Fecal metabolite profiling identifies liver transplant recipients at risk for postoperative infection.

Metabolites produced by the intestinal microbiome modulate mucosal immune defenses and optimize epithelial barrier function. Intestinal dysbiosis, including loss of intestinal microbiome diversity and expansion of antibiotic-resistant pathobionts, is accompanied by changes in fecal metabolite concentrations and increased incidence of systemic infection. Laboratory tests that quantify intestinal dysbiosis, however, have yet to be incorporated into clinical practice. We quantified fecal metabolites in 107 patients undergoing liver transplantation (LT) and correlated these with fecal microbiome compositions, pathobiont expansion, and postoperative infections. Consistent with experimental studies implicating microbiome-derived metabolites with host-mediated antimicrobial defenses, reduced fecal concentrations of short- and branched-chain fatty acids, secondary bile acids, and tryptophan metabolites correlate with compositional microbiome dysbiosis in LT patients and the relative risk of postoperative infection. Our findings demonstrate that fecal metabolite profiling can identify LT patients at increased risk of postoperative infection and may provide guideposts for microbiome-targeted therapies.

Bifidobacteria metabolize lactulose to optimize gut metabolites and prevent systemic infection in patients with liver disease.

Progression of chronic liver disease is precipitated by hepatocyte loss, inflammation and fibrosis. This process results in the loss of critical hepatic functions, increasing morbidity and the risk of infection. Medical interventions that treat complications of hepatic failure, including antibiotic administration for systemic infections and lactulose treatment for hepatic encephalopathy, can impact gut microbiome composition and metabolite production. Here, using shotgun metagenomic sequencing and targeted metabolomic analyses on 847 faecal samples from 262 patients with acute or chronic liver disease, we demonstrate that patients hospitalized for liver disease have reduced microbiome diversity and a paucity of bioactive metabolites, including short-chain fatty acids and bile acid derivatives, that impact immune defences and epithelial barrier integrity. We find that patients treated with the orally administered but non-absorbable disaccharide lactulose have increased densities of intestinal bifidobacteria and reduced incidence of systemic infections and mortality. Bifidobacteria metabolize lactulose, produce high concentrations of acetate and acidify the gut lumen in humans and mice, which, in combination, can reduce the growth of antibiotic-resistant bacteria such as vancomycin-resistant Enterococcus faecium in vitro. Our studies suggest that lactulose and bifidobacteria serve as a synbiotic to reduce rates of infection in patients with severe liver disease.

Immunomodulatory fecal metabolites are associated with mortality in COVID-19 patients with respiratory failure.

Respiratory failure and mortality from COVID-19 result from virus- and inflammation-induced lung tissue damage. The intestinal microbiome and associated metabolites are implicated in immune responses to respiratory viral infections, however their impact on progression of severe COVID-19 remains unclear. We prospectively enrolled 71 patients with COVID-19 associated critical illness, collected fecal specimens within 3 days of medical intensive care unit admission, defined microbiome compositions by shotgun metagenomic sequencing, and quantified microbiota-derived metabolites (NCT #04552834). Of the 71 patients, 39 survived and 32 died. Mortality was associated with increased representation of Proteobacteria in the fecal microbiota and decreased concentrations of fecal secondary bile acids and desaminotyrosine (DAT). A microbiome metabolic profile (MMP) that accounts for fecal secondary bile acids and desaminotyrosine concentrations was independently associated with progression of respiratory failure leading to mechanical ventilation. Our findings demonstrate that fecal microbiota composition and microbiota-derived metabolite concentrations can predict the trajectory of respiratory function and death in patients with severe SARS-Cov-2 infection and suggest that the gut-lung axis plays an important role in the recovery from COVID-19.

Stigma experiences of patients living with gastroparesis.

INTRODUCTION: Stigmatization toward chronic digestive diseases is well documented. Patients perceive others hold negative stereotypes toward their disease and may internalize these beliefs as true. Because of this, stigmatization is associated with poor outcomes across disease-related and psychosocial domains. No study to date evaluates stigmatization toward patients living with gastroparesis (GP), a poorly understood disease affecting gastric motility. We aimed to gain deep understanding of stigma in patients living with gastroparesis. METHODS: Patients with GP were recruited from two university-based gastroenterology practices as well as patient advocacy support groups. Participants underwent a semi-structured qualitative interview about their experiences with stigma related to their GP diagnosis, which were audio-recorded and transcribed to text for analysis using a grounded theory approach. Major themes with representative quotations were documented. RESULTS: Twenty-three patients participated. The majority were White, female, with idiopathic GP under the care of a gastroenterologist. All patients reported stigma related to GP. Seven major themes were found: stigma from healthcare providers, stigma within interpersonal relationships, GP as an invisible disease, blame, unsolicited suggestions on how to manage disease, disclosure, and stigma resistance. CONCLUSIONS: This is the first study to describe stigma experiences in patients with GP. The results suggest patients experience considerable stigmatization toward their condition from multiple sources. Patients also demonstrated resistance to negative beliefs, which can serve as a protective factor for the negative effects of disease stigma. Clinicians should be aware of stigma in GP patients, including their own potential internal biases and behaviors.

