Intestinal Bacteria Maintain Adult Enteric Nervous System and Nitrergic Neurons via Toll-like Receptor 2-induced Neurogenesis in Mice.

BACKGROUND & AIMS: The enteric nervous system (ENS) exists in close proximity to luminal bacteria. Intestinal microbes regulate ENS development, but little is known about their effects on adult enteric neurons. We investigated whether intestinal bacteria or their products affect the adult ENS via toll-like receptors (TLRs) in mice. METHODS: We performed studies with conventional C57/BL6, germ-free C57/BL6, Nestin-creERT2:tdTomato, Nestin-GFP, and ChAT-cre:tdTomato. Mice were given drinking water with ampicillin or without (controls). Germ-free mice were given drinking water with TLR2 agonist or without (controls). Some mice were given a blocking antibody against TLR2 or a TLR4 inhibitor. We performed whole gut transit, bead latency, and geometric center studies. Feces were collected and analyzed by 16S ribosomal RNA gene sequencing. Longitudinal muscle myenteric plexus (LMMP) tissues were collected, analyzed by immunohistochemistry, and levels of nitric oxide were measured. Cells were isolated from colonic LMMP of Nestin-creERT2:tdTomato mice and incubated with agonists of TLR2 (receptor for gram-positive bacteria), TLR4 (receptor for gram-negative bacteria), or distilled water (control) and analyzed by flow cytometry. RESULTS: Stool from mice given ampicillin had altered composition of gut microbiota with reduced abundance of gram-positive bacteria and increased abundance of gram-negative bacteria, compared with mice given only water. Mice given ampicillin had reduced colon motility compared with mice given only water, and their colonic LMMP had reduced numbers of nitrergic neurons, reduced neuronal nitric oxide synthase production, and reduced colonic neurogenesis. Numbers of colonic myenteric neurons increased after mice were switched from ampicillin to plain water, with increased markers of neurogenesis. Nestin-positive enteric neural precursor cells expressed TLR2 and TLR4. In cells isolated from the colonic LMMP, incubation with the TLR2 agonist increased the percentage of neurons originating from enteric neural precursor cells to approximately 10%, compared with approximately 0.01% in cells incubated with the TLR4 agonist or distilled water. Mice given an antibody against TLR2 had prolonged whole gut transit times; their colonic LMMP had reduced total neurons and a smaller proportion of nitrergic neurons per ganglion, and reduced markers of neurogenesis compared with mice given saline. Colonic LMMP of mice given the TLR4 inhibitor did not have reduced markers of neurogenesis. Colonic LMMP of germ-free mice given TLR2 agonist had increased neuronal numbers compared with control germ-free mice. CONCLUSIONS: In the adult mouse colon, TLR2 promotes colonic neurogenesis, regulated by intestinal bacteria. Our findings indicate that colonic microbiota help maintain the adult ENS via a specific signaling pathway. Pharmacologic and probiotic approaches directed towards specific TLR2 signaling processes might be developed for treatment of colonic motility disorders related to use of antibiotics or other factors.

Quality of Life and Functional Outcome After Transanal Abdominal Transanal Proctectomy for Low Rectal Cancer.

BACKGROUND: Transanal abdominal transanal proctectomy is a sphincter-preserving procedure designed to avoid colostomy in patients with cancer in the distal third of the rectum. Oncologic outcomes of this procedure have been established. However, data regarding patient satisfaction and quality of life are scant. OBJECTIVE: The purpose of this study was to evaluate the quality of life and functional outcomes of patients after transanal abdominal transanal proctectomy. DESIGN: This is a cross-sectional study. SETTINGS: The study was conducted at a tertiary referral colorectal center. PATIENTS: Patients who underwent transanal abdominal transanal proctectomy were included and surveyed using the Fecal Incontinence Quality of Life Scale, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, the Quality of Life Questionnaire CR38 module, and a questionnaire designed by the authors to assess satisfaction with quality of life. MAIN OUTCOME MEASURES: Quality of life, functional outcomes, and patient satisfaction were measured and compared by age, tumor level, and stage of the disease. RESULTS: A total of 133 surveys were mailed, and 90 patients responded and were included in the study. Patient quality of life was not significantly different after surgery. Patients with more proximal tumors had better lifestyle, physical, and emotional scores. Older patients performed better on multiple levels, including coping, emotional, body image, future perspective, and digestive. Stage of disease had no impact on quality of life. Compared with reference values, patients who underwent transanal abdominal transanal proctectomy performed better on most of the components. All of patients preferred transanal abdominal transanal proctectomy over having a stoma based on their current anal sphincter function, and >97% of patients preferred transanal abdominal transanal proctectomy based on their current quality of life, sexual function, and level of activities. LIMITATIONS: This study is limited by the lack of a comparison group and a potential selection bias. CONCLUSIONS: Satisfaction with quality of life and functional outcomes is high after transanal abdominal transanal proctectomy. Older patients and those with more proximal tumors performed better. This patient population clearly preferred a sphincter-preserving option for treatment of their rectal cancer.

