Damianos, John

ABSTRACTIntroductionUpper and lower gastrointestinal (GI) dysfunctions frequently coexist, potentially mediated by gastrocolonic or cologastric neural reflexes. This study aims to assess the prevalence of impaired gastric accommodation (GA) and delayed gastric emptying (GE) among patients with slow colonic transit (CT), dyssynergic defecation (DD), and to evaluate relationships between CT or DD with impaired GA and delayed GE.MethodsWe reviewed records of 178 adult patients at Mayo Clinic (2005–2025) with documented slow CT or DD (respectively based on scintigraphy and high‐resolution anorectal manometry [ARM] and balloon expulsion [BE]) who underwent 99mTc‐SPECT measurement of GA and scintigraphic GE of 320‐kcal, 30% fat egg meal. Slow CT was defined by geometric center (GC) at 48 h < 2.1 for males and < 1.9 for females. Abnormal GA ratio was assessed as reduced < 2.62 or increased > 3.85, and delayed GE % < 75% at 4 h. Correlations were assessed using Spearman rank test.ResultsReduced GA was found in 23.7% with DD and 26.7% with slow CT, while increased GA was observed in 30.1% and 24.4%, respectively. Delayed GE was present in 20.5% DD patients and 35.6% slow CT patients. GC 48 h and 24 h were positively correlated with GE% 4 h (Rs = 0.279, and Rs = 0.294 respectively, both p < 0.001) suggesting slow CT retards GE. GC 48 h was moderately correlated with resting anal pressure (Rs = 0.259, p < 0.001) and negatively with the rectoanal pressure gradient (Rs = −0.166, p = 0.027). No significant correlations were observed between CT and GA.ConclusionSlow CT is associated with slower GE, suggesting cologastric reflex inhibition, but not with GA. There is a high prevalence of impaired GA and delayed GE in slow CT and DD.

A 32-year-old woman with Alport syndrome and prior history of diffuse leiomyomatosis of the oesophagus and bronchial tree presented with severe constipation. MRI revealed extensive leiomyomatosis of the anorectum with obstructed defecation. Colonic manometry showed megacolon, and the patient underwent total colectomy. Surgical pathology confirmed leiomyomatosis and neuronal loss in the anorectum and reduced enteric ganglion cells in the colon. Prior literature suggests obstruction-induced enteric neuropathy as a potential mechanism for megacolon. This report shows that Alport syndrome with diffuse leiomyomatosis may have other gastrointestinal involvement including megacolon in affected patients presenting with constipation.

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP1RAs) are increasingly used to treat obesity and other metabolic conditions; however, they are known to inhibit gastrointestinal motility. Since gastrointestinal microbial overgrowth (MO) can arise in states of intestinal stasis, we sought to investigate the potential association between GLP1RA use and MO. Methods: We analyzed data from 99 patients prescribed GLP1RAs who subsequently underwent testing for MO via intestinal aspirate culture or glucose or lactulose breath tests. Results: Most patients had diabetes. Among patients who underwent culture, 76.2% tested positive for small intestinal bacterial overgrowth (SIBO) at a threshold of ≥10³ CFU/mL, with a significant association found between proton pump inhibitor (PPI) use and SIBO. At ≥10 5 CFU/mL, 33.3% tested positive for SIBO, and neither PPI use nor surgical history was associated. Breath testing revealed a 30.6% positivity rate for MO, predominantly characterized by intestinal methanogen overgrowth (IMO). There was no association between control of diabetes and positive MO tests. Conclusion: GLP1RA use is associated with SIBO, although diabetes may be a confounder.

Coeliac disease is characterised by immune-mediated damage to the small intestine in response to dietary gluten in genetically predisposed individuals. Increased intestinal permeability is a central component to its pathophysiology. This review explores the evidence for increased permeability in coeliac disease and the underlying mechanisms, including the roles of zonulin, inflammatory cytokines, microbial alterations and immune responses to gliadin peptides. We also review comprehensively the therapies targeting barrier integrity and normalising intestinal permeability, including particular diets and supplements, and experimental and improved medications including larazotide acetate and IMU-856. Finally, we highlight the need for reliable biomarkers for evaluating increased permeability in coeliac disease and advocate for further research on therapies which normalise barrier function, particularly as a strategy to maintain remission.

