Stephen J. D. O’Keefe

Association between low colonic short-chain fatty acids and high bile acids in high colon cancer risk populations.

We propose that the influence of diet on colon cancer risk is mediated by the microbiota. To investigate how dietary fat influences risk, we compared the colonic contents of 12 adult high-risk African Americans (AAs) and 10 Caucasian Americans (CAs) who consumed a high-fat diet (123 ± 11 g/d and 129 ± 17 g/d, respectively) to 13 native Africans (NAs) who subsisted on a low-fat (38 ± 3.0 g/d) diet, all aged 50–60 yr. The colonic bile acids were measured by LC-MS and the short-chain fatty acids (SCFAs) by GC. The chief secondary colonic bile acids, deoxycholic acid and lithocholic acid, were correlated with fat intake and similar between AAs and CAs, but 3–4 times higher than in AAs (p < 0.05). The major SCFAs were lower in AAs (p < 0.001) and CAs (p < 0.001) compared to AAs, but conversely, the branched chain fatty acids (BFCA) were higher. Our results suggest that the higher risk of colon cancer in Americans may be partly explained by their high-fat and high-protein, low complex carbohydrate diet, which produces colonic residues that promote microbes to produce potentially carcinogenic secondary bile acids and less antineoplastic SCFAs. The role of BCFA in colonic carcinogenesis deserves further study.

The Microbiota and Its Metabolites in Colonic Mucosal Health and Cancer Risk

Recent advances in our ability to identify and characterize the human microbiota have transformed our appreciation of the function of the colon from an organ principally involved in the reabsorption of secretory fluids to a metabolic organ on a par with the liver. High-throughput technology has been applied to the identification of specific differences in microbial DNA, allowing the identification of trillions of microbes belonging to more than 1000 different species, with a metabolic mass of approximately 1.5 kg. The close proximity of these microbes with the mucosa and gut lymphoid tissue helps explain why a balanced microbiota is likely to preserve mucosal health, whereas an unbalanced composition, as seen in dysbiosis, may increase the prevalence of diseases not only of the mucosa but also within the body due to the strong interactions with the gut immune system, the largest immune organ of the body. Such abnormalities have been pinpointed as etiological factors in a wide range of diseases, including autoimmune disorders, allergy, irritable bowel syndrome, inflammatory bowel disease, obesity, and colon cancer. Recognition of the strong potential for food to manipulate microbiota composition has opened up new therapeutic strategies against these diseases based on dietary intervention.

Early Jejunal Feeding Initiation and Clinical Outcomes in Patients with Severe Acute Pancreatitis

BACKGROUND Compared with parenteral nutrition, enteral nutrition reduces infectious complications and mortality in patients with severe acute pancreatitis (SAP). This study used clinical outcomes to investigate the association between time to initiation of distal jejunal feeding (DJF) and time to achievement of goal enteral feeding with clinical outcomes. METHODS A retrospective chart review was performed on all patients with SAP admitted to the medical intensive care unit (ICU) during a 1-year period. Collected data included demographic information, body mass index (BMI; kg/m(2)), Acute Physiology and Chronic Health Evaluation (APACHE) II scores at admission, time of onset of DJF, time to goal feeding, ICU length of stay, and mortality. RESULTS Time to starting DJF was longer in nonsurvivors (n = 4) than in survivors (n = 12) (17 vs 7 days, P < .05). All nonsurvivors had BMI >30 kg/m(2) (50% had BMI > 50 kg/m(2)). ICU length of stay was significantly associated with achievement of goal feeding. Three patients never reached goal feeding and spent 45.3 ± 19.6 days in the ICU; 7 patients reached goal feeding within 3 days of initiating DJF and spent 18 ± 1.7 days in the ICU; and 4 patients reached goal feeding within 3 days and spent 10.5 ± 3.5 days in the ICU. APACHE II scores were not significantly different among the 3 groups (16.7 ± 1.5, 12 ± 0.7, and 16.2 ± 1.2, respectively, P > .05). CONCLUSIONS Early initiation of DJF in the ICU was associated with reduced mortality in this cohort of patients with SAP. Early achievement of jejunal feeding goal early was associated with a shorter ICU length of stay, irrespective of the severity of SAP.

