Human noroviruses (HuNoVs) are a leading cause of acute gastroenteritis worldwide. The primary symptoms of HuNoV-associated disease are vomiting and diarrhea; yet the mechanisms underlying these symptoms are poorly understood. Neuroactive hormones such as serotonin (5-hydroxytryptamine; 5-HT) secreted by intestinal enteroendocrine cells (EECs) can activate vomiting centers in the brain and play a critical role in regulating emetic signaling. Serotonin release from infected EECs has been implicated in vomiting during other enteric infections. Recent studies have reported the detection of HuNoV RNA and antigen in EECs in jejunal biopsies from immunocompromised patients with chronic HuNoV infection and rhesus macaques. We therefore investigated whether HuNoV infection of human intestinal organoids (HIOs) induces serotonin secretion. We examined infection and serotonin secretion with multiple genogroup II HuNoV strains using adult and infant jejunal HIO models, including a doxycycline-inducible neurogenin-3 HIO line with increased numbers of EECs. HuNoV infection did not induce serotonin secretion in either adult or infant HIOs as measured by ELISA. Consistent with enterocytes being the primary target cell type for HuNoVs, GII.4 HuNoV replication was robust in parental HIOs but reduced in EEC-enriched cultures. Furthermore, supernatants from parental HIOs failed to stimulate serotonin release from EEC-enriched HIOs. Together, these findings demonstrate that HuNoV infection of intestinal epithelial cells is insufficient to trigger serotonin release in HIOs. These results suggest that HuNoV-associated vomiting is unlikely to result from direct epithelial serotonin secretion and may require additional cellular components such as immune or neuronal signaling pathways or may involve other neuroactive hormones.IMPORTANCEVomiting is a hallmark symptom of human norovirus disease. Yet, the biological mechanisms responsible for this response are unknown. Infection of enteroendocrine cells and secretion of serotonin play key roles in the emetic response to other gastrointestinal viruses such as rotavirus. Since recent studies have detected human norovirus antigens and RNA in enteroendocrine cells, we hypothesized that human norovirus infection could stimulate serotonin secretion. We used jejunal human intestinal organoids from adults and infants, including organoids enriched for enteroendocrine cells, and found that infection with several clinically important strains did not induce serotonin secretion, even under conditions supporting robust viral replication. These data indicate that serotonin release from intestinal epithelial cells alone is unlikely to explain norovirus-induced vomiting and highlights the need to investigate alternative mechanisms, including other neuroactive hormones, and neuronal signaling pathways to better understand the pathogenesis of norovirus-associated vomiting.

[This corrects the article DOI: 10.3389/fvets.2025.1720932.].

Eosinophilic gastrointestinal diseases (EGIDs) are chronic, TH2-mediated conditions. Eosinophilic esophagitis (EoE) is the most common type, while non-EoE EGIDs affect other gut segments. This retrospective study of 111 patients (50 EoE and 61 non-EoE) from 2011 to 2022 compared the clinical aspects of these 2 types. Dysphagia and food impaction dominated in EoE, while abdominal pain, nausea, and diarrhea were more common in non-EoE EGIDs. Atopic comorbidities were frequent. Diagnostic delays>1 year were more common in EoE (72% vs 47.5%). The overall clinical response rate was 88.29%, with most patients using food avoidance (90.99%) and proton pump inhibitors (94.59%). Clinical relapses occurred in 38.88% over the mean follow-up of 4.62 years and were unaffected by therapy type. Failure to thrive was seen in 26.7%, with no significant intergroup difference. This study highlights a prolonged diagnostic delay in EoE vs non-EoE EGIDs. Both groups showed similar, favorable response rates, underscoring a need for greater awareness. Prospective studies with standardized measures are required to optimize management.

S100 calcium-binding protein B (S100B) is conventionally viewed as a marker of astrocytic injury, blood-brain barrier (BBB) disruption, and neurological disorders. Emerging evidence places S100B within the broader brain-gut-liver axis of inflammatory signaling. This review proposes that S100B is a glial-derived integrating effector that couples enteric glial activation, barrier dysfunction, hepatic fibrosis, and hepatic encephalopathy (HE) into a multi-organ inflammatory network. Its spatial expression map, release kinetics, alarmin (damage-associated molecular pattern, DAMP) activity, and immune-cell infiltration differ among the gut, liver, and brain, shaping axis signaling. S100B is predominantly expressed in astrocytes of the central nervous system, Schwann cells, and enteric glial cells and is also detected in liver tumor immune cells, biliary epithelial cells, and activated hepatic stellate cell (HSC)-associated lesions. It exerts context-dependent functions: at low, nanomolar concentrations it supports neurotrophic activity and barrier integrity, whereas sustained elevation acts as a DAMP that amplifies inflammatory responses through receptor for advanced glycation end products (RAGE), Toll-like receptor 2 (TLR2)/Toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) and a disintegrin and metalloproteinase 10 (ADAM10)/β-catenin pathways. Clinically, S100B kinetics, a rapid release with a short half-life after acute injury versus chronic multi-organ spillover in cirrhosis, determines whether elevation reflects a local glial event or systemic disease burden. S100B has been implicated in enteric infectious enteritis, inflammatory bowel disease (IBD), diarrhea-predominant irritable bowel syndrome (IBS-D), cholestatic fibrosis, metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), viral hepatitis, hepatocellular carcinoma (HCC), and HE with comorbid neuroinflammation. Available evidence suggests that S100B is a candidate link between glial responses, barrier dysfunction, hepatic inflammation, and neuroinflammation within the brain-gut-liver axis, although its causal role, tissue origin, and clinical utility require further validation.

