Transcutaneous vagal nerve stimulation for treating gastrointestinal symptoms in individuals with diabetes: a randomised, double-blind, sham-controlled, multicentre trial.

AIMS/HYPOTHESIS: Diabetic gastroenteropathy frequently causes debilitating gastrointestinal symptoms. Previous uncontrolled studies have shown that transcutaneous vagal nerve stimulation (tVNS) may improve gastrointestinal symptoms. To investigate the effect of cervical tVNS in individuals with diabetes suffering from autonomic neuropathy and gastrointestinal symptoms, we conducted a randomised, sham-controlled, double-blind (participants and investigators were blinded to the allocated treatment) study. METHODS: This study included adults (aged 20-86) with type 1 or 2 diabetes, gastrointestinal symptoms and autonomic neuropathy recruited from three Steno Diabetes Centres in Denmark. Participants were randomly allocated 1:1 to receive active or sham stimulation. Active cervical tVNS or sham stimulation was self-administered over two successive study periods: 1 week of four daily stimulations and 8 weeks of two daily stimulations. The primary outcome measures were gastrointestinal symptom changes as measured using the gastroparesis cardinal symptom index (GCSI) and the gastrointestinal symptom rating scale (GSRS). Secondary outcomes included gastrointestinal transit times and cardiovascular autonomic function. RESULTS: Sixty-eight participants were randomised to the active group, while 77 were randomised to the sham group. Sixty-three in the active and 68 in the sham group remained for analysis in study period 1, while 62 in each group were analysed in study period 2. In study period 1, active and sham tVNS resulted in similar symptom reductions (GCSI: -0.26 ± 0.64 vs -0.17 ± 0.62, p=0.44; GSRS: -0.35 ± 0.62 vs -0.32 ± 0.59, p=0.77; mean ± SD). In study period 2, active stimulation also caused a mean symptom decrease that was comparable to that observed after sham stimulation (GCSI: -0.47 ± 0.78 vs -0.33 ± 0.75, p=0.34; GSRS: -0.46 ± 0.90 vs -0.35 ± 0.79, p=0.50). Gastric emptying time was increased in the active group compared with sham (23 min vs -19 min, p=0.04). Segmental intestinal transit times and cardiovascular autonomic measurements did not differ between treatment groups (all p>0.05). The tVNS was well-tolerated. CONCLUSIONS/INTERPRETATION: Cervical tVNS, compared with sham stimulation, does not improve gastrointestinal symptoms among individuals with diabetes and autonomic neuropathy. TRIAL REGISTRATION: ClinicalTrials.gov NCT04143269 FUNDING: The study was funded by the Novo Nordisk Foundation (grant number NNF180C0052045).

Early Economic Assessment of Faecal Microbiota Transplantation for Patients with Urinary Tract Infections Caused by Multidrug-Resistant Organisms.

INTRODUCTION: The use of faecal microbiota transplantation (FMT) to eradicate intestinal carriage of multidrug-resistant organisms (MDRO) has been described in case reports and small case series. Although few in numbers, these patients suffer from recurrent infections that may exacerbate both the patients' comorbidities and their healths. In the current study, we hypothesized that FMT for MDRO-related urinary tract infections (UTIs) reduces hospitalisations and associated costs. METHODS: In a cohort of patients referred for FMT from 2015 to 2020, we selected all patients who had consecutively been referred for eradication of MRDO carriage with UTIs. An early economic assessment was performed to calculate hospital-related costs. The overall study cohort was registered at ClinicalTrials, study identifier NCT03712722. RESULTS: We consecutively included five patients with UTIs caused by MDROs. Four of the patients were renal transplant recipients. Patients were followed for median 126 days (range 60-320), where the follow-up duration for each patient was aligned with the number of days from the first UTI to FMT. The median number of UTIs per patient dropped from 4 to 0. Investigating hospital costs, hospital admission days dropped by 87% and monthly hospital costs by 79%. CONCLUSIONS: FMT was effective in reducing the occurrence of UTIs and mediated a marked reduction in hospital costs. We suggest that this strategy is cost-effective. TRIAL REGISTRATION: ClinicalTrials, study identifier NCT03712722.

