Leaky Gut Syndrome: Myths and Management.

Leaky gut syndrome is a condition widely popularized in the lay literature, although it is not currently accepted as a formal medical diagnosis. Multiple gastrointestinal symptoms are ascribed to leaky gut syndrome, including diarrhea, bloating, distension, abdominal pain, and dyspeptic symptoms of early satiety, nausea, and postprandial fullness. The etiology and pathophysiology of leaky gut syndrome are multifactorial; a preceding gastrointestinal infection, inflammatory bowel disease, and certain medications may be relevant factors in some patients. The diagnosis of leaky gut syndrome is problematic. Although patients are frequently informed that the diagnosis can be readily made using results from blood work or stool studies, no validated test currently exists to make this diagnosis. Patients report a variety of myths about the etiology, diagnosis, and treatment of leaky gut syndrome, which can cause alarm and can frequently lead to expensive, unnecessary tests and unproven, sometimes dangerous treatments. This article reviews some of the most common myths about leaky gut syndrome and provides data from the scientific literature to correct these statements. Management strategies, based on data, are provided when available.

Gastroparesis: time for a paradigm change.

PURPOSE OF REVIEW: Gastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm. RECENT FINDINGS: An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted. SUMMARY: Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.

Response and Adverse Event Rates With Placebo in Gastroparesis: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Multiple drugs have been used to treat gastroparesis symptoms, yet their therapeutic benefits are poorly understood partly due to lack of insight into response and adverse event rates with placebo in randomized controlled trials (RCTs). We evaluated these issues systematically in drug trials for gastroparesis. METHODS: We searched the medical literature through August 2, 2022 to identify RCTs comparing active drug with placebo in patients with gastroparesis. We assessed placebo response rates according to at least one of the following endpoints: improvement according to a composite outcome, nausea, vomiting, abdominal pain, bloating, or fullness, as well as total adverse events, and adverse events leading to withdrawal. We extracted data as intention-to-treat analyses with dropouts assumed to be treatment failures. We pooled placebo response and adverse event rates using a random effects model and expressed as proportions with 95% confidence intervals (CIs). RESULTS: Thirty-five studies were eligible. Among 23 trials reporting a composite endpoint of improvement, the pooled placebo response rate was 29.3% (95% CI, 23.7%-35.2%). Pooled placebo response rates were higher in idiopathic compared with diabetic gastroparesis (34.2% vs 28.1%), among trials that did not use validated symptom questionnaires (31.2% vs 27.4%), and in RCTs of shorter duration (<4 weeks, 32.6% vs ≥9 weeks, 23.2%). Adverse events occurred in 33.8% (95% CI, 26.4%-41.8%) of patients with placebo, in 27 trials, and were less common in idiopathic compared with diabetic gastroparesis (17.9% vs 43.4%), trials of shorter duration (<4 weeks, 33.7% vs ≥9 weeks, 40.7%), and trials with lower randomization ratios of active drug to placebo (1:1, 26.7% vs 3:1, 50.5%). CONCLUSIONS: This meta-analysis assessed placebo response and adverse event rates in gastroparesis. To accurately assess therapeutic gain, future trials should be a minimum of 8 weeks duration, use validated questionnaires, and distinguish gastroparesis subtypes.

Development and validation of a novel scoring system for bloating and distension: The Mayo Bloating Questionnaire.

BACKGROUND: Abdominal bloating and distension are prevalent gastrointestinal symptoms. Our aim was to design and validate a questionnaire to reliably measure the multiple symptom components of bloating and distension in the outpatient setting. METHODS: A 45-item questionnaire was developed after an extensive literature review. Face and content validity were established through expert review and a focus group. Validation was achieved by administering an identical questionnaire 1 week apart. Data were assessed using standard methods. KEY RESULTS: Forty one patients returned both questionnaires (85% women; mean age = 44 years). Respondents reported a variety of diagnoses, including irritable bowel syndrome (63%), gastroesophageal reflux disease (54%), functional dyspepsia (27%), small intestinal bacterial overgrowth (22%), and gastroparesis (17%). Test-retest reliability revealed excellent agreement (k ≥ 0.81) and substantial agreement (0.61 ≤ k < 0.81) for 29% and 43% of categorical questions, respectively. Alternate-parallel form reliability was supported by association between responses for questions that evaluated missing school/work and questions that evaluated symptom impact on daily activities (p < 0.05). Patients who missed school/work due to bloating symptoms were more likely to report a severe impact on their ability to enjoy life (p < 0.05) and their overall well-being (p < 0.01). Contingency analyses revealed an association between overall 7-day symptom severity and impact on daily activities (p < 0.001), enjoying life (p < 0.001), and overall well-being (p < 0.001). CONCLUSIONS AND INFERENCES: This novel questionnaire demonstrated good validity and reliability in patients with symptoms of bloating and distension. The questionnaire was easy to use and score, making it a potentially useful tool for both research studies and clinical purposes.