Idiopathic pulmonary fibrosis is a chronic, progressive fibrosing interstitial lung disease with a poor prognosis, carrying a median survival of two to three years without antifibrotic therapy. Nintedanib, an oral intracellular tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptors (VEGFRs 1-3), platelet-derived growth factor receptor (PDGFR)-α/β, and fibroblast growth factor receptors (FGFRs) 1-3, has emerged as a cornerstone of therapy, reducing the rate of forced vital capacity (FVC) decline by approximately 50% in the INPULSIS trials. While diarrhea is the most common adverse event, generalized body swelling has not been previously described with nintedanib, although it is a well-recognized class effect of several oncologic TKIs, including imatinib and mesenchymal-epithelial transition factor (MET) inhibitors. We report a 66-year-old male ex-smoker with a 45-pack-year smoking history and comorbidities including ischemic heart disease, bronchial asthma, and gastroesophageal reflux disease who presented with five months of progressive dyspnea, classified as modified Medical Research Council grade III. High-resolution computed tomography revealed bilateral peripheral reticulation with mild honeycombing, traction bronchiectasis, and basal predominance without ground-glass opacities, fulfilling the criteria for a definite usual interstitial pneumonia pattern. Spirometry demonstrated a moderate restrictive pattern (FVC, 65%), and autoimmune screening was comprehensively negative. Following multidisciplinary review, nintedanib was initiated at 100 mg twice daily and subsequently escalated to the standard 150 mg twice-daily dose. The patient developed mild generalized body swelling at initiation, which worsened markedly after dose escalation. Extensive cardiology, nephrology, endocrine, hepatic, and metabolic evaluations identified no alternative cause. Discontinuation of nintedanib resulted in near-complete resolution of swelling within two months. Rechallenge at a tertiary interstitial lung disease center precipitated recurrence of identical generalized swelling within one month, necessitating a second discontinuation. The temporal relationship, dose dependence, and reproducible recurrence on rechallenge strongly suggest a causal association between nintedanib and generalized body swelling in this patient. This previously unreported adverse event warrants clinician vigilance and formal pharmacovigilance reporting.

Whipple's disease (WD) is a rare, chronic systemic disorder caused by Tropheryma whipplei (T. whipplei), a bacterium belonging to the Actinobacteria phylum. Clinical manifestations of WD include weight loss, diarrhea, and arthralgia. To date, no cases of rectal stenosis caused by T. whipplei infection have been reported in the literature. This paper presents a case of rectal stenosis associated with T. whipplei infection, evaluates the effectiveness of comprehensive, multidisciplinary management, and provides guidelines for optimizing disease management. A 40-year-old male patient presented with a one-year history of constipation and weight loss. He reported the passage of narrow-calibre stools, approximately the width of a little finger, and a 10-kilogram weight loss over the past year. A diagnosis of WD was indicated by bronchoalveolar lavage (BAL) fluid analysis, but no microbiological evidence of rectal T. whipplei infection was found at that time. The patient received 14 days of intravenous antibiotic therapy, followed by a one-year course of oral cotrimoxazole, combined with a comprehensive management plan that included structured medication adherence education, targeted intestinal nursing care, nutritional support, psychological intervention, and multidisciplinary follow-up. After five months of treatment, the patient showed significant improvement, including four-kilogram weight gain, a return to normal bowel movements, and resolution of pulmonary inflammation. This case highlights the importance of early recognition of atypical WD manifestations and demonstrates that a multidisciplinary model integrating standardized antimicrobial therapy with structured nursing management may significantly improve patient outcomes in rare systemic infections.

Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) haploinsufficiency with autoimmune infiltration (CHAI) is an autosomal dominant condition featuring both immunodeficiency and autoimmunity. We describe the first published mainland Chinese patient harboring the heterozygous CTLA4 c.529dupT frameshift variant. While multiple CHAI cases have been documented in mainland China, this specific variant has not been reported in this population to date. The patient developed recurrent thrombocytopenia, recurrent respiratory infections and hypogammaglobulinemia at age 2. She was diagnosed with immune thrombocytopenia (ITP) at age 15. The disease subsequently progressed to Evans syndrome, alongside complications including chronic diarrhea, cerebral vasculitis, biliary tract infection and interstitial pneumonia. She received standard anti-infective therapy, combined glucocorticoids and immunosuppressants, as well as intravenous immunoglobulin (IVIG) replacement; however, these interventions yielded only limited and temporary benefits. After 38 years of disease progression, a primary immunodeficiency was suspected. Whole-exome sequencing (WES) verified the diagnosis of CHAI. Treatment with sirolimus led to amelioration of infection and diarrheal symptoms. This case exhibited phenotypic differences from prior patients carrying the identical variant. Our observations expand the known phenotypic spectrum of this variant and offer clinical references for the management and genetic testing of patients presenting with early-onset multisystem autoimmunity and immunodeficiency.

A woman in her early 50s presented with a 4-month history of erythema and scaling of the limbs, weight loss, anasarca and chronic foul-smelling diarrhoea, suggestive of nutritional dermatosis with steatorrhoea due to malabsorption. She was non-obese and had no prior history of diabetes or exocrine deficiency. During admission, she experienced abdominal pain and hyperglycaemia consistent with diabetic ketoacidosis. CT of the abdomen revealed a diffusely enlarged, entirely fatty pancreas with preserved shape and a dilated main pancreatic duct containing intraductal calculi, indicating lipomatous pseudohypertrophy (LPH) with chronic calcific pancreatitis (CCP). Clinical and imaging findings confirmed exocrine insufficiency, while coexisting diabetes mellitus, which can be attributed to CCP, suggested a type 3 c diabetes mellitus. She developed sepsis and despite intensive medical management, she died of refractory septic shock. Enlarged pancreatic volume distinguishes LPH from the usual degenerative fatty replacement commonly seen in older patients or patients with obesity or diabetes.