF15 levels were obtained from age- and sex-matched controls for comparison. Results: A total of 57 participants enrolled (N=30, cancer group; N=27, control group) with a median age of 8.8 years (IQR 5.6-15.9 years). The participants were primarily male (54.4%), white (82.5%), and non-Hispanic (82.5%). Cancer diagnoses included acute lymphoblastic leukemia (N=8), lymphoma (N=8), neuroblastoma (N=5), soft tissue tumors (N=4), acute myeloid leukemia (N=2), and single participants with brain, kidney, and bone tumors. Baseline GDF15 was higher in the cancer cohort compared to the control cohort (median=614.6pg/mL and 320.5pg/mL, respectively; p<0.001). When examining participants with evaluable baseline and 3-month follow-up GDF15 levels (N=18), GDF15 was not statistically different (median=657.1pg/mL and 675.3pg/mL, respectively; p=0.702). A total of 13 of the 30 participants and 21 caregivers completed the PedsQL™ Core and Gastrointestinal symptom modules. QOL scores did not differ significantly at 3-month follow-up compared to baseline, but diarrhea worsened (p=0.017). Median participant response for diarrhea at baseline was 92.9 (IQR=92.9-96.4; N=13), which was significantly better than the follow-up (median=78.6; IQR= 71.4-92.9; p=0.017). There were no correlations between change in height, weight, or MUAC and change in GDF15 levels (p=0.351, 0.920, and 0.269 respectively). Conclusion: GDF15 was elevated in children with cancer at diagnosis compared to controls but did not correlate with anthropometric measurements or QOL. This pilot study will inform future prospective studies to better describe the natural history of GDF15 and its role in cachexia and as a potential therapeutic target.

Education and documentation strategies to improve malnutrition diagnosis in hospitalized children: A quality improvement project.

BACKGROUND: The Academy of Nutrition and Dietetics/American Society for Parenteral and Enteral Nutrition (AND/ASPEN) published malnutrition guidelines in 2014. In 2015, our institution implemented a quality improvement project focused on malnutrition identification with the goal to improve the diagnosis of malnutrition in hospitalized children. METHODS: Our project included three approaches: education, nutrition assessment, and documentation initiatives. Education initiatives focused on physicians at all levels of training. Nutrition screening was completed on all patients admitted to our institution. Registered dietitians (RDs) conducted nutrition assessments and identified and documented malnutrition based on AND/ASPEN guidelines. Documentation initiatives included development of automatic text and template changes to allow import of RD-assigned malnutrition diagnosis into physician documentation. We met with members of our clinical documentation integrity team regularly to review the results of these initiatives starting in 2016. RESULTS: The total diagnosed cases of malnutrition increased from 208 cases in 2016 at the start of our monitoring to >800 cases per year in 2020-2022. Unspecified (no severity assigned) protein calorie malnutrition as a percentage of total malnutrition diagnoses decreased from 36.9% in 2016 to <10% since 2018. Children with severe malnutrition have remained the largest portion of children with a malnutrition diagnosis, with >40% of children with malnutrition diagnosed with severe malnutrition. CONCLUSION: Our education and documentation initiatives have led to both improved diagnosis of malnutrition and accurate identification and documentation of malnutrition severity. These initiatives could be utilized to improve malnutrition diagnosis and documentation at other institutions caring for hospitalized children.

Lipid strategies to prevent intestinal failure-associated liver disease in neonates: A pilot trial.

