Biology subjects

Bäckhed, F.

Publications and source records attributed to Bäckhed, F..

3 recordsLinked to original sources

bioRxiv2025

Gut bacterial metabolite imidazole propionate potentiates Alzheimer's disease pathology

The gut microbiome modulates metabolic and neurovascular processes implicated in Alzheimers disease and related dementias (ADRD), but the underlying mechanisms remain unclear. Here, we identify the bacterial metabolite imidazole propionate (ImP) as a modifier of ADRD pathology. In a cohort of 1,196 cognitively unimpaired adults, higher plasma ImP levels were associated with lower preclinical cognitive scores and biomarkers of ADRD, both cross-sectionally and longitudinally. Fecal metagenomic analysis linked putative ImP producers to ADRD phenotypes. Genome-wide integrative analysis revealed a locus on chromosome 12 associated with both plasma ImP levels and AD risk in humans, supporting a host genetic contribution to ImP regulation and a causal role of this metabolite in AD. In mice, chronic ImP administration exacerbated AD-like pathology. Mechanistically, ImP impaired brain endothelial barrier and promoted tau hyperphosphorylation in primary neurons, an effect blocked by glycogen synthase kinase-3{beta} inhibition. Together, our study links ImP to hallmarks of neurodegeneration and suggest that targeting ImP may represent a potential strategy to modify ADRD risk.

pathology↗

bioRxiv2024

Gut microbial metabolite imidazole propionate impairs endothelial cell function and promotes the development of atherosclerosis

BackgroundThe microbially generated amino acid-derived metabolite imidazole propionate (ImP) contributes to the pathogenesis of type 2 diabetes. However, the effect of ImP on endothelial cell physiology and its role in atherosclerotic coronary artery disease (CAD) is unknown. Using both human and animal model studies, we investigated the potential contributory role of ImP in the development of atherosclerosis. MethodsPlasma levels of ImP were measured in patients undergoing elective cardiac angiography (n = 831) by means of ultra high-performance liquid chromatography coupled to tandem mass spectrometry. Odds ratios (ORs) and corresponding 95% confidence intervals for CAD were calculated based on the ImP quartiles using both univariable and multivariable logistic regression models. Atheroprone apolipoprotein E-/- (Apoe-/-) mice fed a high-fat diet were additionally treated with ImP (800 {micro}g) or vehicle and aortic atherosclerotic lesion area was evaluated after 12 weeks. In a mouse model of carotid artery injury, the effect of ImP on vascular regeneration was examined. Using human aortic endothelial cells (HAECs) the effect of ImP on functional properties of endothelial cells were assessed. Next-generation sequencing, western blot analysis, siRNA-based gene knockdown and tamoxifen-inducible Cre-loxP experiments were performed to investigate ImP-mediated molecular mechanisms. ResultsPlasma ImP levels in subjects undergoing cardiac evaluation were associated with increased risk for prevalent CAD. In atheroprone Apoe-/- mice ImP increased atherosclerotic lesion size. We found that ImP dose-dependently impaired migratory and angiogenic properties of human endothelial cells, and promoted an increased inflammatory response. Long-term exposure to ImP impaired the repair potential of the endothelium after an arterial insult. Mechanistically, ImP attenuated insulin receptor signaling by suppressing PI3K/AKT pathway leading to the sustained activation of the forkhead box protein O1 (FOXO1) transcription factor. Genetic inactivation of endothelial FOXO1 signaling in ImP-treated mice enhanced the angiogenic activity and preserved the vascular repair capacity of endothelial cells after carotid injury. ConclusionsOur findings reveal a hitherto unknown role of the microbially produced histidine-derived metabolite ImP in endothelial dysfunction and atherosclerosis, suggesting that ImP metabolism is a potential therapeutic target in atherosclerotic cardiovascular disease.

systems biology↗

bioRxiv2022

Oral delivery of GLP-1R agonist by an engineered probiotic yeast strain has anti-obesity effects in mice

Obesity is rapidly increasing within the global population and is one of the leading causes of chronic diseases, including type 2 diabetes (T2D), non-alcoholic fatty liver disease, and cardiovascular diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonists have emerged as promising therapeutic agents for treating T2D and obesity. However, the route of administration of the GLP-1R agonists is currently by injection or high oral dosages of the therapeutic combined with absorption enhancers. Oral delivery of GLP-1R agonists remains the preferred administration route due to convenience and high patient compliance. Thus, strategies to improve the oral delivery of this therapeutic are needed. In this study, we engineered the probiotic yeast Saccharomyces boulardii strain to produce Exendin-4, a GLP-1R agonist, in the gastrointestinal tract to reduce the adverse effects of diet-induced obesity in male C57BL/6 mice. The biological efficiency of the secreted Exendin-4 from S. boulardii was characterised ex vivo on isolated pancreatic islets, demonstrating induced insulin secretion. Furthermore, in vivo characterisation of the engineered strain identified a synergistic effect of cold exposure and Sb-Exe4 by successfully inhibiting appetite and promoting body weight loss under cold exposure (8{degrees}C). In addition, the combination of cold and Sb-Exe4 improved the glucose and lipid homeostasis in the mice by increasing the circulating glucagon level and reducing the inflammatory marker TNF-. Our results demonstrate that S. boulardii can be genetically modified to secrete and deliver active therapeutic GLP-1R agonists in the gastrointestinal tract improving the metabolism of the host.

synthetic biology↗