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The ketogenic diet (KD) is hypothesized to impact tumor progression by altering tumor metabolism. In this study, we assessed the impact of an unrestricted KD on epithelial ovarian cancer (EOC) tumor growth, gene expression, and metabolite concentration in a mouse model. ID8 EOC cells, which were syngeneic with C57Bl/6J mouse strain and transfected with luciferase (ID8-luc), were injectedand monitored for tumor development. Female mice were fed either a strict KD, a high fat/low carbohydrate (HF/LC) diet, or a low fat/high carbohydrate (LF/HC) diet (n = 10 mice per group) ad libitum. EOC tumor growth was monitored weekly, and tumor burden was determined based on luciferase fluorescence (photons/second). At the endpoint (42 days), tumors were collected and processed for RNA sequencing. Plasma and tumor metabolites were evaluated using LC-MS. The KD-fed mice exhibited a statistically significant increase in tumor progression in comparison to the HF/LC- and LF/HC-fed groups (9.1 vs. 2.0 vs. 3.1-fold, respectively, p < 0.001). The EOC tumors of the KD-fed mice exhibited significant enrichment of the peroxisome proliferator-activated receptor (PPAR) signaling and fatty acid metabolism pathways based on the RNA sequencing analysis when compared to the LF/HC- and HF/LC-fed mice. Thus, unrestricted KD diet enhanced tumor progression in our mouse EOC model. KD was associated with the upregulation of fatty acid metabolism and regulation pathways, as well as enrichment of fatty acid and glutamine metabolites.

Background Dietary modification shows promise as therapy in inflammatory bowel disease (IBD); however, it is unknown whether adolescents are interested in a dietary approach. Methods Cross-sectional survey of adolescents with IBD ages 14–21 on disease knowledge, dietary habits, and perceptions of diet therapy. Results A total of 132 subjects (48.5% female), mean age of 17.8 years and median disease length of 5 years (range 0, 16), completed the survey. Diet was perceived as a symptom trigger by 59.8% of subjects, and 45.4% had tried using diet as a treatment for symptom resolution, often without physician supervision and with limited success. Overall, subjects reported following a diet significantly more often than documented in the electronic medical record (EMR) by the physician (25.0% vs. 15.0%, p=0.033), with 72% agreement between subject response and EMR documentation on current status of diet modification (AC1=0.59, CI=0.45, 0.73). Subjects experiencing active disease symptoms as determined by Manitoba IBD Index were more likely to be currently modifying their diet compared to subjects without active disease symptoms (OR = 4.11, CI=1.58, 10.73, p=0.003). The subjects reporting unsuccessful dietary modification compliancy (25.7%, n=34) most commonly cited perceived lack of improvement in their IBD symptoms as the primary reason for stopping the diet (48.4%, n=15). Conclusions Adolescents with IBD perceive a relationship between diet and disease symptoms and are interested in dietary modification as a symptom management option. Our study suggests that a large proportion of adolescent IBD patients may already be attempting dietary modification, and therefore would be receptive to a modified dietary plan under the guidance of their gastroenterologist and dietitian. Much is still unknown about how dietary modification will fit in with current treatment regimens, but patient interest informs us that it is necessary to continue development and research of this promising therapeutic option.

Dysregulation of gut microbiota and intestinal barrier function has emerged as potential mechanisms underlying digestive diseases, yet targeted therapies are lacking The purpose of this investigation was to assess the efficacy of UCC118, a characterized probiotic strain, on exercise‐induced GI permeability in healthy humans. In a randomized, double‐blind, placebo‐controlled crossover study, seven healthy adults received 4 weeks of daily UCC118 or placebo supplementation. GI hyperpermeability was induced by strenuous treadmill running performed before and after each supplementation period. While running, participants ingested 5 g of lactulose, rhamnose, and sucrose. Urine was collected before, immediately after, and every hour for 5 h after exercise to assess GI permeability. Metagenomic sequencing was performed on fecal homogenates collected prior to exercise to identify changes in microbial diversity and taxon abundances. Inflammatory biomarkers were assessed from blood and fecal homogenates collected prior to and immediately following the cessation of exercise. Exercise significantly induced intestinal permeability of lactulose, rhamnose, and sucrose (P, Dysregulation of gut microbiota and intestinal barrier function have emerged as potential mechanisms underlying digestive diseases, yet targeted therapies are lacking. In a randomized, double‐blind, placebo‐controlled crossover study, 7 healthy adults 30 received 4 weeks of daily UCC118 or placebo supplementation. UCC118 significantly reduced sucrose recovery. Taxonomic sequencing revealed 99 differentially regulated gut microbes by UCC118. The results herein provide proof of principle that UCC118 supplementation can reduce intestinal hyperpermeability.