Short Bowel Syndrome in Adults The Need for an Interdisciplinary Approach and Coordinated Care

Short bowel syndrome (SBS) is a heterogeneous disorder with broad variation in disease severity arising from different types of intestinal resection. The spectrum of malabsorption ranges from intestinal insufficiency to intestinal failure. Individualized patient strategies involving modifications of dietary macro- and micronutrients, fluid, and pharmacologic options are required to maximize health and quality-of-life outcomes and to minimize complications and SBS-associated mortality. Intestinal rehabilitation (IR) is an established but evolving approach to improving patient outcomes by decreasing long-term dependency on parenteral support (PS) for nutrition and fluid requirements. Specialized IR programs employ team-based interdisciplinary approaches to coordinate individualized patient care and treatment management through centralized facilities. Such facilities are often specialized intestinal care centers (ICCs) established at large medical centers. A multifaceted IR program offers the comprehensive interrelated services required by patients with SBS-associated intestinal failure throughout the course of disease. Components of interdisciplinary IR programs should include medical services offering diagnostics and monitoring, pharmacologic management, and symptom and complication control; nutrition services, including dietary modifications and interventions; and supportive psychosocial and educational services. A model of care centered on the IR concept means that long-term patient management, including decisions on long-term PS, is overseen by a member of the specialized care center. Rational, seamless, and timely communication among the patients network of home-based and ICC healthcare providers is crucial to the success of any IR program. This paradigm shift to specialized IR programs will likely result in improvements across the patient care continuum.

Effect of fiber supplementation on the microbiota in critically ill patients

AIM To determine tolerance to fiber supplementation of semi-elemental tube feeds in critically ill patients and measure its effect on colonic microbiota and fermentation. METHODS Thirteen intensive care unit patients receiving jejunal feeding with a semi-elemental diet for predominantly necrotizing pancreatitis were studied. The study was divided into 2 parts: first, short-term (3-9 d) clinical tolerance and colonic fermentation as assessed by fecal short chain fatty acid (SCFA) concentrations and breath hydrogen and methane was measured in response to progressive fiber supplementation increasing from 4 g tid up to normal requirement levels of 8 g tid; second, 4 patients with diarrhea were studied for 2-5 wk with maximal supplementation to additionally assess its influence on fecal microbiota quantitated by quantitative polymerase chain reaction (qPCR) of microbial 16S rRNA genes and Human Intestinal Tract Chip (HITChip) microarray analysis. Nearly all patients were receiving antibiotics (10/13) and acid suppressants (11/13) at some stage during the studies. RESULTS In group 1, tolerance to progressive fiber supplementation was good with breath hydrogen and methane evidence (P = 0.008 and P < 0.0001, respectively) of increased fermentation with no exacerbation of abdominal symptoms and resolution of diarrhea in 2 of 4 patients. In group 2 before supplementation, fecal microbiota mass and their metabolites, SCFA, were dramatically lower in patients compared to healthy volunteers. From qPCR and HITChip analyses we calculated that there was a 97% reduction in the predominant potential butyrate producers and starch degraders. Following 2-5 wk of fiber supplementation there was a significant increase in fecal SCFA (acetate 28.4 ± 4.1 μmol/g to 42.5 ± 3.1 μmol/g dry weight, P = 0.01; propionate 1.6 ± 0.5 vs 6.22 ± 1.1, P = 0.006 and butyrate 2.5 ± 0.6 vs 5.9 ± 1.1, P = 0.04) and microbial counts of specific butyrate producers, with resolution of diarrhea in 3 of 4 patients. CONCLUSION Conventional management of critically ill patients, which includes the use of elemental diets and broad-spectrum antibiotics, was associated with gross suppression of the colonic microbiota and their production of essential colonic fuels, i.e., SCFA. Our investigations show that fiber supplementation of the feeds has the potential to improve microbiota mass and function, thereby reducing the risks of diarrhea due to dysbiosis.

Enteral Feeding Patients With Gastric Outlet Obstruction

Patients with upper gastrointestinal obstructions were previously managed with gastric decompression and parenteral feeding. The authors present their experience in 50 patients with obstructions chiefly due to complicated severe acute (n = 31) or chronic cystic pancreatitis (n = 11) using a double-lumen nasogastric decompression and jejunal feeding tube system (NGJ) held in place with a nasal bridle that passes through the obstructed gastroduodenal segments, allowing distal jejunal feeding, and at the same time decompresses the stomach to prevent vomiting and aspiration. The tip of the jejunal tube was placed approximately 40 cm down the jejunum to maintain pancreatic rest. Duration of feeding ranged from 1-145 days (median 25 days); 19 patients were discharged home with tube feeds. Only 1 patient could not tolerate feeding and needed to be converted to parenteral feeding. Average tube life was 14 days, with replacement being needed most commonly for kinking or clogging of the jejunal tube (56%) or accidental dislodgement (24%). The obstruction resolved spontaneously in 60%, allowing resumption of normal eating. Of the patients with severe acute pancreatitis or pancreatic pseudocysts, pancreatic rest resulted in resolution of the disease without surgery in 87%, and need for surgery in the remainder was put off for 31-76 days. Seven patients died predominantly of complications of acute pancreatitis between 1 and 31 days. In conclusion, NGJ feeding provides a relatively safe conservative management for critically ill patients with upper gastrointestinal obstructions, reducing the need for surgery and parenteral feeding.

