Basso, P. J. | Search bioRxiv

bioRxiv2024

Maternal humoral factors modulate offspring gut immune homeostasis to mitigate diabetes development

Environmental risk factors possess the potential to modulate the pathogenesis of type I diabetes (T1D). Foremost among these factors are early life influences impacting the gastrointestinal (GI) tract. During infancy, both the microbiota and immune system are influenced by maternal factors contributing to key events in the neonatal GI tract. Despite the well-known importance of maternal factors on infant immune development, whether maternal immune dysregulation and dysbiosis can perpetuate the same in offspring remains largely unknown. To explore how these maternal factors impact offspring disease development, we used IgA-deficiency induced maternal dysbiosis in Non-Obese Diabetic (NOD) dams to study T1D development in their progeny. We found that maternal dysbiosis and absence of IgA led to changes in IgA-sufficient offspring immune development resulting in heightened GI immune activity. Maternal dysbiosis also contributed to altered microbiome establishment in progeny, such that pups exhibited reduced colonic abundance of Akkermansia muciniphila and Clostridoides difficile. In adulthood, these mice exhibited a lowered incidence of T1D. This protection was replicated by fostering high incidence offspring to dysbiotic dams, prompting us to propose that altered breast milk composition in dysbiotic dams can influence immune development and microbiome establishment in offspring, contributing to T1D resistance.

immunology↗

bioRxiv2021

MS-driven metabolic alterations are recapitulated in iPSC-derived astrocytes

ObjectiveAstrocytes play a significant role in the pathology of Multiple Sclerosis (MS). Nevertheless, for ethical reasons, most of the studies in these cells were performed on the Experimental Autoimmune Encephalomyelitis model. As there are significant differences between human and mouse cells, we aimed here to better characterize astrocytes from patients with MS (PwMS), focusing mainly on mitochondrial function and cell metabolism. MethodsWe obtained and characterized induced pluripotent stem cell (iPSC)-derived astrocytes from three PwMS and three unaffected controls and performed functional assays including electron microscopy, flow cytometry, cytokine measurement, gene expression, in situ respiration, and metabolomics. ResultsWe detected several differences in MS astrocytes including: (i) enrichment of genes associated with mitophagy and neurodegeneration, (ii) increased mitochondrial fission and decreased mitochondrial to nuclear DNA ratio, indicating disruption of mitochondrial content, (iii) increased production of superoxide and MS-related proinflammatory chemokines, (iv) increased electron transport capacity and proton leak, in line with the increased oxidative stress, and (v) a distinct metabolic profile, with a deficiency in amino acid catabolism and increased sphingolipid metabolism, which have already been linked to MS. InterpretationTo our knowledge, this is the first study thoroughly describing the metabolic profile of iPSC-derived astrocytes from PwMS, and validating this model as a powerful tool to study disease mechanisms and to perform non-invasive drug targeting assays in vitro. Our findings recapitulate several disease features described in patients and provide new mechanistic insights into the metabolic rewiring of astrocytes in MS, which could be targeted in future therapeutic studies.

neuroscience↗