Controversy continues to surround the appropriate form and timing of nutrition support for the patient with circulatory shock. Clinical studies have demonstrated improvements in outcome with the administration of enteral nutrition to critically ill patients; however, the provision of enteral nutrition to critically ill patients with ongoing shock remains controversial. This article reviews gut perfusion during normal states and during circulatory shock as well as alterations in perfusion when enteral feeding is provided. Pharmaconutrients studied during ischemia and reperfusion are discussed.

SLC5A8, expressed predominantly in the colon, is a Na(+)-coupled transporter for short-chain fatty acids. In this paper, we report on the characterization of butyrate transport by SLC5A8 and the relevance of SLC5A8-mediated butyrate transport to colon cancer.SLC5A8 transports butyrate via a Na(+)-dependent electrogenic process. Na(+) activation of the transport process exhibits sigmoidal kinetics, indicating involvement of more than one Na(+) in the activation process. SLC5A8 is silenced in colon cancer in humans, in a mouse model of intestinal/colon cancer, and in colon cancer cell lines. The tumor-associated silencing of SLC5A8 involves DNA methylation by DNA methyltransferase 1. Reexpression of SLC5A8 in colon cancer cells leads to apoptosis but only in the presence of butyrate. SLC5A8-mediated entry of butyrate into cancer cells is associated with inhibition of histone deacetylation. The changes in gene expression in SLC5A8/butyrate-induced apoptosis include upregulation of pro-apoptotic genes and downregulation of anti-apoptotic genes. In addition, the expression of phosphatidylinositol-3-kinase subunits is affected differentially, with downregulation of p85alpha and upregulation of p55alpha and p50alpha.These studies show that SLC5A8 mediates the tumor-suppressive effects of the bacterial fermentation product butyrate in the colon.

Specialized nutrition support, particularly enteral feeding, has been used for centuries. Technologic advancements have affected the provision of enteral feeding. Feeding solutions and devices, as well as the techniques to place the feeding devices, have evolved. This article reviews the history of bedside placement methods for short-term enteral access devices.

Objective The benefits of enteral nutrition when compared with parenteral nutrition are well established. However, provision of enteral nutrition may not occur for several reasons, including lack of optimal feeding access. Gastric feeding is easier to initiate, but many hospitalized patients are intolerant to gastric feeding, although they can tolerate small bowel feeding. Many institutions rely on costly methods for placing small bowel feeding tubes. Our goal was to evaluate the effectiveness of a hospital-developed protocol for bedside-blind placement of postpyloric feeding tubes. Methods The Surgical Nutrition Service established a protocol for bedside placement of small bowel feeding tubes. The protocol uses a 10- or 12-French, 110-cm stylet containing the feeding tube; 10 mg of intravenous metoclopramide; gradual tube advancement followed by air injection and auscultation; and an abdominal radiograph for tube position confirmation. In a prospective manner, consults received by the surgical nutrition dietitian for feeding tube placements were followed consecutively for a 10-mo period. The registered dietitian recorded the number of radiograph examinations, the final tube position, and the time it took to achieve tube placement. Results Because all consults were included, feeding tube placements occurred in surgical and medical patients in the intensive care unit and on the ward. Of the 135 tube placements performed, 129 (95%) were successfully placed postpylorically, with 84% (114 of 135) placed at or beyond D3. Average time for tube placement was 28 min (10 to 90 min). One radiograph was required for 92% of the placements; eight of 135 (6%) required two radiographs. No acute complications were associated with the tube placements. Conclusions Hospitalized patients can receive timely enteral feeding with a cost-effective feeding tube placement protocol. The protocol is easy to implement and can be taught to appropriate medical team members through proper training and certification.