BACKGROUND: Intestinal failure-associated liver disease (IFALD) occurs in up to 50% of neonates treated with prolonged parenteral nutrition. Preventative strategies for IFALD include soybean oil lipid emulsion (SOLE) minimization and use of mixed-oil intravenous lipid emulsions (ILE). We conducted a pilot study prospectively comparing these two ILE strategies in the prevention of IFALD in neonates who required abdominal surgery. METHODS: We randomized eligible neonates to SOLE at 1 g/kg/day (SOLE Min) or mixed-oil ILE containing fish oil (MOLE) at 3 g/kg/day. These treatment groups were also compared with historic controls who received SOLE at 2-3 g/kg/day (SOLE Historic). We defined IFALD as a direct bilirubin >2 mg/dl on two measurements. Secondary outcomes included laboratory, growth, clinical, and nutrition outcomes. RESULTS: A total of 24 prospective and 24 historic patients were included. There was no difference in the rate of IFALD. However, there was a difference in the weekly change of direct bilirubin levels (SOLE Historic +0.293 mg/dl/week vs MOLE, P < 0.001; SOLE Min +0.242 mg/dl/week vs MOLE, P < 0.001). The MOLE group also had a lower direct bilirubin at study completion (SOLE Historic, 1.7 ± 1.7 mg/dl; SOLE Min, 1.6 ± 1.4 mg/dl; MOLE, 0.4 ± 0.4 mg/dl; P = 0.002) and received greater total calories (P = 0.008). CONCLUSION: The rate of IFALD did not differ when comparing ILE strategies in neonates requiring abdominal surgery. However, the MOLE group maintained significantly lower direct bilirubin levels over time while receiving increased calories. This pilot study highlights the need for further randomized controlled trials comparing these ILE strategies.

Intestinal Injury Biomarkers Predict Mortality in Pediatric Severe Malaria.

Severe malaria (SM) increases the risk of invasive bacterial infection, and there is evidence to suggest increased gastrointestinal permeability. Studies have shown sequestration of infected erythrocytes in intestinal microvasculature, and in vivo studies of rectal mucosa have demonstrated disruption of microvascular blood flow. However, the extent of intestinal injury in pediatric malaria is not well characterized. In this study, two serum biomarkers of intestinal injury, trefoil factor 3 (TFF3) and intestinal fatty acid binding protein (I-FABP), were analyzed in 598 children with SM and 120 healthy community children (CC), 6 months to 4 years of age. Serum was collected at enrollment and 1 month for laboratory studies, and participants were monitored for 12 months. Intestinal injury biomarkers were significantly elevated in children with SM, with 18.1% having levels of TFF3 and/or I-FABP greater than the 99th percentile of CC levels. TFF3 levels continued to be elevated at 1 month, while I-FABP levels were comparable to CC levels. Both markers predicted in-hospital mortality {odds ratio (OR) (95% confidence interval [CI]), 4.4 (2.7, 7.3) and 2.3 (1.7, 3.1)} for a natural log increase in TFF3 and I-FABP, respectively. TFF3 was also associated with postdischarge mortality (OR, 2.43 [95% CI, 1.1, 4.8]). Intestinal injury was associated with acute kidney injury (AKI), acidosis (P < 0.001 for both), and angiopoietin 2, a maker of endothelial activation. In conclusion, intestinal injury is common in pediatric severe malaria and is associated with an increased mortality. It is strongly associated with AKI, acidosis, and endothelial activation. IMPORTANCE In children with severe malaria, intestinal injury is a common complication associated with increased mortality. Intestinal injury is associated with acute kidney injury, acidosis, and endothelial activation. Interventions promoting intestinal regeneration and repair represent novel approaches to improve outcomes.

Growth and nutrition in children with established bronchopulmonary dysplasia: A review of the literature.

BACKGROUND: Bronchopulmonary dysplasia (BPD) remains the most common late morbidity of preterm birth. Clinical care and research have largely focused on the pathogenesis and prevention of BPD. Preterm infants who develop BPD have significant medical needs that persist throughout their hospital course and continue after discharge, including those associated with growth and nutrition. The objective of this study was to review the available literature on nutrition and growth in infants with established BPD and to identify the knowledge and research gaps to provide direction for future studies. METHODS: We conducted a literature search in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using Ovid MEDLINE, CINAHL, and Embase. Titles, abstracts, and full texts were independently reviewed by the authors and selected based on predetermined inclusion/exclusion criteria. Results were summarized qualitatively. RESULTS: Excluding duplicates, 2315 articles were identified. Thirty articles were selected for inclusion. We identified the following key components of nutrition support and clinical care: energy expenditure, growth, and metabolism; body composition; enteral nutrition; supplements; parenteral nutrition; and respiratory outcomes. CONCLUSIONS: Despite a large body of literature describing the role of growth and nutrition in the prevention of BPD, research is lacking with respect to interventions and management in the population with established BPD. Thus, organized approaches for clinical interventions and trials with respect to growth and nutrition in infants and young children with established BPD are needed. These studies should include multiple centers because of the small numbers of patients with BPD at each site.

