WNT2B Deficiency Causes Enhanced Susceptibility to Colitis Due to Increased Inflammatory Cytokine Production.

BACKGROUND & AIMS: Humans with WNT2B deficiency have severe intestinal disease, including significant inflammatory injury, highlighting a critical role for WNT2B. We sought to understand how WNT2B contributes to intestinal homeostasis. METHODS: We investigated the intestinal health of Wnt2b knock out (KO) mice. We assessed the baseline histology and health of the small intestine and colon, and the impact of inflammatory challenge using dextran sodium sulfate (DSS). We also evaluated human intestinal tissue. RESULTS: Mice with WNT2B deficiency had normal baseline histology but enhanced susceptibility to DSS colitis because of an increased early injury response. Although intestinal stem cells markers were decreased, epithelial proliferation was similar to control subjects. Wnt2b KO mice showed an enhanced inflammatory signature after DSS treatment. Wnt2b KO colon and human WNT2B-deficient organoids had increased levels of CXCR4 and IL6, and biopsy tissue from humans showed increased neutrophils. CONCLUSIONS: WNT2B is important for regulation of inflammation in the intestine. Absence of WNT2B leads to increased expression of inflammatory cytokines and increased susceptibility to gastrointestinal inflammation, particularly in the colon.

Antimicrobial peptides modulate lung injury by altering the intestinal microbiota.

BACKGROUND: Mammalian mucosal barriers secrete antimicrobial peptides (AMPs) as critical, host-derived regulators of the microbiota. However, mechanisms that support microbiota homeostasis in response to inflammatory stimuli, such as supraphysiologic oxygen, remain unclear. RESULTS: We show that supraphysiologic oxygen exposure to neonatal mice, or direct exposure of intestinal organoids to supraphysiologic oxygen, suppresses the intestinal expression of AMPs and alters intestinal microbiota composition. Oral supplementation of the prototypical AMP lysozyme to hyperoxia-exposed neonatal mice reduced hyperoxia-induced alterations in their microbiota and was associated with decreased lung injury. CONCLUSIONS: Our results identify a gut-lung axis driven by intestinal AMP expression and mediated by the intestinal microbiota that is linked to lung injury in newborns. Together, these data support that intestinal AMPs modulate lung injury and repair. Video Abstract.

WNT2B Deficiency Causes Increased Susceptibility to Colitis in Mice and Impairs Intestinal Epithelial Development in Humans.

Background and aims: WNT2B is a canonical Wnt ligand previously thought to be fully redundant with other Wnts in the intestinal epithelium. However, humans with WNT2B deficiency have severe intestinal disease, highlighting a critical role for WNT2B. We sought to understand how WNT2B contributes to intestinal homeostasis. Methods: We investigated the intestinal health of Wnt2b knock out (KO) mice. We assessed the impact of inflammatory challenge to the small intestine, using anti-CD3χ antibody, and to the colon, using dextran sodium sulfate (DSS). In addition, we generated human intestinal organoids (HIOs) from WNT2B-deficient human iPSCs for transcriptional and histological analyses. Results: Mice with WNT2B deficiency had significantly decreased Lgr5 expression in the small intestine and profoundly decreased expression in the colon, but normal baseline histology. The small intestinal response to anti-CD3χ antibody was similar in Wnt2b KO and wild type (WT) mice. In contrast, the colonic response to DSS in Wnt2b KO mice showed an accelerated rate of injury, featuring earlier immune cell infiltration and loss of differentiated epithelium compared to WT. WNT2B-deficient HIOs showed abnormal epithelial organization and an increased mesenchymal gene signature. Conclusion: WNT2B contributes to maintenance of the intestinal stem cell pool in mice and humans. WNT2B deficient mice, which do not have a developmental phenotype, show increased susceptibility to colonic injury but not small intestinal injury, potentially due to a higher reliance on WNT2B in the colon compared to the small intestine.WNT2B deficiency causes a developmental phenotype in human intestine with HIOs showing a decrease in their mesenchymal component and WNT2B-deficient patients showing epithelial disorganization. Data Transparency Statement: All RNA-Seq data will be available through online repository as indicated in Transcript profiling. Any other data will be made available upon request by emailing the study authors.

Inequities in Telemedicine Use Among Patients With Stroke and Cerebrovascular Diseases: A Tricenter Cross-sectional Study.