Diarrhea is a significant worldwide health problem. The bacterial flora of the gastrointestinal tract plays an essential role in maintaining the integrity of the enterocyte, modulating metabolic and immunologic processes, and protecting against colonization by invasive pathogens. Disruptions of this finely tuned and stable gut flora has profound effects on the protective barrier. Antibiotics used to treat infectious diarrhea promote the emergence of resistant organisms, and multiple-antibiotic resistance has become a major public health issue. Preservation of protective species or recolonization with nonpathogenic lactobacilli, particularly Lactobacilli GG, has shown promising results in treating several forms of diarrhea, including rotavirus diarrhea, bacterial diarrhea, traveler's diarrhea, and Clostridium difficile relapsing diarrhea.

Postoperative ileus is a natural part of recovery following abdominal and intestinal surgery. Research in the laboratory and clinical arenas has challenged the long-held belief that enteral nutrition (EN) should not be administered until bowel function has resumed, which is typically judged by a subjective bowel function assessment. Traditional postoperative management begins with clinical monitoring of return of bowel function, followed by a clear liquid diet that is advanced to regular solid food as tolerated. Studies have consistently demonstrated that early EN is safe and well tolerated, showing a reduction in wound morbidity and healing, fewer septic complications, diminished weight loss, and improved protein kinetics in patients administered early EN. Barriers to early enteral feeding include fear of GI morbidity, anastomotic disruption or leak but have not been proven valid in clinical or experimental trials. A clear liquid diet is the most frequently ordered first postoperative meal regardless of early or delayed administration. Although generally well tolerated, this diet fails to provide adequate nutrients to the postsurgical patient. In contrast, advancement to a regular diet as the initial meal has been shown to be well tolerated and provides significantly more nutrients than a clear liquid diet. This article reviews basic GI physiology, including motility, nutrient absorption, and the changes that occur in regulation and function of the GI tract following surgery, as well as clinical data regarding postoperative GI function and diet advancement. This will be applied to the clinical practices of postoperative dietary advancement to discuss the timing and choice of initial feeding in the postoperative patient.

Short-chain fatty acids, generated in colon by bacterial fermentation of dietary fiber, protect against colorectal cancer and inflammatory bowel disease. Among these bacterial metabolites, butyrate is biologically most relevant. GPR109A is a G-protein–coupled receptor for nicotinate but recognizes butyrate with low affinity. Millimolar concentrations of butyrate are needed to activate the receptor. Although concentrations of butyrate in colonic lumen are sufficient to activate the receptor maximally, there have been no reports on the expression/function of GPR109A in this tissue. Here we show that GPR109A is expressed in the lumen-facing apical membrane of colonic and intestinal epithelial cells and that the receptor recognizes butyrate as a ligand. The expression of GPR109A is silenced in colon cancer in humans, in a mouse model of intestinal/colon cancer, and in colon cancer cell lines. The tumor-associated silencing of GPR109A involves DNA methylation directly or indirectly. Reexpression of GPR109A in colon cancer cells induces apoptosis, but only in the presence of its ligands butyrate and nicotinate. Butyrate is an inhibitor of histone deacetylases, but apoptosis induced by activation of GPR109A with its ligands in colon cancer cells does not involve inhibition of histone deacetylation. The primary changes in this apoptotic process include down-regulation of Bcl-2, Bcl-xL, and cyclin D1 and up-regulation of death receptor pathway. In addition, GPR109A/butyrate suppresses nuclear factor-κB activation in normal and cancer colon cell lines as well as in normal mouse colon. These studies show that GPR109A mediates the tumor-suppressive effects of the bacterial fermentation product butyrate in colon. [Cancer Res 2009;69(7):2826–32]

