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INTRODUCTION: Preclinical studies reveal that the microbiome broadly affects immune responses and the deposition and/or clearance of amyloid-beta (Aß) in mouse models of Alzheimer's disease (AD). Whether the microbiome shapes central and peripheral immune profiles in AD models remains unknown. METHODS: We examined adaptive immune responses in two mouse models containing AD-related genetic predispositions (3xTg and 5xFAD) in the presence or absence of the microbiome. RESULTS: T and B cells were altered in brain-associated and systemic immune tissues between genetic models and wildtype mice, with earlier signs if inflammation in female mice. Systemic immune responses were modulated by the microbiome and differed by sex. Further, the absence of a microbiome in germ-free mice resulted in reduced cognitive deficits, primarily in female mice. DISCUSSION: These data reveal sexual dimorphism in early signs of inflammation and the effects of the microbiome, and highlight a previously unrecognized interaction between sex and the microbiome in mouse models of AD. Research in Context: Systemic review: We reviewed the literature related to Alzheimer's disease (AD), inflammation, and the microbiome using PubMed. We cite several studies that demonstrate the influence of the microbiome on inflammation and cognitive performance in both animal models and humans. However, the mechanisms linking immunity to AD are not well understood. Interpretation: Using two well-established mouse models of AD, we found that the microbiome does not strongly influence the onset of inflammation in brain-draining lymph nodes; rather, it largely modulates systemic immune responses, local cytokine production, and cognitive performance. Notably, the inflammatory state in mice was affected by sex, and this sex effect differed between local and systemic tissues and mice with or without a microbiome. Future directions: Our work identified a sex- and microbiome-mediated effect on inflammation and cognitive performance. Future studies may focus on microbiome-dependent mechanisms that intersect with sex hormone and immune responses to determine peripheral effects on AD outcomes. Highlights: Adaptive immunity is activated at early ages and differentially by sex in mouse models of AD.Inflammation in 5xFAD mice is characterized by increased IL-17A-producing T cells.Inflammation in 3xTg mice is characterized by increased cytokine responses in males, but attenuated cytokine responses in female mice.Longitudinal immune responses differ between 3xTg mice and 5xFAD mice.Both 3xTg and 5xFAD female mice show improved learning and cognition in the absence of a microbiome.
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The gastrointestinal (GI) tract is innervated by intrinsic neurons of the enteric nervous system (ENS) and extrinsic neurons of the central nervous system and peripheral ganglia. The GI tract also harbors a diverse microbiome, but interactions between the ENS and the microbiome remain poorly understood. Here, we activate choline acetyltransferase (ChAT)-expressing or tyrosine hydroxylase (TH)-expressing gut-associated neurons in mice to determine effects on intestinal microbial communities and their metabolites as well as on host physiology. The resulting multi-omics datasets support broad roles for discrete peripheral neuronal subtypes in shaping microbiome structure, including modulating bile acid profiles and fungal colonization. Physiologically, activation of either ChAT+ or TH+ neurons increases fecal output, while only ChAT+ activation results in increased colonic contractility and diarrhea-like fluid secretion. These findings suggest that specific subsets of peripherally activated neurons differentially regulate the gut microbiome and GI physiology in mice without involvement of signals from the brain.