ABSTRACT Background Several genetic syndromes that affect nerve development and functioning may involve the enteric nervous system and present clinically as dysmotility syndromes, typically in childhood. Aim To review the enteric neuromuscular manifestations, predominantly observed in adults, of neurofibromatosis type I at a tertiary referral center. Methods We conducted a medical records review at the Mayo Clinic and documented clinical manifestations and findings on radiology, pathology, and specialized motility tests of the esophagus, stomach, colon, and rectal evacuatory functions. The tests included scintigraphic gastrointestinal and colonic transit measurements, intraluminal esophageal, gastrointestinal, colonic, and anorectal manometry, and balloon expulsion test. Results Among 2406 with documented NF1, the gastrointestinal manifestations were obstruction or dysmotility, seen in 2% of the cohort. Thirteen patients had small bowel or colonic obstructions: 4 gastrointestinal stromal tumors, 3 malignant peripheral nerve sheath tumors, 3 neurofibromas, 1 diffuse ganglioneuromatosis, 1 schwannoma, and 1 inflammatory fibroid polyp. In addition, 38 patients had abnormal gut motility, including esophageal achalasia or spasm, delayed gastric emptying, slow colonic transit, and dyssynergic defecation. Gastric, small bowel, and colonic manometry were characterized by normal amplitude incoordinated contractions suggestive of neuropathy. In the few resected specimens, myenteric plexus proliferation or diffuse ganglioneuromatosis was identified histologically. Conclusions In addition to mechanical obstruction, typically due to benign tumors affecting smooth muscle or components of nerve (sheath or nerve fiber), patients with NF1 may present with dysmotility syndromes such as gastroparesis, slow colonic transit, or global dysmotility. Neuropathic dysmotility in NF1 can be identified by manometry and by histological evidence of myenteric plexus proliferation or diffuse ganglioneuromatosis.

Background/Objectives: Our objective was to review published studies of the intestinal barrier and permeability, the deleterious effects of dietary components (particularly fat), the impact of altered intestinal permeability in disease models and human diseases, the role of the microbiome and epigenomics in control of barrier function, and the opportunities to restore normal barrier function with dietary interventions and products of the microbiota. Methods: We conducted a literature review including the following keywords alone or in combination: intestinal barrier, permeability, microbiome, epigenomics, diet, irritable bowel syndrome, inflammatory bowel disease, probiotics. Results: Intestinal permeability is modified by a diet including fat, which increases permeability, and nutrients such as fiber, glutamine, zinc, vitamin D, polyphenols, emulsifiers, and anthocyanins, which decrease permeability. There is significant interaction of the microbiome and barrier function, including the inflammatory of luminal/bacterial antigens, and anti-inflammatory effects of commensals or probiotics and their products, including short-chain fatty acids. Epigenomic modification of barrier functions are best illustrated by effects on junction proteins or inflammation. Detailed documentation of the protective effects of diet, probiotics, prebiotics, and microbiota is provided. Conclusion: intestinal permeability is a critical factor in protection against gastrointestinal diseases and is impacted by nutrients that preserve or heal and repair the barrier and nurture anti-inflammatory effects.

Abstract Acute severe ulcerative colitis (ASUC) remains a clinical challenge associated with considerable morbidity, including colectomy. Upadacitinib (UPA), a selective Janus kinase (JAK)-1 inhibitor, is approved for moderate-to-severe ulcerative colitis in patients intolerant or not responding to tumor necrosis factor-alpha inhibitors. It has also increasingly been used off-label for ASUC. We performed a systematic review of all available literature on UPA in ASUC. We identified 11 studies, with a pooled total of 55 patients. Most patients experienced rapid and sustained improvement. Colectomy rate at 90 days was 16.3%. Among those who did not get colectomy, 80% were in steroid-free remission at follow-up. The reported adverse events were low, including 2 venous thromboembolic events. Overall, UPA appears to represent a safe and effective therapy for ASUC.