Biology subjects

Macnaughtan, J.

Publications and source records attributed to Macnaughtan, J..

3 recordsLinked to original sources

bioRxiv2024

Exploring the relationship between GBA1 host genotype and gut microbiome in the GBA1L444P/WT mouse model: Implications for Parkinson disease pathogenesis

BackgroundHeterozygous variants in GBA1 are the commonest genetic risk factor for Parkinson disease (PD) but penetrance is incomplete. GBA1 dysfunction can cause gastrointestinal disturbances and microbiome changes in preclinical models. Mounting evidence suggests that the microbiota-gut-brain axis is potentially implicated in PD pathogenesis. Whether the gut microbiome composition is influenced by host GBA1 genetics in heterozygosis has never been explored. ObjectivesTo evaluate whether heterozygosity for the GBA1 pathogenic L444P variant can cause perturbations in gut microbiome composition. MethodsFaecal samples collected from GBA1L444P/WT and GBA1WT/WT mice at 3 and 6 months of age were analysed through shotgun metagenomic sequencing. ResultsNo differences in - and {beta}-diversity were detected between genotyped groups, at either time points. Overall, we found a little variation of the gut microbiome composition and functional potential between GBA1L444P/WT and GBA1WT/WT mice over time. ConclusionHost GBA1 genotype does not impact gut microbiome structure and composition in the presented GBA1L444P/WT mouse model. Studies investigating the effect of a second hit on gut physiology and microbiome composition could explain the partial penetrance of GBA1 variants in PD.

neuroscience↗

bioRxiv2023

Impact of Yaq-001, a non-absorbable, engineered carbon bead of controlled porosity in rodent models of cirrhosis and acute on chronic liver failure

ObjectiveTranslocation of gut bacterial lipopolysaccharide (LPS) is associated with complications of cirrhosis. Current strategies to target bacterial translocation are limited to antibiotics with risk of resistance. This study aims to explore therapeutic potential of a non-absorbable, engineered carbon bead, Yaq-001 in cirrhosis and acute-on-chronic liver failure (ACLF) models. DesignThe performance of Yaq-001 was evaluated in in vitro studies. Two-rodent models of cirrhosis (4-week, bile duct ligation (BDL): Sham (n=36); Sham-Yaq-001 (n=30); BDL (n=37); BDL-Yaq-001 (n=44)) and ACLF (BDL-LPS: Sham-LPS (n=9); Sham-LPS-Yaq-001 (n=10); BDL-LPS (n=16); BDL-LPS-Yaq-001(n=12)). The treated-groups received Yaq-001 for 2-weeks. Samples were collected for assessment of organ and immune function, transcriptomics, microbiome composition and metabolomics. ResultsIn vitro, Yaq-001 exhibited rapid adsorption kinetics for endotoxin and bile acids without exerting an antibiotic effect. In vivo, Yaq-001 produced significant improvement in ALT, ammonia, liver cell death, portal pressure, markers of systemic inflammation and renal function in BDL animals. Yaq-001-treated ACLF animals had significantly better survival, ALT, portal pressure, brain water and creatinine. Ex-vivo LPS-induced reactive oxygen species production in portal venous monocytes and Kupffer cell populations was diminished with Yaq-001 treatment. Transcriptome analysis demonstrated a significant modulation of inflammation, cell death and senescence pathways in the liver, kidneys, brain and colon of Yaq-001-treated BDL rats. Yaq-001 impacted positively on the microbiome composition with significant modulation of Family Porphyromonadaceae and Genus Barnesiella. Urinary 1HNMR analysis suggested a shift in metabolomic signature in Yaq-001-treated BDL rats. ConclusionsThis study provides strong pre-clinical rationale for developing Yaq-001 for treatment of patients with cirrhosis. Significance of this studyO_ST_ABSWhat is already known on this topic?C_ST_ABSCurrent strategies to target bacterial translocation in cirrhosis are limited to antibiotics with risk of resistance. Yaq-001 is an insoluble, non-absorbable, non-antibiotic, engineered carbon bead of tailored porosities, which works as an adsorbent in the gut and is completely excreted after oral administration. What this study adds?O_LIYaq-001 rapidly adsorbs endotoxin, ammonia and bile acids without influencing bacterial growth kinetics in vitro. C_LIO_LIYaq-001 reduces mortality of ACLF animals and impacts positively on markers of gut permeability, liver injury, portal pressure, brain and kidneys in rodent models of cirrhosis and ACLF. C_LIO_LIYaq-001 administration was associated with positive impact on the composition of the gut microbiota, reduction in severity of endotoxemia and ammonia, which significantly reduced the severity of inflammation, cell death, signaling pathways and LPS sensitivity. C_LI How this study might affect research, practice or policy?The data provide the pre-clinical rationale to proceed to clinical trials in patients with cirrhosis aiming to prevent the occurrence of complications.

animal behavior and cognition↗

bioRxiv2023

α-synuclein expression in response to bacterial ligands and metabolites in gut enteroendocrine cells

BackgroundCaudo-rostral migration of pathological forms of -synuclein from the gut to the brain is proposed as an early feature in Parkinson disease (PD) pathogenesis, but the underlying mechanisms remain unknown. Intestinal enteroendocrine cells sense and respond to numerous luminal signals, including bacterial factors, and transmit this information to the brain via the enteric nervous system and vagus nerve. There is evidence that gut bacteria composition and their metabolites change in PD patients and these alterations can trigger -synuclein pathology in animal models. ObjectiveHere we investigated the effect of toll-like receptor (TLR) and free fatty acid receptor (FFA2/3) agonists on -synuclein levels in mouse STC-1 enteroendocrine cells. MethodsSTC-1 cells were treated with TLR and FFA2/3 agonists alone and in combination with selective antagonists. The level of -synuclein protein was measured in cell lysates and cell culture media by western blot and ELISA. And the level of -synuclein and tumour necrosis factor (TNF) mRNA was measured by quantitative RT-PCR. ResultsTLR and FFA receptor agonists significantly increased intracellular and extracellular -synuclein levels and antagonists significantly reduced these effects. TLR and FFA receptor agonists also significantly increased TNF transcription and this was inhibited by corresponding antagonists. ConclusionsElevated intracellular -synuclein increases the likelihood of aggregation and conversion to toxic forms. Factors derived from bacteria induce -synuclein accumulation in STC-1 cells. Here we provide support for a mechanism by which exposure of enteroendocrine cells to specific bacterial factors found in PD gut dysbiosis might facilitate accumulation and transmission of -synuclein pathology from the gut to the brain.

neuroscience↗