Non-canonical NF-κB signaling limits the tolerogenic ß-catenin-Raldh2 axis in gut dendritic cells to exacerbate intestinal pathologies.

Dendritic cell (DC) dysfunction is known to exacerbate intestinal pathologies, but the mechanisms compromising DC-mediated immune regulation in this context remain unclear. Here, we show that intestinal dendritic cells from a mouse model of experimental colitis exhibit significant levels of noncanonical NF-κB signaling, which activates the RelB:p52 heterodimer. Genetic inactivation of this pathway in DCs alleviates intestinal pathologies in mice suffering from colitis. Deficiency of RelB:p52 diminishes transcription of Axin1, a critical component of the ß-catenin destruction complex, reinforcing ß-catenin-dependent expression of Raldh2, which imparts tolerogenic DC attributes by promoting retinoic acid synthesis. DC-specific impairment of noncanonical NF-κB signaling leads to increased colonic numbers of Tregs and IgA+ B cells, which promote luminal IgA production and foster eubiosis. Experimentally introduced ß-catenin haploinsufficiency in DCs with deficient noncanonical NF-κB signaling moderates Raldh2 activity, reinstating colitogenic sensitivity in mice. Finally, inflammatory bowel-disease patients also display a deleterious noncanonical NF-κB signaling signature in intestinal DCs. In sum, we establish how noncanonical NF-κB signaling in dendritic cells can subvert retinoic acid synthesis to fuel intestinal inflammation.

Correlation of severity & clinical outcomes of COVID-19 with virus variants: A prospective, multicentre hospital network study.

BACKGROUND OBJECTIVES: The clinical course of COVID-19 and its prognosis are influenced by both viral and host factors. The objectives of this study were to develop a nationwide platform to investigate the molecular epidemiology of SARS-CoV-2 (Severe acute respiratory syndrome Corona virus 2) and correlate the severity and clinical outcomes of COVID-19 with virus variants. METHODS: A nationwide, longitudinal, prospective cohort study was conducted from September 2021 to December 2022 at 14 hospitals across the country that were linked to a viral sequencing laboratory under the Indian SARS-CoV-2 Genomics Consortium. All participants (18 yr and above) who attended the hospital with a suspicion of SARS-CoV-2 infection and tested positive by the reverse transcription-PCR method were included. The participant population consisted of both hospitalized as well as outpatients. Their clinical course and outcomes were studied prospectively. Nasopharyngeal samples collected were subjected to whole genome sequencing to detect SARS-CoV-2 variants. RESULTS: Of the 4972 participants enrolled, 3397 provided samples for viral sequencing and 2723 samples were successfully sequenced. From this, the evolution of virus variants of concern including Omicron subvariants which emerged over time was observed and the same reported here. The mean age of the study participants was 41 yr and overall 49.3 per cent were female. The common symptoms were fever and cough and 32.5 per cent had comorbidities. Infection with the Delta variant evidently increased the risk of severe COVID-19 (adjusted odds ratio: 2.53, 95% confidence interval: 1.52, 4.2), while Omicron was milder independent of vaccination status. The independent risk factors for mortality were age >65 yr, presence of comorbidities and no vaccination. INTERPRETATION CONCLUSIONS: The authors believe that this is a first-of-its-kind study in the country that provides real-time data of virus evolution from a pan-India network of hospitals closely linked to the genome sequencing laboratories. The severity of COVID-19 could be correlated with virus variants with Omicron being the milder variant.

Collinsella aerofaciens linked with increased ethanol production and liver inflammation contribute to the pathophysiology of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is an emerging global health problem and a potential risk factor for metabolic diseases. The bidirectional interactions between liver and gut made dysbiotic gut microbiome one of the key risk factors for NAFLD. In this study, we reported an increased abundance of Collinsella aerofaciens in the gut of obese and NASH patients living in India. We isolated C. aerofaciens from the fecal samples of biopsy-proven NASH patients and observed that their genome is enriched with carbohydrate metabolism, fatty acid biosynthesis, and pro-inflammatory functions and have the potency to increase ethanol level in blood. An animal study indicated that mice supplemented with C. aerofaciens had increased levels of circulatory ethanol, high levels of hepatic hydroxyproline, triglyceride, and inflammation in the liver. The present findings indicate that perturbation in the gut microbiome composition is a key risk factor for NAFLD.

Dose-Effect Relationship of Motor Nerve Inexcitability on Outcome in Guillain-Barré Syndrome: A Prospective Cohort Study.

Objective: One or more inexcitable motor (IM) nerves are common during electrodiagnostic (EDx) study in Guillain-Barré syndrome (GBS). This study assessed the dose-effect relationship of IM nerves on outcome in patients with acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor and/or sensory axonal neuropathy (AMAN and AMSAN). Materials and Methods: Eighty-eight GBS patients admitted during May 2018-June 2023 underwent detailed clinical evaluation and EDx study. Admission and follow-up disability were assessed on a 0-10 Clinical Grading Scale (CGS). Outcome was recovery at 6 months, defined as good (CGS <3) and poor (CGS ≥3). Binary multivariate logistic regression with backward elimination was used to calculate independent predictors of outcome. Results: Proportion of patients with complete recovery decreased significantly with increasing numbers of IM nerves (P < 0.01). Seventy-six patients were followed for 6 months. Among patients with IM nerves (n = 28), complete recovery was similar between AIDP and axonal GBS (70% vs. 50%, respectively; P = 0.40). However, in patients with recordable compound muscle action potentials (CMAPs) in all the motor nerves (n = 26), axonal GBS had significantly poor recovery compared to AIDP (75% vs. 9.1%; P = 0.01). Among patients receiving intravenous immunoglobulin (IVIg; n = 42), poor recovery was seen in 53.6% with IM nerves compared to 35.7% without (P = 0.28), while it was 37.5% versus 5.6% (P = 0.04), respectively, in those who did not receive IVIg (n = 34). However, only admission disability (odds ratio [OR] 0.88, 95% confidence interval [CI] 0.81-0.97; P = 0.007) was found to be an independent predictor of outcome. Conclusion: Although increasing numbers of IM nerves were associated with poor outcome on univariate analysis, they did not predict 6 months' outcome independently. Outcome did not differ between axonal GBS and AIDP among those with IM nerves. IVIg improved outcome in patients with IM nerves.