Opioids in the Treatment of Chronic Idiopathic Diarrhea in Humans-A Systematic Review and Treatment Guideline.

In patients with chronic idiopathic diarrhea resistant to standard treatment, opioids are often used as rescue therapy. This systematic review investigated opioid effects on gut function in chronic diarrhea. PubMed and Embase were searched regarding effects of opioid agonists on the gastrointestinal tract in humans with chronic or experimentally induced diarrhea. A total of 1472 relevant articles were identified and, after thorough evaluation, 11 clinical trials were included. Generally, studies reported a reduction in stool frequency and an increase in transit time during treatment with the opioid receptor agonists loperamide, asimadoline, casokefamide, and codeine compared with placebo. Loperamide and diphenoxylate significantly improved stool consistency compared with placebo, whereas asimadoline showed no such effects. Compared with placebo, loperamide treatment caused less abdominal pain and urgency. Asimadoline showed no significant subjective improvements, but fedotozine was superior to placebo in reducing abdominal pain and bloating in selected patients. Only two relevant studies were published within the last 20 years, and standardized endpoint measures are lacking. Most trials included few participants, and further evidence is needed from larger, prospective studies. Likewise, consensus is needed to standardize endpoints for stool frequency, transit time, and consistency to conduct future meta-analyses on opioids in management of chronic idiopathic diarrhea.

Assessment of Gastrointestinal Autonomic Dysfunction: Present and Future Perspectives.

The autonomic nervous system delicately regulates the function of several target organs, including the gastrointestinal tract. Thus, nerve lesions or other nerve pathologies may cause autonomic dysfunction (AD). Some of the most common causes of AD are diabetes mellitus and α-synucleinopathies such as Parkinson's disease. Widespread dysmotility throughout the gastrointestinal tract is a common finding in AD, but no commercially available method exists for direct verification of enteric dysfunction. Thus, assessing segmental enteric physiological function is recommended to aid diagnostics and guide treatment. Several established assessment methods exist, but disadvantages such as lack of standardization, exposure to radiation, advanced data interpretation, or high cost, limit their utility. Emerging methods, including high-resolution colonic manometry, 3D-transit, advanced imaging methods, analysis of gut biopsies, and microbiota, may all assist in the evaluation of gastroenteropathy related to AD. This review provides an overview of established and emerging assessment methods of physiological function within the gut and assessment methods of autonomic neuropathy outside the gut, especially in regards to clinical performance, strengths, and limitations for each method.

The acute effects of growth hormone in adipose tissue is associated with suppression of antilipolytic signals.

AIM: Since GH stimulates lipolysis in vivo after a 2-hr lag phase, we studied whether this involves GH signaling and gene expression in adipose tissue (AT). METHODS: Human subjects (n = 9) each underwent intravenous exposure to GH versus saline with measurement of serum FFA, and GH signaling, gene array, and protein in AT biopsies after 30-120 min. Human data were corroborated in adipose-specific GH receptor knockout (FaGHRKO) mice versus wild-type mice. Expression of candidate genes identified in the array were investigated in 3T3-L1 adipocytes. RESULTS: GH increased serum FFA and AT phosphorylation of STAT5b in human subjects. This was replicated in wild-type mice, but not in FaGHRKO mice. The array identified 53 GH-regulated genes, and Ingenuity Pathway analysis showed downregulation of PDE3b, an insulin-dependent antilipolytic signal, upregulation of PTEN that inhibits insulin-dependent antilipolysis, and downregulation of G0S2 and RASD1, both encoding antilipolytic proteins. This was confirmed in 3T3-L1 adipocytes, except for PDE3B, including reciprocal effects of GH and insulin on mRNA expression of PTEN, RASD1, and G0S2. CONCLUSION: (a) GH directly stimulates AT lipolysis in a GHR-dependent manner, (b) this involves suppression of antilipolytic signals at the level of gene expression, (c) the underlying GH signaling pathways remain to be defined.