Background and Objectives: In response to the COVID-19 pandemic, outpatient stroke care delivery was rapidly transformed to outpatient evaluation through video (VTM) and telephone (TPH) telemedicine (TM) visits around the world. We sought to evaluate the sociodemographic differences in outpatient TM use among stroke patients. Methods: We conducted a retrospective chart review of outpatients evaluated at 3 tertiary stroke centers in the early period of the pandemic, 3/16/2020 through 7/31/2020. We compared the use of TM by patient characteristics including age, sex, race/ethnicity, insurance status, stroke type, patient type, and site. The association between TM use and patient characteristics was measured using the relative risk (RR) from a modified Poisson regression, and site-specific effects were controlled using a multilevel analysis. Results: A total of 2,024 visits were included from UTHealth (n = 878), MedStar Health (n = 269), and Columbia (n = 877). The median age was 64 [IQR 52-74] years, and 53% were female. Approximately half of the patients had private insurance, 36% had Medicare, and 15% had Medicaid. Two-thirds of the visits were established patients. TM accounted for 90% of total visits, and the use of TM over office visits was primarily associated with site, not patient characteristics. TM utilization was associated with Asian and other/unknown race. Among TM users, older age, Black race, Hispanic ethnicity, and Medicaid insurance were associated with lower VTM use. Black (aRR 0.88, 95% CI 0.86-0.91, p < 0.001) and Hispanic patients (aRR 0.92, 95% CI 0.87-0.98, p = 0.005) had approximately 10% lower VTM use, while Asian patients (aRR 0.98, 95% CI 0.89-1.07, p = 0.59) had similar VTM use compared with White patients. Patients with Medicaid were less likely to use VTM compared with those with private insurance (aRR 0.86, 95% CI 0.81-0.91, p < 0.001). Discussion: In our diverse cohort across 3 centers, we found differences in TM visit type by race and insurance early during the COVID-19 pandemic. These findings suggest disparities in VTM access across different stroke populations. As VTM remains an integral part of outpatient neurology practice, steps to ensure equitable access are essential.

Antimicrobial peptides modulate lung injury by altering the intestinal microbiota.

Mammalian mucosal barriers secrete antimicrobial peptides (AMPs) as critical host-derived regulators of the microbiota. However, mechanisms that support homeostasis of the microbiota in response to inflammatory stimuli such as supraphysiologic oxygen remain unclear. Here, we show that neonatal mice breathing supraphysiologic oxygen or direct exposure of intestinal organoids to supraphysiologic oxygen suppress the intestinal expression of AMPs and alters the composition of the intestinal microbiota. Oral supplementation of the prototypical AMP lysozyme to hyperoxia exposed neonatal mice reduced hyperoxia-induced alterations in their microbiota and was associated with decreased lung injury. Our results identify a gut-lung axis driven by intestinal AMP expression and mediated by the intestinal microbiota that is linked to lung injury. Together, these data support that intestinal AMPs modulate lung injury and repair. In Brief: Using a combination of murine models and organoids, Abdelgawad and Nicola et al. find that suppression of antimicrobial peptide release by the neonatal intestine in response to supra-physiological oxygen influences the progression of lung injury likely via modulation of the ileal microbiota. Highlights: Supraphysiologic oxygen exposure alters intestinal antimicrobial peptides (AMPs).Intestinal AMP expression has an inverse relationship with the severity of lung injury.AMP-driven alterations in the intestinal microbiota form a gut-lung axis that modulates lung injury.AMPs may mediate a gut-lung axis that modulates lung injury.

A sepsis trigger tool reduces time to antibiotic administration in the NICU.

OBJECTIVE: Prolonged time to antibiotic administration is associated with increased morbidity and mortality. Interventions to decrease the time to antibiotic administration may improve mortality and morbidity. STUDY DESIGN: We identified possible change concepts for reducing time to antibiotic usage in the NICU. For the initial intervention, we developed a sepsis screening tool based on NICU-specific parameters. The main goal of the project was to reduce time to antibiotic administration by 10%. RESULTS: The project was conducted from April 2017 until April 2019. There were no missed cases of sepsis in the project period. Time to antibiotic administration for patients who were started on antibiotics decreased during the project, with the mean shifting from 126 to 102 min, a reduction of 19%. CONCLUSIONS: We successfully reduced time to antibiotic delivery in our NICU using a trigger tool to identifying potential cases of sepsis in the NICU environment. The trigger tool requires broader validation.

Insights into the Role of Commensal-Specific T Cells in Intestinal Inflammation.

Trillions of microorganisms exist in the human intestine as commensals and contribute to homeostasis through their interactions with the immune system. In this review, we use previous evidence from published papers to elucidate the involvement of commensal-specific T cells (CSTCs) in regulating intestinal inflammatory responses. CSTCs are generated centrally in the thymus or peripherally at mucosal interfaces and present as CD4+ or CD8+ T cells. Bacteria, fungi, and even viruses act commensally with humans, warranting consideration of CSTCs in this critical relationship. Dysregulation of this immunological balance can result in both intestinal inflammation or damaging autoimmune responses elsewhere in the body. Given the relative novelty of CSTCs in the literature, we aim to introduce the importance of their role in maintaining immune homeostasis at barrier sites such as the intestine.