Isabel Valenbreder

The metabolic axis linking the gut microbiome and heart is increasingly being researched in the context of cardiovascular health. The gut microbiota-derived trimethylamine/trimethylamine N-oxide (TMA/TMAO) pathway is responsible along this axis for the bioconversion of dietary precursors into TMA/TMAO and has been implicated in the progression of heart failure and dysbiosis through a positive-feedback interaction. Systems biology approaches in the context of researching this interaction offer an additional dimension for deepening the understanding of metabolism along the gut-heart axis. For instance, genome-scale metabolic models allow to study the functional role of pathways of interest in the context of an entire cellular or even whole-body metabolic network. In this mini review, we provide an overview of the latest findings on the TMA/TMAO super pathway and summarize the current state of knowledge in a curated pathway map on the community platform WikiPathways. The pathway map can serve both as a starting point for continual curation by the community as well as a resource for systems biology modeling studies. This has many applications, including addressing remaining gaps in our understanding of the gut-heart axis. We discuss how the curated pathway can inform a further curation and implementation of the pathway in existing whole-body metabolic models, which will allow researchers to computationally simulate this pathway to further understand its role in cardiovascular metabolism.

Abstract Description Genome-wide association studies (GWAS) in Alzheimer’s disease (AD) have identified over 200 diseased-associated genes that are predominantly expressed in microglia. While these studies implicate microglia in AD pathogenesis, the intrinsic role of AD risk genes in regulating microglia phenotype and function is unknown. Recent work has shown that microglia acquire a protective Disease-associated state, also known as DAM/MGnD when associated with Aβ-plaques. To identify how these GWAS-associated genes may regulate DAM/MGnD state, we developed an in vivo CRISPR screen that ex vivo introduces pools of sgRNAs into CAS9-GFP donor stem cells before intrathecal injecting these cells into P2-P4 5xFAD pups lacking microglia. After two months, these perturbed cells differentiated into functional microglia and completely repopulated the CNS, providing us with an ideal system to interrogate microglial biology in AD at scale. Our screen identified regulators of DAM/MGnD state, notably highlighting the known role of Tgfbr1, Mertk and Clec7a as potent inducers of this phenotype. Genetic deletion of Tim3, an immune checkpoint and recently identified AD-GWAS hit, showed a major effect in inducing a partial DAM/MGnD phenotype with reduction in plaque load and increase in synapse density. These studied validate our perturbation platform and provide a means by which to identify the role of other GWAS hits in microglial development and function in vivo. Topic Categories Neuroimmunology (NEUR)