Biology subjects

Sohrabji, F.

Publications and source records attributed to Sohrabji, F..

3 recordsLinked to original sources

bioRxiv2026

Gut Stem Cell Secretome Therapy Promotes Durable Neuroprotection and Functional Recovery After Stroke

Background: Stroke causes rapid neuronal death and gut barrier disruption in the acute phase, with persistent cognitive-affective impairment in the chronic phase. We previously showed that transplants of intestinal epithelial stem cells ameliorated the acute and chronic impairment of stroke. The current study tested the efficacy of a cell free strategy, specifically, the secretome of intestinal epithelial stem cells. Methods: Middle aged male and female rats underwent middle cerebral artery occlusion or sham surgery and received intestinal epithelial stem cell secretome from healthy sex-matched adult or control media. Behavioral assays (social interaction, novel object recognition and Barnes maze), gut histology, markers of gut permeability, serum cytokines were performed at acute and chronic time points. Group differences were assessed by two-way ANOVA. Results: In the acute phase, vehicle-treated stroke animals displayed histopathological changes in the gut including villus blunting, loss of goblet cells, increased markers of gut permeability and elevated systemic inflammation. In the chronic phase, stroke resulted in cognitive/affective changes including social withdrawal, recognition memory and spatial memory deficits. In middle-aged males, three doses of IESC secretome treatment 4h/24h/48h after stroke restored mucosal architecture, goblet cells and dampened inflammatory cytokines in the acute phase. Cognitive and social outcomes, tested 4+ weeks after stroke, were significantly improved compared to vehicle-treated stroke animals. However, in middle-aged females treated with the same regimen of intestinal epithelial stem cell secretome, gut architecture was not restored and inflammatory cytokines remained elevated. Long term cognitive impairment was only partially improved in this group. Proteomic analysis of the secretome revealed a largely shared core of proteins between males and females with sex differences in pathway level regulation. Subsequently, another cohort of middle-aged females was administered four doses of secretome 4h/12h/24h/36h after stroke. This regimen restored gut architecture and dampened inflammatory cytokines in the acute phase, and improved long term cognitive outcomes. Conclusions: Collectively, these studies underscore the therapeutic potential of IESC secretome and the importance of tailoring post stroke therapy by demographics such as biological sex. These data further support the hypothesis that gut repair is tightly associated with long-term improvement in stroke outcomes.

neuroscience↗

bioRxiv2026

Sex Differences in the Effects of Controlled Circadian Dysregulation on Gut Microbiome and Intestinal Barrier Architecture

Disturbances of 24-hour or circadian rhythms imposed by everyday irregular work and/or social schedules have been linked to vascular disease, including ischemic stroke. Using an established shift work-like paradigm and preclinical model for ischemic stroke, we have shown that environment-induced circadian dysregulation exacerbates stroke outcomes differentially to a greater extent in male than female rats. Because more severe stroke outcomes and circadian rhythm disturbances have been linked to gut pathophysiology, present study examined the effects of chronic LD cycle shifting on gut cytoarchitecture, microbiota composition, metabolites, and gut-derived inflammatory mediators. Adult (5-7mo) rats were divided into 2 groups and exposed for 50d to a fixed or shifted (lights-on advanced by 12hr/5d) LD 12:12 cycle. Circadian entrainment of activity rhythms was stable in all rats on the fixed LD 12:12 cycle but was severely disrupted during exposure to shifted LD cycles. Significant changes in the composition of the gut microbiome including reduced alpha diversity, shifts in beta diversity and correlations between the abundance of beneficial gut bacteria and stroke survival were observed in male but not female rats exposed to shifted LD cycles relative to fixed LD controls. This effect of circadian dysregulation on gut microbiota was accompanied by evidence of pathologic gut morphology (i.e., shorter and blunted villi, crypt hyperplasia disruption of tight junction proteins and gut barrier integrity), elevated serum endotoxin concentrations, decreased levels of the short-chain fatty acid (SCFA) butyrate, and increased circulating levels of the inflammatory cytokine IL-17A in shifted LD male rats. These results suggest that alterations in gut morphology, microbiota and metabolites may contribute to sex differences in the effects of shift work-related circadian dysregulation on ischemic stroke outcomes.

physiology↗

bioRxiv2025

Loss of white matter tracts and persistent microglial activation in the chronic phase of ischemic stroke in female rats and the effect of miR-20a-3p treatment

Our previous studies showed that intravenous injections of the small non-coding RNA mir-20a-3p is neuroprotective for stroke in the acute phase and attenuates long-term cognitive impairment in middle-aged female rats. In this study, we evaluated postmortem brain pathology at 100+d after stroke in a set of behaviorally characterized animals. This included Sham (no stroke) controls or stroke animals that received either mir20a-3p at 4h, 24h and 70d iv post stroke (MCAo+mir20a-3p) or a scrambled oligo (MCAo+Scr). Brain volumetric features were analyzed with T2 weighted and Diffusion Tensor magnetic resonance imaging (MRI) followed by histological analysis. Principal component analysis of Fractional Anisotropy (FA)-diffusion tensor MRI measures showed that MCAo+Scr and MCAo+mir20a-3p groups differed significantly in the volume of white matter but not gray matter. Weil myelin-stained sections confirmed decreased volume of the corpus callosum, internal capsule and the anterior commissure in the ischemic hemisphere of MCAo+Scr animals compared to the non-ischemic hemisphere, while sham and MCAo+Mir-20a-3p showed no hemispheric asymmetries. The MCAo+Scr group also exhibited asymmetry in hemisphere and lateral ventricle volumes, with ventricular enlargement in the ischemic hemisphere as compared to the non-ischemic hemisphere. The numbers of microglia were significantly elevated in white matter tracts in the MCAo+Scr group, with a trend towards increased myelin phagocytic microglia in these tracts. Regression analysis indicated that performance on an episodic memory test (novel object recognition test; NORT) was associated with decreased white matter volume and increased microglial numbers. These data support the hypothesis that stroke-induced cognitive impairment is accompanied by white matter attrition and persistent microglial activation and is consistent with reports that cognitive deterioration resulting from vascular diseases, such as stroke, is associated with secondary neurodegeneration in regions distal from the initial infarction.

neuroscience↗