The 7-α-dehydroxylation pathway: An integral component of gut bacterial bile acid metabolism and potential therapeutic target.

The gut microbiome plays a significant role in maintaining host metabolic health through the production of metabolites. Comprising one of the most abundant and diverse forms of gut metabolites, bile acids play a key role in blood glucose regulation, insulin sensitivity, obesity, and energy expenditure. A central pathway in gut bacterial bile acid metabolism is the production of secondary bile acids via 7-ɑ-dehydroxylation. Despite the important role of 7-ɑ-dehydroxylation in gut bacterial bile acid metabolism and the pathophysiology of metabolic disease, the regulation of this pathway is not completely understood. This review aims to outline our current understanding of 7-ɑ-dehydroxylation and to identify key knowledge gaps that will be integral in further characterizing gut bacterial bile acid metabolism as a potential therapeutic target for treating metabolic dysregulation.

GLP-1 receptor signaling increases PCSK1 and ß cell features in human α cells.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that potentiates glucose-stimulated insulin secretion. GLP-1 is classically produced by gut L cells; however, under certain circumstances α cells can express the prohormone convertase required for proglucagon processing to GLP-1, prohormone convertase 1/3 (PC1/3), and can produce GLP-1. However, the mechanisms through which this occurs are poorly defined. Understanding the mechanisms by which α cell PC1/3 expression can be activated may reveal new targets for diabetes treatment. Here, we demonstrate that the GLP-1 receptor (GLP-1R) agonist, liraglutide, increased α cell GLP-1 expression in a ß cell GLP-1R-dependent manner. We demonstrate that this effect of liraglutide was translationally relevant in human islets through application of a new scRNA-seq technology, DART-Seq. We found that the effect of liraglutide to increase α cell PC1/3 mRNA expression occurred in a subcluster of α cells and was associated with increased expression of other ß cell-like genes, which we confirmed by IHC. Finally, we found that the effect of liraglutide to increase bihormonal insulin+ glucagon+ cells was mediated by the ß cell GLP-1R in mice. Together, our data validate a high-sensitivity method for scRNA-seq in human islets and identify a potentially novel GLP-1-mediated pathway regulating human α cell function.

Gastric Emptying Scans: Poor Adherence to National Guidelines.

BACKGROUND: Accurately diagnosing gastroparesis relies upon gastric emptying scintigraphy (GES) being performed correctly. Jointly published protocol guidelines have long been available; however, the extent to which practitioners adhere to these guidelines is unknown. AIMS: This study aimed to assess national compliance with established GES protocol guidelines. METHODS: We developed a questionnaire addressing the key protocol measures outlined in the Consensus Recommendations for Gastric Emptying Scintigraphy. Survey questions addressed patient information collection (15), patient preparation and procedure protocol (16), meal content and preparation (7), imaging (3), interpretation (4), reporting (7), and institutional demographic data (7). The anonymous questionnaire was distributed electronically to members of the Society of Nuclear Medicine and Medical Imaging (SNMMI) and non-member recipients of the SNMMI daily email newsletter. One response per medical institution was permitted. RESULTS: A total of 121 out of 872 potential medical institutions (MI) responded (13.9%); 49 (40.4%) were academic/teaching medical centers. The annual number (mean) of GES procedures was 199.9 (range 5-2000 GES/year). On average, MI performed 33.5/52 (64%) of protocol measures according to guidelines while academic medical centers performed 31.5/52 (61%) of protocol measures according to guidelines. Only 4 out of 88 MI (4.5%) performed GES while adhering to three critical measures: validated study duration; controlled blood glucose levels; and proper restriction of medications. CONCLUSIONS: Low compliance with GES protocol guidelines, even among academic medical centers, raises the likely possibility of misdiagnosis and improper management of upper gastrointestinal symptoms. These results highlight a need for increased awareness of protocol guidelines for gastric scintigraphy.