Biology subjects

Sampson, T. R.

Publications and source records attributed to Sampson, T. R..

4 recordsLinked to original sources

bioRxiv2024

Diet-microbiome interactions promote enteric nervous system resilience following spinal cord injury

Spinal cord injury (SCI) results in a plethora of physiological dysfunctions across all body systems, including intestinal dysmotility and atrophy of the enteric nervous system (ENS). Typically, the ENS has capacity to recover from perturbation, so it is unclear why intestinal pathophysiologies persist after traumatic spinal injury. With emerging evidence demonstrating SCI-induced alterations to the gut microbiome composition, we hypothesized that modulation of the gut microbiome could contribute to enteric nervous system recovery after injury. Here, we show that intervention with the dietary fiber, inulin prevents ENS atrophy and limits SCI-induced intestinal dysmotility in mice. However, SCI-associated microbiomes and exposure to specific SCI-sensitive gut microbes are not sufficient to modulate injury-induced intestinal dysmotility. Intervention with microbially-derived short-chain fatty acid (SCFA) metabolites prevents ENS dysfunctions and phenocopies inulin treatment in injured mice, implicating these microbiome metabolites in protection of the ENS. Notably, inulin-mediated resilience is dependent on signaling by the cytokine IL-10, highlighting a critical diet-microbiome-immune axis that promotes ENS resilience following SCI. Overall, we demonstrate that diet and microbially-derived signals distinctly impact recovery of the ENS after traumatic spinal injury. This protective diet-microbiome-immune axis may represent a foundation to uncover etiological mechanisms and future therapeutics for SCI-induced neurogenic bowel.

neuroscience↗

bioRxiv2024

APP-KI mice do not display the hallmark age-dependent cognitive decline of amyloid diseases

APP knock-in (KI) mice serve as an exciting new model system to understand amyloid beta (A{beta}) pathology, overcoming many of the limitations of previous overexpression-based model systems. The APPSAA mouse model (containing the humanized APP with three familial Alzheimers disease mutations) and the APPWT control are the first commercially available APP KI mice within the United States. While APPSAA mice have been shown to develop progressive A{beta} pathology and neuroinflammation, behavioral changes, particularly in cognitive functions, have yet to be described. Therefore, we performed an in-depth longitudinal study over 12 months, assessing cognition in these two strains, as well as assessments of motor and GI function. We surprisingly note no overt, progressive cognitive impairment or motor deficits. However, we do observe a significant increase in fecal output in APPSAA mice compared to APPWT at 12 months old. These data provide a baseline for these models behavioral attributes. HighlightsO_LIAPPSAA and APPWT knock-in mice do not display age related cognitive decline C_LIO_LIFecal output appears altered by APP genotype, but no other measure of GI function is impacted. C_LIO_LIBoth genotypes behave equally in motor function tests C_LI

neuroscience↗

bioRxiv2024

Diet-induced metabolic and immune impairments are sex-specifically modulated by soluble TNF signaling in the 5xFAD mouse model of Alzheimers disease

Emerging evidence indicates that high-fat, high carbohydrate diet (HFHC) impacts central pathological features of Alzheimers disease (AD) across both human incidences and animal models. However, the mechanisms underlying this association are poorly understood. Here, we identify compartment-specific metabolic and inflammatory dysregulations that are induced by HFHC diet in the 5xFAD mouse model of AD pathology. We observe that both male and female 5xFAD mice display exacerbated adiposity, cholesterolemia, and dysregulated insulin signaling. Independent of biological sex, HFHC diet also resulted in altered inflammatory cytokine profiles across the gastrointestinal, circulating, and central nervous systems (CNS) compartments demonstrating region-specific impacts of metabolic inflammation. In male mice, we note that HFHC triggered increases in amyloid beta, an observation not seen in female mice. Interestingly, inhibiting the inflammatory cytokine, soluble tumor necrosis factor (TNF) with the brain-permeant soluble TNF inhibitor XPro1595 was able to restore aspects of HFHC-induced metabolic inflammation, but only in male mice. Targeted transcriptomics of CNS regions revealed that inhibition of soluble TNF was sufficient to alter expression of hippocampal and cortical genes associated with beneficial immune and metabolic responses. Collectively, these results suggest that HFHC diet impairs metabolic and inflammatory pathways in an AD-relevant genotype and that soluble TNF has sex-dependent roles in modulating these pathways across anatomical compartments. Modulation of energy homeostasis and inflammation may provide new therapeutic avenues for AD. HighlightsO_LIHFHC diet triggers metabolic and inflammatory dysregulation in 5xFAD mice C_LIO_LIA{beta}42 and A{beta}40 increase in the CNS of male 5xFAD mice fed a HFHC diet. C_LIO_LISolTNF inhibition partially reverts HFHC diet-induced metabolic and inflammatory dysregulation in male, but not female, 5xFAD mice. C_LI

neuroscience↗

bioRxiv2024

Alpha-synuclein overexpression can drive microbiome dysbiosis in mice

Growing evidence indicates that persons living with Parkinson disease (PD), have a unique composition of indigenous gut microbes. Given the long prodromal or pre-diagnosed period, longitudinal studies of the human and rodent gut microbiome prior to symptomatic onset and for the duration of the disease period are currently lacking. PD is characterized in part by accumulation of the protein -synuclein (-syn) into insoluble aggregates, in both the central and enteric nervous systems. As such, a number of experimental rodent and non-human primate models of -syn overexpression recapitulate some of hallmark pathophysiologies of PD. These animal models provide an opportunity to assess how the gut microbiome changes with age under disease relevant conditions. Here, we used a transgenic mouse strain, the Thy1-hSYN "line 61" mice which over express wild-type human -syn to test how the gut microbiome composition responds in this model of PD pathology during aging. Using shotgun metagenomics, we find significant, age and genotype dependent bacterial taxa that become altered over age. We reveal that -syn overexpression can drive alterations to the gut microbiome composition and suggest that it limits the expansion of diversity through age. Given emerging data on potential contributions of the gut microbiome to PD pathologies, our data provide an experimental foundation to understand how the PD-associated microbiome may arise as a trigger or co-pathology to disease.

microbiology↗