Purpose GPR109A has been identified as a G-protein-coupled receptor for niacin. β-hydroxybutyrate (β-HB) is a physiologic ligand for the receptor. β-HB, the predominate ketone body in circulation, is an important energy source for neurons, including retinal neurons, under various physiologic and pathologic conditions. The identification of GPR109A as the receptor for β-HB suggests additional, hitherto unknown, functions for this metabolite. The circulating levels of β-HB increase in diabetes. Since retinopathy is a serious complication associated with diabetes, we investigated GPR109A expression in retina and in different retinal cell types to determine if the receptor may have a role in the pathophysiology of diabetic retinopathy. Methods RT–PCR, fluorescent in situ hybridization, and immunofluorescent techniques were used to analyze GPR109A expression in mouse retina and in three transformed retinal cell lines: ARPE-19 (RPE), RGC-5 (ganglion), and rMC-1 (Müller). Activation of GPR109A by niacin and β-HB was demonstrated in ARPE-19 cells by cAMP assay. Results Studies conducted using mouse retinal tissues demonstrated that GPR109A is expressed in retina with its expression restricted to RPE, where it differentially polarizes to the basolateral membrane. These results were confirmed with cell lines, which demonstrated GPR109A expression in ARPE-19, but not in rMC-1 and RGC-5 cells. Primary cultures of mouse RPE also showed robust expression of GPR109A. cAMP assay demonstrated that GPR109A expressed in RPE is functional. Conclusions These data represent the first report on GPR109A expression in retina. The exclusive expression of GPR109A in RPE basolateral membrane, which has access to β-HB in blood, may have biologic importance in diabetic retinopathy.

This article discusses issues related to nutrition support for the critically ill (CCI), especially those who are dependent on ventilators for long periods. A large and growing population of patients survives acute critical illness only to become CCI with profound debilitation, weeks to months of hospitalization, and often permanent dependence on mechanical ventilation and other life-sustaining modalities. Despite resource-intensive treatment, outcomes for CCI remain poor. Topics addressed in this article include neuroendocrine profiles in CCI patients, allostatic overload, causes of prolonged mechanical ventilation, and the metabolism of chronic ventilator dependence. The article also describes issues related to assessing the nutrition, determining nutrition requirements, and deciding the route of nutrient delivery for CCI patients.

We apply currently published clinical outcomes data to length of stay and hospital cost to determine the potential economic benefit associated with the use of specialized nutritional formulations in elective surgical, trauma, and medical patients. Although the use of immune-modulating formulations has repeatedly shown favorable clinical outcomes, including decreased complications (both infectious and noninfectious), length of stay (both ICU and total days), and ventilator days, the cost-effectiveness of nutritional modulation of the immune response in a US-based population has not previously been explored.Data for the current study were obtained from a large national database with 126 member hospitals and data from over 1 million patients. Data extracted from the database included patient type (surgical, medical, and trauma) and subservice, whether the hospital stay was "complicated" or "uncomplicated" (as determined by diagnosis-related groups and International Classification of Diseases, Ninth Revision coding), mean length of stay, mean cost, and incremental cost per complication experienced. The clinical outcomes measures from 3 major peer-reviewed studies were then applied to the cost data in order to determine the cost savings associated with the use of specialized nutritional formulations in each of the patient populations. Additionally, cost data were segmented by region of the United States (New England, mid-Atlantic, South, Midwest, Southwest, and West) and by primary focus of the health care facility (academic, indigent care, large community) to enable more meaningful cost comparisons.For the medical patient population, according to the published rate of 51% decrease in risk of infectious complications and a decreased length of hospital stay of 9.7 days, net cost savings (after accounting for the increased costs of administering immune modulating formula) is $2066. The same calculations were done for surgical and trauma patients, with $688 and $308 net cost savings per patient, respectively. These figures assume a base infection rate of 5%. Expected cost savings vary markedly for deviations in base infection rate and slightly for differences in facility type or region of the country.This study demonstrates that specialized nutritional formulations are a cost-effective way for hospitals to improve clinical outcomes while reducing resource consumption and total cost. These benefits are observable in all patient types, all facility types, and all regions of the United States.