Gut rehabilitation and intestinal transplantation

The field of short bowel syndrome and gastrointestinal failure has recently evolved, particularly after the clinical introduction of intestinal and multivisceral transplantation. For nearly three decades, the management of short bowel syndrome was limited to the natural adaptation process and lifelong intravenous supplementation. However, recent clinical availability of intestinal transplantation as an alternative to total parenteral nutrition, has fueled the field with relentless efforts to enhance intestinal adaptation and gut rehabilitation with the achievement of full nutritional autonomy. Intestinal and multivisceral transplantation has added new dimensions as a creative therapy to short bowel syndrome patients, as well as those with extensive abdominal pathology that could not be treated with conventional methods. With continuous improvement in the survival outcome, the procedure has become more widely applicable and commonly utilized, with more than 65 intestinal transplant centers worldwide. With the procedure currently showing improvement in therapeutic indices, including cost effectiveness and quality of life, we believe intestinal and multivisceral transplantation should promptly be offered to short bowel syndrome patients who fail conventional rehabilitation as well as those with complex abdominal pathology.

Study of teduglutide effectiveness in parenteral nutrition-dependent short-bowel syndrome subjects

Loss of intestinal absorptive capacity from congenital defect, surgical resection or mucosal disease results in short bowel syndrome (SBS)-associated intestinal failure. In the past, few medical management options were available besides dietary modification, controlling diarrhea or high stomal output, and providing parenteral fluid, electrolyte and nutrient support (parenteral support). Recent research on strategies to enhance the intestinal absorptive capacity focused on glucagon-like peptide-2, an intestinotrophic hormone that has been shown to increase the villus height and crypt depth, and decrease gastric motility and intestinal secretory losses. STEPS is a Phase III randomized double-blinded controlled trial in which teduglutide, a recombinant analog of glucagon-like peptide-2, or placebo was given subcutaneously to SBS patients for 24 weeks. A clinically meaningful response, defined as a 20–100% reduction in parenteral support volume, was achieved in 63% of the treatment group compared with 30% in the placebo group (p = 0.002) without an increase in serious side effects. Teduglutide offers a new targeted approach to SBS-associated intestinal failure management. Its specific role in clinical practice remains to be evaluated.

Endoscopic evaluation of small intestine transplant grafts.

Background The management of small bowel transplantation is unique because signs of rejection can be obtained visually by endoscopy. The aim of this study was to evaluate the accuracy of endoscopic appearance in assessing histologic evidence of acute cellular rejection (ACR). Methods Endoscopies were performed in 66 asymptomatic “surveillance” small bowel transplant recipients and 71 symptomatic recipients from a single center. For surveillance patients, 125 ileoscopies were performed to collect 590 biopsies, and for the symptomatic group, 229 ileoscopies and jejunoscopies were conducted to obtain 434 biopsies. Results The sensitivity and specificity of endoscopic visualization in detecting ACR was 50% and 91.5% for the surveillance group and 43% and 67% for the symptomatic patients. In surveillance, visual impression alone would have missed three cases of moderate and no cases of severe ACR, whereas in the symptomatic group, visual inspection alone would have missed 20 cases of moderate ACR, and findings from visual inspection of the chimney were normal in 55% of cases with proximal ACR. However, chimney biopsy was generally representative of biopsy findings in the proximal graft but would have missed moderate to severe rejection in three patients (1%). In a subset of 23 endoscopies, zoom endoscopy did not improve visual discrimination. The only complication was a biopsy-related non–life-threatening bleed. Conclusions In symptomatic patients, visual inspection detected all cases of severe rejection but would have missed patients with early readily treatable rejection and thus making biopsy mandatory in clinical practice. Our results support the current practice of ileoscopic biopsy alone for graft surveillance in asymptomatic patients.

Jejunal Feeding in Patients With Pancreatitis

Patients with severe acute pancreatitis complicated by organ failure and/or pancreatic necrosis or fluid collections should have placement of a double-lumen nasogastric-jejunal tube to be used for both gastric decompression and jejunal feeding. These patients are at risk for gastric outlet obstruction, which may be treated so that complications such as aspiration and reflux are avoided. Furthermore, early enteral feeding can prevent ileus, suppress further organ failure, and ultimately restore gut function if continued in an uninterrupted manner. Ultimately, this patient population will benefit from pancreatic rest and jejunal feeding specifically when compared with patients using nasogastric feeding tubes.