Caleb James Kelly

Purpose of the Review The field of nutrition is in debt to a cadre of women who led the field through its formative years. This review highlights the contributions of these women that are gleaned through analysis of biographical articles published in The Journal of Nutrition. Recent Findings Forces emerged during the development of nutrition science, such as departments of home economics and the majority-female field of dietetics, that suggest women might be well represented in biographical articles in the field of nutrition. However, just 29 women have been the subject of biographical articles in The Journal of Nutrition representing 14.3% of the 202 biographical articles published to date — a percentage lower than scientific journals overall. Summary This review explores these biographies to identify factors that facilitated and hindered careers and to highlight the manifold scientific contributions of women in nutrition science. This review looks toward the past to provide perspective and inspiration for those working in the field of nutrition today.

Purpose of Review Epidemiologic studies and clinical trials have demonstrated the benefits of dietary fiber. This occurs through a combination of the physiochemical properties of fiber and through microbial fermentation that occurs in the colon which result in the production of short-chain fatty acids (SCFA). The purpose of this review is to highlight the physiochemical properties of fiber that result in the range of physiologic effects and to review the literature on the health benefits of acetate, propionate, and butyrate. Recent Findings Of the variety of properties and functions exerted by dietary fibers, the fermentability and production of SCFA’s are emphasized in this review. Studies done in both animal and humans reveal the anti-obesity, anti-inflammatory, and possible anti-neoplastic roles SCFAs exert at the mucosal level. Summary Many clinical questions remain regarding the optimal dose, type, and method of delivery of fiber to exert the desired beneficial effects. It has the potential to be used in the management of clinical symptoms, prevention of disease, and improvement in human health. Further studies to address this novel use of fiber has the potential to make a large impact in clinical practice

Epithelial barrier dysfunction is a significant factor in many allergic diseases, including eosinophilic esophagitis (EoE). Infiltrating leukocytes and tissue adaptations increase metabolic demands and decrease oxygen availability at barrier surfaces. Understanding of how these processes impact barrier is limited, particularly in allergy. Here, we identified a regulatory axis whereby the oxygen-sensing transcription factor HIF-1α orchestrated epithelial barrier integrity, selectively controlling tight junction CLDN1 (claudin-1). Prolonged experimental hypoxia or HIF1A knockdown suppressed HIF-1α–dependent claudin-1 expression and epithelial barrier function, as documented in 3D organotypic epithelial cultures. L2-IL5^OXA mice with EoE-relevant allergic inflammation displayed localized eosinophil oxygen metabolism, tissue hypoxia, and impaired claudin-1 barrier via repression of HIF-1α/claudin-1 signaling, which was restored by transgenic expression of esophageal epithelial-targeted stabilized HIF-1α. EoE patient biopsy analysis identified a repressed HIF-1α/claudin-1 axis, which was restored via pharmacologic HIF-1α stabilization ex vivo. Collectively, these studies reveal HIF-1α’s critical role in maintaining barrier and highlight the HIF-1α/claudin-1 axis as a potential therapeutic target for EoE.

Vitamin B₁₂ is a critical nutrient for humans as well as microbes. Due to saturable uptake, high dose oral B₁₂ supplements are largely unabsorbed and reach the distal gut where they are available to interact with the microbiota. The aim of this study was to determine if oral B₁₂ supplementation in mice alters 1) the concentration of B₁₂ and related corrinoids in the distal gut, 2) the fecal microbiome, 3) short chain fatty acids (SCFA), and 4) susceptibility to experimental colitis. C57BL/6 mice (up to 24 animals/group) were supplemented with oral 3.94 µg/ml cyanocobalamin (B₁₂), a dose selected to approximate a single 5 mg supplement for a human. Active vitamin B₁₂ (cobalamin), and four B₁₂-analogues ([ADE]CN-Cba, [2Me-ADE]CN-Cba, [2MeS-ADE]CN-Cba, CN-Cbi) were analyzed in cecal and fecal contents using liquid chromatography/mass spectrometry (LC/MS), in parallel with evaluation of fecal microbiota, cecal SCFA, and susceptibility to dextran sodium sulfate (DSS) colitis. At baseline, active B₁₂ was a minor constituent of overall cecal (0.86%) and fecal (0.44%) corrinoid. Oral B₁₂ supplementation increased active B₁₂ at distal sites by >130-fold (cecal B₁₂ increased from 0.08 to 10.60 ng/mg, fecal B₁₂ increased from 0.06 to 7.81 ng/ml) and reduced microbe-derived fecal corrinoid analogues ([ADE]CN-Cba, [2Me-ADE]CN-Cba, [2MeS-ADE]CN-Cba). Oral B₁₂ had no effect on cecal SCFA. Microbial diversity was unaffected by this intervention, however a selective decrease in Bacteroides was observed with B₁₂ treatment. Lastly, no difference in markers of DSS-induced colitis were detected with B₁₂ treatment.

Commensal interactions between the enteric microbiota and distal intestine play important roles in regulating human health. Short-chain fatty acids (SCFAs), such as butyrate, produced through anaerobic microbial metabolism represent a major energy source for the host colonic epithelium and enhance epithelial barrier function through unclear mechanisms. Separate studies revealed that the epithelial anti-inflammatory IL-10 receptor α subunit (IL-10RA) is also important for barrier formation. Based on these findings, we examined if SCFAs promote epithelial barrier through IL-10RA–dependent mechanisms. Using human intestinal epithelial cells (IECs), we discovered that SCFAs, particularly butyrate, enhanced IEC barrier formation, induced IL-10RA mRNA, IL-10RA protein, and transactivation through activated Stat3 and HDAC inhibition. Loss and gain of IL-10RA expression directly correlates with IEC barrier formation and butyrate represses permeability-promoting claudin-2 tight-junction protein expression through an IL-10RA–dependent mechanism. Our findings provide a novel mechanism by which microbial-derived butyrate promotes barrier through IL-10RA–dependent repression of claudin-2.

Recent work has revealed a central role for neddylation (the conjugation of a Nedd8 moiety to Cullin proteins) in the fine-tuning of the NF-κB response (via Cullin-1). In the present study, we investigated the contribution of Cullin-1 neddylation and NF-κB signaling to mucosal inflammatory responses in vitro and in vivo. Initial in vitro studies using cultured intestinal epithelial cells revealed that the neddylation inhibitor MLN4924 prominently induces the deneddylation of Cullin-1. Parallel Western blot, luciferase reporter, and gene target assays identified MLN4924 as a potent inhibitor of intestinal epithelial NF-κB. Subsequent studies revealed that MLN4924 potently induces epithelial apoptosis but only in the presence of additional inflammatory stimuli. In vivo administration of MLN4924 (3 mg/kg per day) in a TNBS-induced colitis model significantly accentuated disease severity. Indeed, MLN4924 resulted in worsened clinical scores and increased mortality early in the inflammatory response. Histologic analysis of the colon revealed that neddylation inhibition results in increased tissue damage and significantly increased mucosal apoptosis as determined by TUNEL and cleaved caspase-3 staining, which was particularly prominent within the epithelium. Extensions of these studies revealed that ongoing inflammation is associated with significant loss of deneddylase-1 (SENP8) expression. These studies reveal that intact Cullin-1 neddylation is central to resolution of acute inflammation.