Modulatory Effects of Gut Microbiota on the Central Nervous System: How Gut Could Play a Role in Neuropsychiatric Health and Diseases.

Gut microbiome is an integral part of the Gut-Brain axis. It is becoming increasingly recognized that the presence of a healthy and diverse gut microbiota is important to normal cognitive and emotional processing. It was known that altered emotional state and chronic stress can change the composition of gut microbiome, but it is becoming more evident that interaction between gut microbiome and central nervous system is bidirectional. Alteration in the composition of the gut microbiome can potentially lead to increased intestinal permeability and impair the function of the intestinal barrier. Subsequently, neuro-active compounds and metabolites can gain access to the areas within the central nervous system that regulate cognition and emotional responses. Deregulated inflammatory response, promoted by harmful microbiota, can activate the vagal system and impact neuropsychological functions. Some bacteria can produce peptides or short chain fatty acids that can affect gene expression and inflammation within the central nervous system. In this review, we summarize the evidence supporting the role of gut microbiota in modulating neuropsychological functions of the central nervous system and exploring the potential underlying mechanisms.

Increased Incidence of Benign Pancreatic Pathology following Pancreaticoduodenectomy for Presumed Malignancy over 10 Years despite Increased Use of Endoscopic Ultrasound.

Despite using imaging studies, tissue sampling, and serologic tests about 5-10% of surgeries done for presumed pancreatic malignancies will have benign findings on final pathology. Endoscopic ultrasound (EUS) is used with increasing frequency to study pancreatic masses. The aim of this study is to examine the effect of EUS on prevalence of benign diseases undergoing Whipple over the last decade. Patients who underwent Whipple procedure for presumed malignancy at Emory University Hospital from 1998 to 2011 were selected. Demographic data, history of smoking and drinking, history of diabetes and pancreatitis, imaging data, pathology reports, and tumor markers were extracted. 878 patients were found. 95 (10.82%) patients had benign disease. Prevalence of benign finding had increased over the recent years despite using more EUS. Logistic regression models showed that abdominal pain (OR: 5.829, 95% CI 2.681-12.674, P ≤ 0.001) and alcohol abuse (OR: 3.221, CI 95%: 1.362-7.261, P: 0.002) were predictors of benign diseases. Jaundice (OR: 0.221, 95% CI: 0.084-0.58, P: 0.002), mass (OR: 0.145, 95% CI: 0.043-0.485, P: 0.008), and ductal dilation (OR: 0.297, 95% CI 0.134-0.657, P: 0.003) were associated with malignancy. Use of imaging studies, ERCP, and EUS has not decreased the percentage of benign findings after surgery for presumed pancreatic malignancy.

Optic neuropathy, myelopathy, anemia, and neutropenia caused by acquired copper deficiency after gastric bypass surgery.

Malabsorptive bariatric surgery is rapidly becoming a major cause of copper deficiency given the increasing prevalence of these procedures for morbid obesity. Acquired copper deficiency can present with clinically significant hematologic and neurological manifestations. Although hematologic manifestations of copper deficiency are rapidly reversible, significant neurological improvement after copper supplementation therapy is unusual and many patients remain debilitated and may only experience, at best, stabilization of the neurological manifestations. Here we present a case of an undiagnosed copper deficiency several years after bariatric gastric bypass surgery, in a patient who concomitantly used zinc-containing denture cream for several years, associated with anemia, neutropenia, myelopathy, respiratory failure, and bilateral optic neuropathy, which caused major vision loss. This patient was also a heterozygote carrier of the 5,10-methylenetetrahydrofolate reductase A1298C gene polymorphism, which may affect copper metabolism. Intravenous copper repletion resulted in rapid correction of hematologic indices. However, neurological manifestations, including vision loss responded only modestly to copper supplementation, despite achieving normal blood copper concentrations. Clinicians should consider copper deficiency in patients at risk, as in this case, as a delayed diagnosis can lead to irreversible disability due to neurological manifestations.

MicroRNA 375 mediates palmitate-induced enteric neuronal damage and high-fat diet-induced delayed intestinal transit in mice.