Efficacy and Safety of Neostigmine and Decompressive Colonoscopy for Acute Colonic Pseudo-Obstruction: A Single-Center Analysis.

BACKGROUND: Acute colonic pseudo-obstruction (ACPO) is characterized by acute colonic dilation in the absence of anatomical obstruction. Neostigmine is an acetylcholinesterase inhibitor recommended as first-line salvage therapy for uncomplicated ACPO. Decompressive colonoscopy is recommended if neostigmine is contraindicated or unsuccessful. There is a need to better characterize relative efficacy and factors impacting treatment choice. The aim of the study was to examine the use, efficacy, and safety of neostigmine and decompressive colonoscopy in the management of ACPO at a single academic center. METHODS: Patients ≥ 18 years of age meeting established criteria for uncomplicated ACPO and with cecal diameter ≥ 10 cm on imaging between 1999 and 2019 were identified. Individuals were categorized as having received supportive care alone or subsequent trials of neostigmine or decompressive colonoscopy. Demographics and pre- and post-intervention data were collected, including indication and contraindication to intervention used, time to intervention, initial response, and adverse events. RESULTS: In 46 cases of ACPO (N = 42 patients), all but one individual received initial supportive care. Seven responded to conservative measures alone. Of the patients failing supportive care, 15 cases were initially treated with neostigmine (response rate 86.7%) and 24 initially underwent decompressive colonoscopy (response rate 95.8%) (P = 0.390). One episode of transient bradycardia, resolved with atropine, occurred in the neostigmine group. One patient experienced respiratory instability during colonoscopy. CONCLUSIONS: Both neostigmine and decompressive colonoscopy appear effective for treating uncomplicated ACPO in individuals failing conservative therapy. Adverse events were infrequent in both cohorts. Future prospective studies examining treatment for ACPO should focus on whether either intervention is superior to the other.

Gastric Mucosal Immune Profiling and Dysregulation in Idiopathic Gastroparesis.

INTRODUCTION: It is unclear how immune perturbations may influence the pathogenesis of idiopathic gastroparesis, a prevalent functional disorder of the stomach which lacks animal models. Several studies have noted altered immune characteristics in the deep gastric muscle layer associated with gastroparesis, but data are lacking for the mucosal layer, which is endoscopically accessible. We hypothesized that immune dysregulation is present in the gastroduodenal mucosa in idiopathic gastroparesis and that specific immune profiles are associated with gastroparesis clinical parameters. METHODS: In this cross-sectional prospective case-control study, routine endoscopic biopsies were used for comprehensive immune profiling by flow cytometry, multicytokine array, and gene expression in 3 segments of the stomach and the duodenal bulb. Associations of immune endpoints with clinical parameters of gastroparesis were also explored. RESULTS: The gastric mucosa displayed large regional variation of distinct immune profiles. Furthermore, several-fold increases in innate and adaptive immune cells were found in gastroparesis. Various immune cell types showed positive correlations with duration of disease, proton pump inhibitor dosing, and delayed gastric emptying. DISCUSSION: This initial observational study showed immune compartmentalization of the human stomach mucosa and significant immune dysregulation at the level of leukocyte infiltration in idiopathic gastroparesis patients that extends to the duodenum. Select immune cells, such as macrophages, may correlate with clinicopathological traits of gastroparesis. This work supports further mucosal studies to advance our understanding of gastroparesis pathophysiology.

Open-label pilot study: Non-invasive vagal nerve stimulation improves symptoms and gastric emptying in patients with idiopathic gastroparesis.

