Biology subjects

Keenan, C. M.

Publications and source records attributed to Keenan, C. M..

3 recordsLinked to original sources

bioRxiv2024

The gut microbiota is a determinant of sexual dimorphism in ALS-linked TDP43 mice

The mechanisms underlying the earlier onset and male predominance of amyotrophic lateral sclerosis (ALS), the most common form of human motoneuron disease, are poorly understood. Here we show that the gut microbiota protects against TDP43 toxicity and contributes to the sexual dimorphism in mice expressing a mutant form of TDP43 (A315T) linked to ALS. TDP43 mice raised under germ-free conditions, or treated with antibiotics to deplete the gut microbiota, develop motoneuron disease earlier and show no sex differences in onset and lifespan. Behavioral and histopathological analyses confirm the exacerbation in neurodegeneration caused by the absence of gut microbiota. Castration did not alter disease course of male TDP43 mice, suggesting that male sex hormones do not interact with the gut microbiota to confer disease phenotype. Future identification of gut bacteria species and their mechanisms of action offers a unique opportunity to understand sexual dimorphism in ALS, with the ultimate goal to develop non-invasive and sex-specific treatments for ALS.

physiology↗

bioRxiv2024

T cells regulate intestinal motility and shape enteric neuronal responses to intestinal microbiota.

The gut microbiota and immune system maintain intestinal homeostasis and regulate gut physiology in concert with the enteric nervous system (ENS). However, the underlying mechanisms remain incompletely understood. Using wildtype and T-cell deficient germ-free mice colonized with segmented filamentous bacteria (SFB) or specific pathogen-free (SPF) microbiota, we studied immune regulation of the ENS and intestinal motility. Colonization markedly increased Th17 cells and Treg expressing ROR{gamma}+T cells in both the ileum and colon of wildtype mice. T cells were necessary for the normalization of intestinal motility after colonization by SPF microbiota, and for SFB to restore neuronal density in the ENS of the ileum of germ-free mice. T cells were also required for neurogenic responses in myenteric neurons of the ileum, but not the colon, and for regulating the levels of nestin expression. The cytokines IL-1{beta} and IL-17A mediate the enteric neurogenic response to an SPF microbiota but were not involved in the regulation of intestinal motility. Together, our findings provide new insights into the microbiota-neuroimmune dialogue that regulates intestinal physiology.

physiology↗

bioRxiv2019

Contribution of fungal microbiome to intestinal physiology, early-life immune development and mucosal inflammation in mice

Gut microbiomes make major contributions to the physiological and immunological development of the host, but the relative importance of their bacterial and fungal components, and how they interact, remain largely unknown. We applied carefully controlled experiments in gnotobiotic mice colonized with defined communities of bacteria, fungi, or both to differentiate the direct role of fungi on microbiome assembly, host development, and susceptibility to colitis and airway inflammation. Our results revealed that fungal colonization alone was insufficient to promote the intestinal anatomic and physiological changes seen in mice colonized by bacteria, and had limited impact on the fecal metabolome. However, fungal colonization promoted major shifts in bacterial microbiome ecology, and had an independent effect on the innate and adaptive immune development in young mice. Fungi further exacerbated some aspects of the inflammatory effects of the bacterial community during OVA-induced airway inflammation by promoting macrophage infiltration in the airway. Our results demonstrate a dominant ecological and physiological role of bacteria in gut microbiomes, but highlight fungi as an ecological factor shaping the assembly of the bacterial community and a direct capacity to impact immune system and modulate disease susceptibility. These findings demonstrate that studies focused on bacteria alone provide an incomplete portrayal on microbiome ecology and functionality, and prompt for the inclusion of fungi in human microbiome studies.

microbiology↗