BACKGROUND & AIMS: A high-fat diet (HFD) can cause serious health problems, including alteration of gastrointestinal transit, the exact mechanism of which is not clear. Several microRNAs (miRNAs) are involved in energy homeostasis, lipid metabolism, and HFD-induced weight gain. We investigated the role of miRNAs in HFD-induced damage to the enteric nervous system. METHODS: Male mice were fed a HFD (60% calories from fat) or regular diets (18% calories from fat) for 11 weeks. Mice on regular diets and HFDs were given intraperitoneal injections of Mir375 inhibitor or a negative control. Body weights, food intake, stool indices, and gastrointestinal transit (following Evans blue gavage) were measured. An enteric neuronal cell line (immorto-fetal enteric neuronal) and primary enteric neurons were used for in vitro studies. RESULTS: HFD delayed intestinal transit, which was associated with increased apoptosis and loss of colonic myenteric neurons. Mice fed a low-palmitate HFD did not develop a similar phenotype. Palmitate caused apoptosis of enteric neuronal cells associated with mitochondrial dysfunction and endoplasmic reticulum stress. Palmitate significantly increased the expression of Mir375 in vitro; transfection of cells with a Mir375 inhibitor prevented the palmitate-induced enteric neuronal cell apoptosis. Mir375 expression was increased in myenteric ganglia of mice fed HFD and associated with decreased levels of Mir375 target messenger RNAs, including Pdk1. Systemic injection of a Mir375 inhibitor for 5 weeks prevented HFD-induced delay in intestinal transit and morphologic changes. CONCLUSIONS: HFDs delay colonic transit, partly by inducing apoptosis in enteric neuronal cells. This effect is mediated by Mir375 and is associated with reduced levels of Pdk1. Mir375 might be targeted to increase survival of enteric neurons and gastrointestinal motility.

Quality of life and fecal incontinence after transanal endoscopic microsurgery for benign and malignant rectal lesions.

BACKGROUND: Transanal endoscopic microsurgery (TEM) is a minimally invasive treatment used to excise a variety of rectal lesions. Potential overstretching of the sphincter's musculature due to dilation of the anal canal to allow placement of a 40-mm-wide scope combined with partial resection of the rectum and subsequent loss of rectal volume creates a concern regarding anorectal function postoperatively. Data regarding patient satisfaction with anorectal function and quality of life after TEM are scant. This report presents data on patient satisfaction gathered during a period of 10 years. METHODS: A prospectively maintained database of patients undergoing TEM from 1997 to 2007 was queried to identify patients to survey using the Fecal Incontinence Quality of Life Scale questionnaire, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) questionnaire version 3, and a questionnaire designed by the authors to assess satisfaction with quality of life. From a group of 86 patients, 57 (66 %) responded to the questionnaires. Patient satisfaction outcomes were determined by age, preoperative diagnosis, tumor level in the rectum, excision method, and radiation treatment. RESULTS: Most of the patients (94.7 %) preferred TEM to having a stoma. Age (p = 0.03) and nature of the lesion (p = 0.03) were the only factors that affected coping. Depression was affected only by the presence of malignancy (p = 0.001). Excision method was the only factor that significantly influenced overall lifestyle (p = 0.002). Neither tumor level (p = 0.8) nor radiation therapy (p = 0.9) affected patient satisfaction with lifestyle after TEM. The presence of malignancy (p = 0.004) and full-thickness excision (p = 0.02) were related to more problems with fecal incontinence. CONCLUSION: Satisfaction with fecal continence generally is high after TEM. Tumor level, size of tumor, and radiation therapy do not affect the level of satisfaction after TEM. Younger age and benign nature of the lesion help patients to cope better with lifestyle changes and reduce depression. Patients with submucosal excision have a significantly higher level of satisfaction.

Functional Dyspepsia in Review: Pathophysiology and Challenges in the Diagnosis and Management due to Coexisting Gastroesophageal Reflux Disease and Irritable Bowel Syndrome.

Functional dyspepsia is a common disorder which imposes significant diagnostic and treatment challenges for patients and physicians. The most recent update of the diagnostic criteria subdivides functional dyspepsia into two subcategories based on the main symptom of epigastric pain or postmeal fullness. As we discuss in this review, several studies have shown significant overlap in symptoms and pathophysiology between functional dyspepsia, irritable bowel syndrome, and the spectrum of reflux disorders. This overlap in symptoms can be informative in helping us to understand the underlying pathophysiology, diagnostic approaches, and treatment strategies. The addition of diagnostic testing such as pH impedance manometry of the distal esophagus to the current common diagnostic tests might be helpful in distinguishing between functional dyspepsia and reflux disease. Importantly, various treatment modalities may be more effective than others if the main symptom is burning rather than pain or postmeal fullness rather than early satiation.