Nutritional Deficiencies in Vegetarian, Gluten-Free, and Ketogenic Diets.

Previously, medical diets, including the ketogenic and gluten-free diets, were rare outside of their target population. Subspecialists more familiar with risks and benefits often managed nutrition and any associated shortcomings. With more patients electively following a gluten-free or ketogenic diet for nonmedical needs, as well as the increasing prevalence of vegetarian diets, general pediatricians are seeing more followers of restrictive diets with general well-child care. Increasingly, general pediatricians can be the first provider to witness presenting signs or symptoms of associated nutritional deficiencies. This article reviews signs and symptoms of possible nutrient deficiencies seen with the vegetarian, ketogenic, and gluten-free diets.

Nutrition and growth in infants with established bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) remains the most common late morbidity of preterm birth. Ongoing clinical care and research have largely focused on the pathogenesis and prevention of BPD in preterm infants. However, preterm infants who develop BPD have significant medical needs that persist throughout their neonatal intensive care unit course and continue post-discharge, including those associated with growth and nutrition. The objective of this manuscript was to provide a review on nutrition and growth in infants with established BPD after discharge from the hospital and to identify the knowledge and research gaps to provide direction for future studies.

Inadequate Bowel Preparation in Pediatric Colonoscopy-Prospective Study of Potential Causes.

OBJECTIVES: Inadequate bowel preparation (IBP) for colonoscopy leads to missed diagnosis, longer anesthesia time, higher chance of complications and increased costs. Adult studies have demonstrated that patient characteristics such as male gender and obesity are associated with IBP. Little is known about factors affecting bowel preparation in children. Our aim was to determine factors associated with IBP in children. METHODS: We prospectively enrolled children undergoing outpatient colonoscopy. Quality of bowel preparation was assessed using Boston Bowel Preparation Scale (BBPS) score (range 0-9). Data collected included patient demographics, indication, and type of insurance. Patients were divided into two groups based on BBPS score-adequate (BBPS score > 5) and inadequate (BBPS score < 5) and groups were compared using Student t-test and chi-square test. Possible predictors were analyzed using multivariate logistic regression models. RESULTS: A total of 334 children were prospectively enrolled of whom 321 were studied further (age range 2-18 years; mean age 12.4 years; 60.4% female; 85.9% Caucasian). The mean BBPS score was 6.8 (standard deviation of ±2). IBP was reported in 12.8% (41/321). Multivariable logistic regression analysis did not show statistical differences between the groups in studied patient factors including age, gender, obesity, race, insurance type, and indication for colonoscopy. CONCLUSION: Contrary to several adult studies, the results of our prospective study did not show any relationship between examined patient factors and IBP in children. Interestingly, IBP was less prevalent in our pediatric study compared to published adult data (12.8% vs 20-40%).

Varied Presentations and Comorbidities in Pediatric Autoimmune Pancreatitis.

Autoimmune pancreatitis (AIP) is a chronic inflammatory condition rarely reported in children. In 2018, to standardize the approach to AIP, INternational Study Group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE) defined AIP, outlined the clinical course, and developed diagnostic and therapeutic recommendations. We performed a retrospective review of cases at our institution from January 1, 2016, to June 1, 2019, and compared their presentations with the INSPPIRE guidelines. Our patients showed variable laboratory, radiographic, and histologic findings, highlighting the difficulty in diagnosing AIP. Histologic samples were obtained in our patients due to diagnostic uncertainty, which ultimately confirmed the diagnosis. One patient was diagnosed with autoimmune hepatitis coexistent with AIP, which has not been previously described in the pediatric population. Exocrine and endocrine complications of AIP were also noted. In all cases, symptoms improved following treatment, and decompression of the common bile duct was seen on repeat imaging.

Pediatric Smoflipid Therapy: Patient Response and Safety Concerns.

