Biology subjects

Gerardy, J.-J.

Publications and source records attributed to Gerardy, J.-J..

3 recordsLinked to original sources

bioRxiv2022

Dietary fibre deprivation and bacterial curli exposure shift gut microbiome and exacerbate Parkinson's disease-like pathologies in an alpha-synuclein-overexpressing mouse

The microbiome-gut-brain axis has been proposed as a pathogenic path in Parkinsons disease (PD). Dietary driven dysbiosis and reduced gut barrier function could facilitate the interaction of toxic external or internal factors with the enteric nervous system, where PD could start. Amyloid bacterial protein such as curli can act as seed to corrupt enteric -synuclein and lead to its aggregation. Misfolded -synuclein can propagate to and throughout the brain. Here, we aimed at understanding if fibre deprivation and amyloidogenic protein curli could, individually or together, exacerbate the phenotype in both enteric and central nervous systems of a transgenic mouse overexpressing wild-type human -synuclein. We analysed the gut microbiome, motor behaviour, gastrointestinal and brain pathologies in these mice. Our findings show that external interventions, akin to unhealthy life habits in humans, can exacerbate PD-like pathologies in mice. We believe that our results shed light on how lifestyle affects PD progression.

neuroscience↗

bioRxiv2022

Increased gut microbial mucin foraging promotes clearance of a parasitic worm

BACKGROUND & AIMSHost-secreted gastrointestinal mucus plays a key role in the expulsion of intestinal nematode parasites. A balance between mucin secretion by the host and the gut microbial mucin foraging is essential to maintain the intestinal homeostasis, yet little is known about how changes in the mucin-microbiome interactions affect worm infections. Here, we aimed to examine how mucin foraging activity by the microbiome changes the course of parasitic worm infections by modulating the host immune responses. METHODSWe utilized a gnotobiotic mouse model containing a synthetic human gut microbiota that allows for: 1) a complete removal of the mucin-degrading bacteria from the community; and 2) diet-driven manipulation of the microbiota toward mucin foraging. We infected mice with a murine nematode, Trichuris muris, which resembles human infection with Trichuris trichiura. We examined the temporal dynamics of worm infection including worm burden and the host immune responses, and coupled these readouts to the microbial changes and mucin foraging activity. RESULTSThe absence of mucin-degrading bacteria in the microbiota enhances susceptibility to parasitic infection--evidenced by higher worm number--by promoting stronger Th1 immune responses. Dietary fiber deprivation increases the microbial mucin-foraging activity, which coincides with a shift in host immune responses from susceptible (chronic, Th1 type) to resistant (acute, Th2 type), thereby promoting worm clearance. CONCLUSIONSOur results provide mechanistic insights into how the colonic mucin-degrading bacteria promote anti-parasitic immunity through modulation of the host immune responses. Our study documents a clinically-relevant, novel link in the microbiome-parasite-host immune axis that is useful prerequisite knowledge in managing parasitic infections.

immunology↗

bioRxiv2022

Concomitant AD and DLB pathologies shape subfield microglia responses in the hippocampus

Hippocampal alteration is at the centre of memory decline in the most common age-related neurodegenerative diseases: Alzheimers disease (AD) and Dementia with Lewy Bodies (DLB). However, the subregional deterioration of the hippocampus differs between both diseases with more severe atrophy in the CA1 subfield of the AD patients. How AD and DLB-typical pathologies compose the various local microenvironment of the hippocampus across AD and DLB needs to be further explored to understand this process. Additionally, microglia responses could further impact the atrophy rate. Some studies suggest that microglia react differently according to the underlying neurodegenerative disorder. How microglia are transformed across hippocampal subfields in AD and DLB, and how their changes are associated with disease-typical pathologies remains to be determined. To these purposes, we performed a volumetric analysis of phospho-Tau (P-Tau), Amyloid-{beta} (A{beta}), and phospho--Synuclein (P-Syn) loads, quantified and classified microglia according to distinct morphological phenotypes using high-resolution confocal 3D microscopy of hippocampal CA1, CA3 and DG/CA4 subfields of late-onset AD (n=10) and DLB (n=8) as well as age-matched control samples (n=11). We found that each of the Tau, A{beta} and Synuclein pathologies followed a specific subregional distribution, relatively preserved across AD and DLB. P-Tau, A{beta} and P-Syn burdens were significantly exacerbated in AD, with Tau pathology being particularly severe in the AD CA1. P-Tau and P-Syn burdens were highly correlated across subfields and conditions (R2Spear = 0.79; P < 0.001) and result from a local co-distribution of P-Tau and P-Syn inclusions in neighbouring neurons, with only a low proportion of double-positive cells. In parallel, we assessed the changes of the microglia responses by measuring 16 morphological features of more than 35,000 individual microglial cells and classifying them into seven-distinct morphological clusters. We found microglia features- and clusters-variations subfield- and condition-dependent. Two of the seven morphological clusters, with more amoeboid and less branched forms, were identified as disease-enriched and found to be further increased in AD. Interestingly, some microglial features or clusters were associated with one but more often with a combination of two pathologies in a subfield-dependent manner. In conclusion, our study shows a multimodal association of the hippocampal microglia responses with the co-occurrence, distribution and severity of AD and DLB pathologies. In DLB hippocampi, pathological imprint and microglia responses follow AD trends but with lesser severity. Our study suggests that the increased pathological burdens of P-Tau and P-Syn and associated microglia alterations are involved in a more severe deterioration of the CA1 in AD as compared to DLB.

neuroscience↗