Objective Nutrition support in the severely injured trauma patient is crucial to minimize the hypermetabolic stress response. Even though enteral nutrition is the preferred method of feeding, it is not always feasible after multiple trauma. We present a complex nutritional case in a patient who sustained severe abdominal trauma with a severe liver injury, rib fractures, and pulmonary contusion. Methods The patient required several repeat laparotomies, abdominal packing, and temporary abdominal closure. The clinical course was complicated by hypotension requiring multiple vasopressors; coagulopathy requiring more than 35 U of packed red cells, more than 50 U of fresh frozen plasma, and more than 80 U of platelets; acute renal failure requiring dialysis; and pneumonia and acute respiratory distress syndrome requiring intricate ventilator management. Nutrition intervention began on post-trauma day 4 with total parenteral nutrition due to hypotension, resuscitation, and massive bowel edema; by post-trauma day 8. the patient was receiving goal nutrients. Results On post-trauma day 27, bowel edema was significantly less, and a nasoenteric feeding tube was placed and enteral feeding initiated. By post-trauma day 31, full enteral feeds were tolerated, and total parenteral nutrition was stopped. Nutrient provision was adjusted daily to account for organ and metabolic changes including hepatic, pulmonary, and renal dysfunction. The patient did well and was eventually extubated and eating a regular diet. Conclusion With careful monitoring and adjusting of the nutritional plan, a hypermetabolic complex trauma patient with an open abdomen can be fed optimally, safely, and successfully despite increased bowel edema and multiple organ dysfunction.

Closer attention to the clear liquid diet and its therapeutic applications has been prompted by critical reviews of nutritional enhancement in the clinical environment. The aim of ongoing research has been to uncover the optimal nutrient complement in various patient groups as well as the most beneficial mode of nutrient delivery. Route of feeding is often the essential determinant in effectiveness of nutritional support. Many studies have sought to demonstrate the superiority of enteral versus parenteral nutrition, whereas comparative studies with clear liquid diets are sparse. Recently, identification of key nutrients in the support of malnourished or immunocompromised patients has been emphasized. Although total parenteral nutrition has undisputed applications in specific patient groups, it has lost favor for general application because of its negative impact on immunocompetence. Efforts have thus been redoubled to explore the potential of the gastrointestinal tract, with the derived benefit in immunosupport for many medical and surgical disease states. Until recently, the clear liquid diet had not received close scrutiny and had retained an unchallenged position in certain applications (eg, bowel preparation). This paper summarizes the published, theorized, and potential benefits as well as the limitations of the clear liquid diet.

The patient is a 26-y-old male who sustained a close-range shotgun wound to the perineum. Following resuscitation at a community hospital in which an exploratory laparotomy with sigmoid loop colostomy was performed, he was transferred to a tertiary referral trauma center. Upon re-exploration, there was no evidence of viable rectum, and the wound was approximately lo- 14 cm in depth and extended from the base of the scrotum to the sacrum. Following several debridements, he was left with an end sigmoid colostomy with the open perineal and abdominal wounds to heal by secondary intention. Postoperatively, the patient’s stay was complicated by the development of multiple enterocutaneous fistulas all confined to the right lower quadrant. Initially these were treated conservatively with control of drainage, octreotide acetate, non per OS (NPO), and total parenteral nutrition (TPN) for nutritional support. Once stable he underwent split-thickness skin graft to his abdominal wounds following a brief course of human recombinant growth hormone (GH) in hopes of enhancing development of granulation tissue of the grafting bed.