BACKGROUND: Intestinal failure-associated liver disease (IFALD) occurs in ≤85% of neonates receiving prolonged parenteral nutrition. Strategies for treatment of IFALD include alternative lipid therapies, such as Smoflipid (Fresenius Kabi). In this study, we reviewed our institutional Smoflipid use, including predictors of patient response and safety concerns. METHODS: This is a retrospective chart review of all pediatric patients who received Smoflipid therapy over a 2-year period at Riley Hospital for Children. Forty-two patients (89%) had cholestasis at the start of Smoflipid therapy and were included in group analysis. We compared patients based on response to Smoflipid therapy, identifying associations and predictors of patient response. We also documented patient safety concerns, including essential fatty acid deficiency (EFAD), rapid infusion, and compatibility/access issues. RESULTS: Sixteen patients (38%) with cholestasis had resolution with Smoflipid. Those patients with resolution were older at initiation (58 vs 33.5 days; P = .010), treated with Smoflipid for longer (85.5 vs 41 days; P = .001), and had lower direct bilirubin at the start of Smoflipid therapy (3.7 vs 5.2 mg/dL; P = .035). We identified multiple safety concerns, including EFAD (54%), rapid infusion (17%), and missed doses (51%). No patient characteristics were found to correlate with Smofllpid therapy and diagnosis of EFAD. CONCLUSION: In our patient population, Smoflipid therapy led to cholestasis resolution in patients with lower direct bilirubin or less-severe IFALD. Use of Smoflipid is also associated with significant safety concerns, and its use should be coupled with close monitoring in pediatric patients, particularly in neonates.

Safety Findings in Pediatric Patients During Long-Term Treatment With Teduglutide for Short-Bowel Syndrome-Associated Intestinal Failure: Pooled Analysis of 4 Clinical Studies.

BACKGROUND: This analysis assessed combined safety data from 4 clinical studies of teduglutide in pediatric patients with short-bowel syndrome-associated intestinal failure (SBS-IF). METHODS: Safety data from teduglutide-treated patients in 4 clinical trials were pooled. The completed 12-week and 24-week phase 3 core studies (NCT01952080/EudraCT 2013-004588-30 and NCT02682381/EudraCT 2015-002252-27) enrolled children aged 1-17 years with SBS-IF. Patients could elect to enroll in ongoing open-label extensions (NCT02949362/EudraCT 2016-000863-17 and NCT02954458/EudraCT 2016-000849-30). Interim data from ongoing studies were included. RESULTS: Safety data are reported for 89 pediatric patients treated with teduglutide for a median (range) of 51.7 (5.0-94.7) weeks. Adverse events (AEs) were reported in all patients; the most common were vomiting (51.7%), pyrexia (43.8%), upper respiratory tract infection (41.6%), and cough (33.7%). Thirty-five patients (39.3%) had AEs considered related to teduglutide treatment; abdominal pain and vomiting were most frequent (5.6% each). Three serious AEs in 3 patients (3.4%) were considered related to teduglutide treatment: ileus, d-lactic acidosis, and gastrointestinal obstruction due to hard stools. All 3 events resolved. One cecal polyp was detected, which was not biopsied or found on repeat colonoscopy. No cases of neoplasia occurred. CONCLUSION: Based on integrated data from 4 clinical studies, including long-term follow-up for ≤161 weeks, teduglutide had a safety profile consistent with the individual core pediatric studies and as expected for pediatric patients with SBS-IF who never received teduglutide. The most frequent AEs reflected treatment with teduglutide, complications of the underlying disease, and typical childhood illnesses.

Incidence of Low Seroimmunity to Hepatitis B Virus in Children With Inflammatory Bowel Disease.