BACKGROUND: Gastroparesis, a chronic motility disorder characterized by delayed gastric emptying, abdominal pain, nausea, and vomiting, remains largely unexplained. Medical therapy is limited, reflecting the complex physiology of gastric sensorimotor function. Vagus nerve stimulation is an attractive therapeutic modality for gastroparesis, but prior methods required invasive surgery. In this open-label pilot study, we aimed to assess the benefit of non-invasive vagal nerve stimulation in patients with mild to moderate idiopathic gastroparesis. METHODS: Patients self-administered the gammaCore vagal nerve stimulator for 4 weeks. The gastroparesis cardinal symptom index daily diary (GCSI-dd) was assessed during a two-week run-in period, ≥4 weeks of therapy, and 4 weeks after therapy was completed. Gastric emptying and autonomic function testing were also performed. The primary endpoint was an absolute reduction in CGSI-dd of 0.75 after nVNS. RESULTS: There was a total improvement in symptom scores (2.56 ± 0.76 to 1.87 ± 1.05; P = .01), with 6/15 (40%) participants meeting our primary endpoint. Therapy was associated with a reduction in gastric emptying (T1/2 155 vs 129 minutes; P = .053, CI -0.4 to 45). Therapy did not correct autonomic function abnormalities, but was associated with modulation of reflex parasympathetic activity. CONCLUSIONS: Short-term non-invasive vagal nerve stimulation led to improved cardinal symptoms and accelerated gastric emptying in a subset of patients with idiopathic gastroparesis. Responders had more severe gastric delay at baseline and clinical improvement correlated with duration of therapy, but not with improvements in gastric emptying. Larger randomized sham-controlled trials of greater duration are needed to confirm the results of this pilot study.

Peer Support and Outcome for Veterans with Posttraumatic Stress Disorder (PTSD) in a Residential Rehabilitation Program.

This observational study aims to determine the characteristics of peer support that change attitudes toward recovery and PTSD symptom severity. The study respondents were a sample of 55 VA patients who were residents at a residential rehabilitation program for PTSD where they were the recipients of peer support. Veterans perceived greater support from other veterans (mean = 4.04 on 1-5 scale, SD = 0.78) than from any other source. Greater perceived support from the peer support provider, other veterans and mental health staff was associated with improvements from intake to discharge in recovery attitudes. Greater perceived support from other veterans and mental health staff was associated with an improvement in PTSD symptoms. Results from this study suggest that positive perceptions of peer support favorably influences attitudes toward recovery, from PTSD, in veterans who are the recipients of such support.

Internalized Stigma of Mental Illness (ISMI) scale: a multinational review.

The Internalized Stigma of Mental Illness (ISMI) scale is a 29-item questionnaire measuring self-stigma among persons with psychiatric disorders. It was developed with substantial consumer input and has been widely used, but its psychometric qualities have not been comprehensively evaluated across multiple versions. Here we review the 55 known versions, and provide the 47 available versions, including: Arabic, Armenian, Bengali, Bulgarian, Chinese (Mainland, Taiwan, Hong Kong), Croatian, Dutch, English (USA, South Africa), Estonian, Farsi, Finnish, French, German, Greek, Hebrew, Hindi, Japanese, Khmer, Korean, Lithuanian, Lugandan, Maltese, Polish, Portuguese (Portugal, Brazil), Romanian, Russian, Samoan, Slovenian, Spanish (Spain), Swahili, Swedish, Tongan, Turkish, Urdu, and Yoruba, and qualitative English and Swahili versions, as well as versions for depression, schizophrenia, substance abuse, eating disorders, epilepsy, inflammatory bowel disease, leprosy, smoking, parents and caregivers of people with mental illness, and ethnicity. The various versions show reliability and validity across a wide range of languages, cultures, and writing systems. The most commonly reported findings of studies using the ISMI are that internalized stigma correlates with higher depression, lower self esteem, and higher symptom severity. Initial studies of ways to reduce internalized stigma are promising and warrant further investigation.

Presenting concerns of veterans entering treatment for posttraumatic stress disorder.

Patient-centered care involves engaging patients as partners in establishing treatment priorities. No prior studies have examined what specific problems veterans hope to address when they enter posttraumatic stress disorder (PTSD) treatment. Veterans starting outpatient (n = 216) and residential (n = 812) PTSD treatment in 2 multisite care management trials specified (open-ended) the 2 or 3 problems that they most wanted to improve through treatment. Over 80% mentioned PTSD-symptom-related concerns including PTSD or trauma (19.2% to 19.9% of patients), anger (31.0% to 36.7%), sleep problems (14.3% to 27.3%), nightmares (12.3% to 19.4%), and estrangement/isolation (7.9% to 20.8%). Other common problems involved depression (23.1% to 36.5%), anxiety not specific to PTSD (23.9% to 27.8%), relationships (20.4% to 24.5%), and improving coping or functioning (19.2% to 20.4%). Veterans' treatment goals varied significantly by outpatient versus residential setting, gender, and period of military service. Our findings confirm the importance of educating patients about how available efficacious treatments relate to clients' personal goals. Our results also suggest that clinicians should be prepared to offer interventions or provide referrals for common problems such as anger, nightmares, sleep, depression, or relationship difficulties if these problems do not remit with trauma-focused psychotherapy or if patients are unwilling to undergo trauma-focused treatment.