Over the past decade, most clinicians tend to agree that enteral nutrition is the preferred route of nutrient delivery for patients with adequately functional gastrointestinal tracts and whose oral nutrient intake is insufficient to meet estimated needs. There are multiple methods for gaining enteral access. The nasoenteric feeding tube is most commonly used due to its low complication rates, relatively low cost, and increased versatility because it can be placed into the stomach, duodenum, or the jejunum. Although many patients can be fed successfully into the stomach, there are those with increased aspiration risk and gastroparesis who require postpyloric feedings.1 Positioning a feeding tube into the small intestine is much more difficult than positioning a tube into the stomach. Several bedside “blind” methods using special placement techniques, weighted versus nonweighted tubes, pH sensor tubes, prokinetic agents, magnets, and bioelectrical detection devices have been reported, all with similar success rates ( 80% to 85%).2–10 Due to lack of universal success in “blind” placement of nasoenteric tubes, fluoroscopic or endoscopic guidance is often sought when local expertise is available. If portable equipment is not available, both of these techniques require patient transport to the radiology or endoscopy suite, which may not be feasible for critically ill patients. Both methods carry an 85% to 95% success rate in obtaining postpyloric feeding tube placement.11 So, despite multiple methods available to gain enteral access, early enteral nutrition often is not used because of the lack of success in obtaining desired positioning of a nasoenteric feeding device. Registered dietitians play an integral role in providing patients with optimal nutrition support. They are typically part of a nutrition support team, if not the sole clinician intimately managing the patient’s nutritional care plan. Typically, a certified nutrition support dietitian is responsible for performing nutrition assessments, making recommendations for enteral and parenteral nutrition care plans, monitoring the patient’s response to the nutrition support regimen, and making recommendations for changes in the nutrition regimen as needed. It is no wonder that dietitians are pursuing competency for placing postpyloric feeding tubes. This task carries an 80% to 90% success rate among the very best and dedicated clinicians, leaving marginal success to those with occasional experience. The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) recently updated and revised their standards of practice for nutrition support dietitians (NSDs).12 Although the main purpose of the standards is to provide guidance for the NSD, they do not supersede the NSD’s professional judgment or health care institution’s policies and procedures in which the NSD practices. This past year, the American Dietetic Association (ADA), with the support of the Dietitians in Nutrition Support practice group, adopted the A.S.P.E.N. Standards of Practice (SOP) for NSDs.13 The SOP states that NSDs shall participate with implementation of a medical nutrition therapy care plan. The NSD’s involvement with implementation may occur at several levels depending on their job responsibilities, professional licensure, and institutional clinical privileges.12 Levels of involvement include recommending not only the placement and management of enteral access devices but also the actual placement and management of nasoenteric access devices after special training and certification.12 If an NSD is interested in placing nasoenteric access devices, there are several issues that require prior investigation. The first is to determine whether the state in which you practice has licensure for dietetics professionals. Only states with licensure, not those with certification acts, will have a scope of practice that affects boundaries of practice.14 Review your state’s scope of practice for possible limitations. Also recommended is to avoid violating another profession’s scope of practice, be certain skills performed would not be considered practicing medicine, and be sure to practice under the direction of the appropriate licensed professional as indicated by state regulations (e.g., physician, physician assistant, and nurse practitioner).14 The placement of nasoenteric access devices is considered an invasive procedure requiring special training, demonstrated competency, and delineated clinical privileges. NSDs should ensure that it is within the interests of the health care facility that employs them to have them place nasoenteric access devices. The NSD should obtain proper training and periodic competency assessment. This training and assessment should be specified in appropriate policies and procedures and in the job description. Personnel files should contain records of training and assessments. In addition, facilities need to check with their insurance carrier to determine whether the insurer will cover an employee trained as a dietetics professional but performing duties across other disciplines.14 Secondary insurance for malpractice coverage may be necessary. Be certain to obtain a copy of your protection and limitations of coverage. For example, the ADA’s liability insurance program covers ADA active members in the provision of professional services as a trained dietetics professional functioning within the guidelines of their state and occupation.14 An activity considered a professional service is one that is expected to be provided based on the education and/or training of a dietetics professional, thus making upskilled duties potentially not covered under liability insurance policies.14 Another option for the NSD is to seek a licensed professional (e.g., physician) willing to carry the liability. Once the NSD has reviewed state and institution policies and restrictions and determines that it is feasible to place nasoenteric access devices, special training and certification must be obtained. The one question I receive most often is how to obtain this special training. First, check within your own institution or geographic location for professionals that already perform the skill and ask them how they were trained. It does not need to be, and most likely will not be, an NSD that trains you to place feeding devices. A registered nurse trained me in my facility. Other avenues for training include skills workshops, nursing or physician assistant training programs, or exchange/liaison programs arranged with other experienced, credentialed individuals. The ADA has a list of allied organizations that may be helpful. This can be obtained by e-mail at alliances@eatright.org. Allied organizations and links to allied web sites are posted on ADA’s web site http://www.eatright.org/healthorg.html. Although placing nasoenteric access devices can add to the burden of daily workload, this route of upskilling has many potential benefits. One very important benefit I have found is more timely delivery of enCorrespondence to: Gail Cresci, MS, RD, CNSD, LD, Medical College of Georgia, Department of Surgery, GI Section, Room 4072, 1120 15 Street, Augusta, GA 30912, USA. E-mail: gcresci@mail.mcg.edu