OBJECTIVES: Patients with inflammatory bowel disease (IBD) often receive immunosuppressive therapy, which may make them vulnerable to infections such as hepatitis B. We hypothesized that hepatitis B virus titers are low in the vaccinated pediatric population with IBD. The aims of our study were to identify the incidence of lower titers of hepatitis B surface antibody (HBsAb) and determine which patient factors may be associated with lower HBsAb titers. METHODS: Patients with diagnosis of IBD, ages 5 to 18 years, were prospectively enrolled. Patients were confirmed to have had a full series of hepatitis B vaccination. Quantitative serum HBsAb titers were measured and logistic regression analysis with independent variables of age, sex, race, disease phenotype, surgery, medications and a dependent variable of adequate HBsAb titers (> 10 mIU/mL) was performed. RESULTS: Of the 116 patients enrolled, 57 were boys and 59 were girls. 75 patients had a diagnosis of Crohn disease; 32 had a diagnosis of ulcerative colitis; and 9 patients had been diagnosed as having indeterminate colitis. At the time of the study, 15 patients were taking corticosteroid, 66 on an immunomodulator, and 53 on a biologic. Sixty percent of patients in the 5- to 10-year age group had protective titers versus 22% to 27% in the older groups, P = 0.04. Only 28% of the 116 patients had HBsAb titers of >10m IU/mL. Twenty percent of the patients taking corticosteroids, 27% taking immunomodulators, and 24% taking biologics were found to be seroimmune. CONCLUSIONS: Nearly two-thirds of pediatric patients with IBD have low titers against hepatitis B virus. Titers were highest in the younger patients. No patient-specific variable, such as the use of immunosuppressants, appeared to influence these low titers.

Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of Teduglutide in Pediatric Short Bowel Syndrome.

OBJECTIVE: To determine safety and pharmacodynamics/efficacy of teduglutide in children with intestinal failure associated with short bowel syndrome (SBS-IF). STUDY DESIGN: This 12-week, open-label study enrolled patients aged 1-17 years with SBS-IF who required parenteral nutrition (PN) and showed minimal or no advance in enteral nutrition (EN) feeds. Patients enrolled sequentially into 3 teduglutide cohorts (0.0125 mg/kg/d [n = 8], 0.025 mg/kg/d [n = 14], 0.05 mg/kg/d [n = 15]) or received standard of care (SOC, n = 5). Descriptive summary statistics were used. RESULTS: All patients experienced ≥1 treatment-emergent adverse event; most were mild or moderate. No serious teduglutide-related treatment-emergent adverse events occurred. Between baseline and week 12, prescribed PN volume and calories (kcal/kg/d) changed by a median of -41% and -45%, respectively, with 0.025 mg/kg/d teduglutide and by -25% and -52% with 0.05 mg/kg/d teduglutide. In contrast, PN volume and calories changed by 0% and -6%, respectively, with 0.0125 mg/kg/d teduglutide and by 0% and -1% with SOC. Per patient diary data, EN volume increased by a median of 22%, 32%, and 40% in the 0.0125, 0.025, and 0.05 mg/kg/d cohorts, respectively, and by 11% with SOC. Four patients achieved independence from PN, 3 in the 0.05 mg/kg/d cohort and 1 in the 0.025 mg/kg/d cohort. Study limitations included its short-term, open-label design, and small sample size. CONCLUSIONS: Teduglutide was well tolerated in pediatric patients with SBS-IF. Teduglutide 0.025 or 0.05 mg/kg/d was associated with trends toward reductions in PN requirements and advancements in EN feeding in children with SBS-IF. TRIAL REGISTRATION: ClinicalTrials.gov:NCT01952080; EudraCT: 2013-004588-30.

Intrahepatic bile duct regeneration in mice does not require Hnf6 or Notch signaling through Rbpj.

The potential for intrahepatic bile duct (IHBD) regeneration in patients with bile duct insufficiency diseases is poorly understood. Notch signaling and Hnf6 have each been shown to be important for the morphogenesis of IHBDs in mice. One congenital pediatric liver disease characterized by reduced numbers of IHBDs, Alagille syndrome, is associated with mutations in Notch signaling components. Therefore, we investigated whether liver cell plasticity could contribute to IHBD regeneration in mice with disruptions in Notch signaling and Hnf6. We studied a mouse model of bile duct insufficiency with liver epithelial cell-specific deficiencies in Hnf6 and Rbpj, a mediator of canonical Notch signaling. Albumin-Cre Hnf6(flox/flox)Rbpj(flox/flox) mice initially developed no peripheral bile ducts. The evolving postnatal liver phenotype was analyzed using IHBD resin casting, immunostaining, and serum chemistry. With age, Albumin-Cre Hnf6(flox/flox)Rbpj(flox/flox) mice mounted a ductular reaction extending through the hepatic tissue and then regenerated communicating peripheral IHBD branches. Rbpj and Hnf6 were determined to remain absent from biliary epithelial cells constituting the ductular reaction and the regenerated peripheral IHBDs. We report the expression of Sox9, a marker of biliary epithelial cells, in cells expressing hepatocyte markers. Tissue analysis indicates that reactive ductules did not arise directly from preexisting hilar IHBDs. We conclude that liver cell plasticity is competent for regeneration of IHBDs independent of Notch signaling via Rbpj and Hnf6.

