Accumulating evidence implicates the gut microbiome (GMB) in the pathogenesis and progression of Alzheimer's disease (AD). We recently showed that the GMB regulates reactive astrocytosis and Aβ plaque accumulation in a male APPPS1-21 AD mouse model. Yet, the mechanism(s) by which GMB perturbation alters reactive astrocytosis in a manner that reduces Aβ deposition remain unknown. Here, we performed metabolomics on plasma from mice treated with antibiotics (ABX) and identified a significant increase in plasma propionate, a gut-derived short-chain fatty acid, only in male mice. Administration of sodium propionate reduced reactive astrocytosis and Aβ plaques in APPPS1-21 mice, phenocopying the ABX-induced phenotype. Astrocyte-specific RNA-Seq on ABX- and propionate-treated mice showed reduced expression of proinflammatory and increased expression of neurotrophic genes. Next, we performed flow cytometry experiments, in which we found that ABX and propionate decreased peripheral RAR-related orphan receptor-γ+ (Rorγt+) CD4+ (Th17) cells and IL-17 secretion, which positively correlated with reactive astrocytosis. Last, using an IL-17 mAb to deplete IL-17, we found that propionate reduced reactive astrocytosis and Aβ plaques in an IL-17-dependent manner. Together, these results suggest that gut-derived propionate regulates reactive astrocytosis and Aβ amyloidosis by decreasing peripheral Th17 cells and IL-17 release. Thus, propionate treatment or strategies boosting propionate production may represent novel therapeutic strategies for the treatment of AD.

Uveitis, an autoimmune disease, often leads to blindness. CD4+ T cells, including regulatory T cells (Tregs) and effector T cells (Th1 and Th17), play a critical role in its pathogenesis. Caloric restriction (CR) has been shown to alleviate autoimmune diseases. However, careful characterization of the impact of CR on experimental autoimmune uveitis (EAU) is poorly understood. This study used single-cell RNA sequencing to analyze cervical draining lymph nodes in mice under ad libitum (AL) and CR diets, with or without EAU. CR increased Tregs, altered immune cell metabolism, reduced EAU symptoms, and downregulated inflammatory and glycolysis genes. Flow cytometry confirmed CR's inhibitory effect on Th1 and Th17 proliferation and its promotion of Treg proliferation. CR also balanced CD4+ T cells by inhibiting the PI3K/AKT/c-Myc pathway and reducing GM-CSF in Th17 cells. These findings suggest CR as a potential therapeutic strategy for autoimmune diseases.
© 2024 The Authors.

Cryptococcosis is a neglected fungal disease that causes many deaths annually, is primarily caused by Cryptococcus neoformans and Cryptococcus gattii species. They are environmental fungus that engages lung pneumonia and a severe systemic infection. The rising incidence of affected immunocompetent hosts, particularly by the aggressive Cryptococcus deuterogattii (R265), underscores the urgency to understand factors influencing its dissemination. The immunopathogenesis of R265 infection is incompletely understood. Therefore, we investigate the role of IL-22 and IL-23 cytokines during R265 cryptocococcosis. Our findings highlight the crucial role of IL-22 and IL-23 cytokines in lung barrier homeostasis, preventing excessive lung damage. IL-22 not only prevents neutrophil infiltration and IL-17A production but also facilitates eosinophil lung infiltration. Ultimately, this study contributes vital insights into the selective role of IL-22 and IL-23 cytokines in immune activation and tissue regulation during the aggressive R265 lung and systemic infection.
© 2024 The Author(s).

ABSTRACT Vaccine adjuvants are typically composed of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) that activate innate immune cells. Advances in basic immunology have demonstrated the need for various ‘types’ of protective immunity, which are difficult to achieve with a single adjuvant. The FDA approval of multiple PAMP-DAMP combinations for clinical use has led to an increased momentum in the area in recent years. Here we report the use of DAMP-inducing peptide nanofibers (PNFs) and CL429 (PAMP) combinations as subunit boosters for Bacille Calmette-Guérin (BCG). We demonstrate that pulmonary boosting with PNFs and CL429 enhances the lung-resident memory phenotype, effector cytokine profiles, and transcription factor bias of antigen-specific CD4 + T cell populations compared to PNFs alone. Importantly, the combination significantly improved the frequency of tissue-resident memory T (T RM ) cells which, have been shown to provide superior protection compared to circulating memory T cells. Interestingly, the T helper (Th) subset profile was driven in part driven by the route of vaccination resulting in a Th17 bias via a mucosal route or a Th1 bias when delivered intravenously. We show that following pulmonary administration, lung-resident antigen presenting cells (APCs) efficiently internalize PNFs and upregulate important co-stimulatory markers that drive T cell priming and activation. Our findings suggest that heterologous booster vaccines composed of DAMP-inducing PNFs and PAMP combinations can engage innate and adaptive immunity for generating T RM cells that protect against TB and potentially other respiratory diseases.

Autism spectrum disorder (ASD) is a cluster of neurodevelopmental disorders characterized by deficits in communication and behavior. Increasing evidence suggests that the microbiota-gut-brain axis and the likely related immune imbalance may play a role in the development of this disorder. Gastrointestinal deficits and gut microbiota dysfunction have been linked to the development or severity of autistic behavior. Therefore, treatments that focus on specific diets may improve gastrointestinal function and aberrant behavior in individuals with ASD. In this study, we investigated whether a diet containing specific prebiotic fibers, namely, 3% galacto-oligosaccharide/fructo-oligosaccharide (GOS/FOS; 9:1), can mitigate the adverse effects of in utero exposure to valproic acid (VPA) in mice. Pregnant BALB/cByJ dams were injected with VPA (600 mg/kg, sc.) or phosphate-buffered saline (PBS) on gestational day 11 (G11). Male offspring were divided into four groups: (1) in utero PBS-exposed with a control diet, (2) in utero PBS-exposed with GOS/FOS diet, (3) in utero VPA-exposed with a control diet, and (4) in utero VPA-exposed with GOS/FOS diet. Dietary intervention started from birth and continued throughout the duration of the experiment. We showed that the prebiotic diet normalized VPA-induced alterations in male offspring, including restoration of key microbial taxa, intestinal permeability, peripheral immune homeostasis, reduction of neuroinflammation in the cerebellum, and impairments in social behavior and cognition in mice. Overall, our research provides valuable insights into the gut-brain axis involvement in ASD development. In addition, dietary interventions might correct the disbalance in gut microbiota and immune responses and, ultimately, might improve detrimental behavioral outcomes in ASD.
© 2024. The Author(s).