Update on diabetes in the elderly and in nursing home residents.

Diabetes is common in the elderly population and in nursing home residents. More than 20% of adults aged 65 to 75 years and 40% of adults older than 80 years suffer from diabetes. Physiological changes in elderly individuals, such as decreased physical activity, abdominal obesity, and increased inflammatory state, increase insulin resistance in peripheral tissue and reduce glucose-dependent insulin release, leading to carbohydrate intolerance and diabetes. The clinical presentation in the elderly and nursing home residents is frequently guided by the high rate of comorbidities such as hypertension, depression, and cardiovascular diseases. Treatment recommendations for glycemic control in elderly ambulatory patients are similar to those in long-term care facilities. Healthy patients with diabetes should aim for near-normal fasting plasma glucose and an HbA1C of about 7%; however, treatment goals must be individualized in patients with impaired cognitive and physical ability, reduced life expectancy, and heavy burden of comorbid disease. Elderly individuals and nursing home residents are at increased risk of hypoglycemia during pharmacological treatment. In general, a conservative and stepwise approach to the treatment of the elderly patient with diabetes is suggested. Treatment may be initiated with dietary and physical activity modification and with a single oral agent, followed by a combination of oral agents and insulin therapy if needed. Evidence from clinical trials indicates that improving glycemic control, as well as cardiovascular risk factors, reduces morbidity and mortality in older individuals with diabetes.

Amino acid composition in parenteral nutrition: what is the evidence?

PURPOSE OF REVIEW: Complete parenteral nutrition solutions contain mixed amino acid products providing all nine essential amino acids and a varying composition of nonessential amino acids. Relatively little rigorous comparative efficacy research on altered parenteral nutrition amino acid composition has been published in recent years. RECENT FINDINGS: Limited data from randomized, double-blind, adequately powered clinical trials to define optimal doses of total or individual amino acids in parenteral nutrition are available. An exception is the growing number of studies on the efficacy of glutamine supplementation of parenteral nutrition or given as a single parenteral agent. Parenteral glutamine appears to confer benefit in selected patients; however, additional data to define optimal glutamine dosing and the patient subgroups who may most benefit from this amino acid are needed. Although some promising studies have been published, little data are available in the current era of nutrition support on the clinical efficacy of altered doses of arginine, branched chain amino acids, cysteine, or taurine supplementation of parenteral nutrition. SUMMARY: Despite routine use of parenteral nutrition, surprisingly little clinical efficacy data are available to guide total or specific amino acid dosing in adult and pediatric patients requiring this therapy. This warrants increased attention by the research community and funding agencies to better define optimal amino acid administration strategies in patient subgroups requiring parenteral nutrition.

Diverse roles of leptin in the gastrointestinal tract: modulation of motility, absorption, growth, and inflammation.

OBJECTIVE: Leptin was discovered in 1994 as a hormone produced by adipose tissue with a modulatory effect on feeding behavior and weight control. Recently, the stomach has been identified as an important source of leptin and growing evidence has shown diverse functions for leptin in the gastrointestinal tract. METHODS: Using leptin as a keyword in PubMed, more than 17 000 articles were identified, of which more than 500 articles were related to the role of leptin in the gastrointestinal tract. Available abstracts were reviewed and more than 200 original articles were reviewed in detail. RESULTS: The available literature demonstrated that leptin can modulate several important functions of the gastrointestinal tract. Leptin interacts with the vagus nerve and cholecystokinin to delay gastric emptying and has a complex effect on motility of the small bowel. Leptin modulates absorption of macronutrients in the gastrointestinal tract differentially in physiologic and pathologic states. In physiologic states, exogenous leptin has been shown to decrease carbohydrate absorption and to increase the absorption of small peptides by the PepT1 di-/tripeptide transporter. In certain pathologic states, leptin has been shown to increase absorption of carbohydrates, proteins, and fat. Leptin has been shown to be upregulated in the colonic mucosa in patients with inflammatory bowel disease. Leptin stimulates gut mucosal cell proliferation and inhibits apoptosis. These functions have led to speculation about the role of leptin in tumorigenesis in the gastrointestinal tract, which is complicated by the multiple immunoregulatory effects of leptin. CONCLUSION: Leptin is an important modulator of major aspects of gastrointestinal tract functions, independent of its more well-described roles in appetite regulation and obesity.