Klein, S. | Search bioRxiv

bioRxiv2018

Altered Bile Acid Profile Associates with Cognitive Impairment in Alzheimer’s Disease – An Emerging Role for Gut Microbiome

IntroductionIncreasing evidence suggests a role for the gut microbiome in central nervous system disorders and specific role for the gut-brain axis in neurodegeneration. Bile acids (BA), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer disease (AD).\n\nMethodsSerum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1,464 subjects including 370 cognitively normal older adults (CN), 284 with early mild cognitive impairment (MCI), 505 with late MCI, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for cofounders and multiple testing.\n\nResultsIn AD compared to CN, we observed significantly lower serum concentrations of a primary BA (cholic acid CA) and increased levels of the bacterially produced, secondary BA, deoxycholic acid (DCA), and its glycine and taurine conjugated forms. An increased ratio of DCA:CA, which reflects 7-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response related genes implicated in AD showed associations with BA profiles.\n\nConclusionWe report for the first time an association between altered BA profile, genetic variants implicated in AD and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut liver brain axis in the pathogenesis of AD.

neuroscience↗

bioRxiv2017

Deep Sequencing Reveals Transient Segregation of T Cell Repertoires in Splenic T Cell Zones During an Immune Response

Immunological differences between hosts, such as diverse T-cell receptor (TCR) repertoires, are widely credited for reducing the risk of pathogen spread and adaptation in a population. Within-host immunological diversity might likewise be important for robust pathogen control, but to what extent naive TCR repertoires differ across different locations in the same host is unclear. T-cell zones (TCZs) in secondary lymphoid organs provide secluded micro-environmental niches. By harboring distinct TCRs, such niches could enhance within-host immunological diversity. On the other hand, rapid T cell migration is expected to dilute such diversity. Here, we combined tissue micro-dissection and deep sequencing of the TCR {beta} chain to examine the extent to which TCR repertoires differ between TCZs in murine spleens. In the absence of antigen, we found little evidence for differences between different TCZs of the same spleen. Yet, three days after immunization with sheep red blood cells, we observed a >10-fold rise in the number of clones that appeared to localize to individual zones. Remarkably, these differences largely disappeared at 4 days after immunization, when hallmarks of an ongoing immune response were still observed. These data suggest that in the absence of antigen, any repertoire differences observed between TCZs of the same host can largely be attributed to random clone distribution. Upon antigen challenge, segregated TCR compartments appear and disappear within days. Such \"transient mosaic\" dynamics could be an important barrier for pathogen adaptation and spread during an immune response.

immunology↗