NASPGHAN Nutrition University as a model for continuing education within pediatric nutrition.

The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Nutrition Committee developed the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Nutrition University (N2U) as an education resource designed to address the nutrition topics identified by pediatric gastroenterologists. N2U was initially designed as a series of lectures. Participants completed a precourse, immediate postcourse, and 6-month postcourse assessment. The average pretest score was 74%. Participants reported learning "a great deal" and immediate postcourse test score average was 90%. Feedback from N2U participants will shape future course design, focusing on the interactive learning sessions. N2U may serve as a model for offering topic-directed continuing medical education based on targeted physician responses and feedback.

Genetic interactions between hepatocyte nuclear factor-6 and Notch signaling regulate mouse intrahepatic bile duct development in vivo.

UNLABELLED: Notch signaling and hepatocyte nuclear factor-6 (HNF-6) are two genetic factors known to affect lineage commitment in the bipotential hepatoblast progenitor cell (BHPC) population. A genetic interaction involving Notch signaling and HNF-6 in mice has been inferred through separate experiments showing that both affect BHPC specification and bile duct morphogenesis. To define the genetic interaction between HNF-6 and Notch signaling in an in vivo mouse model, we examined the effects of BHPC-specific loss of HNF-6 alone and within the background of BHPC-specific loss of recombination signal binding protein immunoglobulin kappa J (RBP-J), the common DNA-binding partner of all Notch receptors. Isolated loss of HNF-6 in this mouse model fails to demonstrate a phenotypic variance in bile duct development compared to control. However, when HNF-6 loss is combined with RBP-J loss, a phenotype consisting of cholestasis, hepatic necrosis, and fibrosis is observed that is more severe than the phenotype seen with Notch signaling loss alone. This phenotype is associated with significant intrahepatic biliary system abnormalities, including an early decrease in biliary epithelial cells, evolving to ductular proliferation and a decrease in the density of communicating peripheral bile duct branches. In this in vivo model, simultaneous loss of both HNF-6 and RBP-J results in down-regulation of both HNF-1ß and Sox9 (sex determining region Y-related HMG box transcription factor 9). CONCLUSION: HNF-6 and Notch signaling interact in vivo to control expression of downstream mediators essential to the normal development of the intrahepatic biliary system. This study provides a model to investigate genetic interactions of factors important to intrahepatic bile duct development and their effect on cholestatic liver disease phenotypes.

Mechanisms of probiotic action: Implications for therapeutic applications in inflammatory bowel diseases.

Probiotics are defined as nonpathogenic living microorganisms, including some commensal bacterial flora, which have beneficial effects on host health and disease prevention and/or treatment. Clinical trials have shown beneficial effects of probiotics on several human diseases, such as inflammatory bowel diseases (IBDs), which are among the most-studied diseases testing probiotics as a potential therapy. However, a significant question regarding clinical use of probiotics is the mechanism underlying the wide range of actions. Studies discussed in this review suggest 3 distinct cellular and molecular mechanisms for probiotic regulation in IBD therapy: 1) Probiotics block pathogenic bacterial effects by producing bactericidal substances and competing with pathogens and toxins for adherence to the intestinal epithelium; 2) Probiotics regulate immune responses by enhancing the innate immunity and modulating pathogen-induced inflammation via toll-like receptor-regulated signaling pathways; and 3) Probiotics regulate intestinal epithelial homeostasis by promoting intestinal epithelial cell survival, enhancing barrier function, and stimulating protective responses. Probiotics modulate host cell signaling pathways, including Akt, mitogen-activated protein kinases, and nuclear factor-kappaB to mediate these intestinal epithelial functions. It is hoped that developing a mechanistic understanding of probiotic action will provide the rationale to support the development of new hypothesis-driven studies to define the clinical efficacy in preventive, adjunctive, or alternative treatments for IBD.