Stephanie Schnorr

Microbial Networks of DHA Synthesis: lipid metabolism for the brain

Our understanding of secondary metabolite provisioning from host-associated microbial ecosystems is in its infancy. Recently, evidence of microbiome-host mutualism arising from genome complementarity has been unearthed, ranging from invertebrate to human hosts, but by no means are these examples comprehensive. Still, these few observations are powerful demonstrations of the concept of integrated ecological systems. Prokaryote microbiota are known to possess incalculable biosynthesis potential in their genomes, a natural consequence of their primacy in organismal life. Surprisingly late in the attribution of microbial production competency are the anaerobic polyketide fatty acid synthesis genes (pfa) that enable bacteria and archaea to manufacture long-chain polyunsaturated fatty acids (LC-PUFAs). These lipids are physiologically essential for all organisms, but membrane incorporation of the highly unsaturated and long-chain varieties (LC-HUFAs) is especially conserved in sperm, neural, and retinal tissue [1] and yet are extremely rare in terrestrial ecosystems [2]. Studies have shown that insufficient LC-HUFA availability in diverse organisms such as invertebrates, birds, and humans results in slowed growth and negatively impacts multiple markers of fitness [3]. In human evolutionary scenarios specifically, regular access to preformed eicosapentaenoic acid (EPA; 20:5ω3), arachidonic acid (ARA, 20:4ω6), and docosahexaenoic acid (DHA; 22:6ω3) is thought to have induced encephalization in the human lineage beginning around two million years ago [4]. Incorporation of DHA into the brain of the developing fetus and in later neonates enables expansion of cortical tissue that generates complex cognitive abilities [1]. Yet, the source and ubiquity of these lipids remains widely debated. How the terrestrial food-chain can enable higher trophic levels to concentrate essential LC-HUFAs remains incompletely understood, but accumulating evidence points to soil-living bacteria, fungi, and microfauna as possible primary producers [5]. In other words, the unity of tiny organisms in an ecosystem may make an impact through their network of interactions leading to the production of rare secondary metabolites. Bacterial synthesis of LC-P/HUFA is contingent upon presence of a highly conserved pfa gene complex that propagates horizontally and which has been identified in up to 45 microbial genera across 10 different phyla [6]. However, to date only individual genomes of well-characterized bacteria have been interrogated, and a wider ecological survey of the presence of this bacterial gene cluster is needed in order to advance our understanding of terrestrial sources of preformed LC-HUFAs that can support complex life. This leaves open the tantalizing question of whether LC-HUFA producing bacteria have arrived to the microbial ecosystem of mammalian guts, and whether a nutritional mutualist functional role exists between mammalian hosts and these bacteria, as is seen among marine animal hosts. Furthermore, it should be explored whether microbial ecosystems such as those in soil or in animal guts have the power to produce LC-HUFA under certain conditions, and whether this potential can be harnessed for the purposes of sustainably producing or aggregating LC-HUFA that are essential for human health.

The purpose of this project is to understand the context of lipid metabolism within diverse terrestrial microbial ecosystems, particularly of soil and animal hosts, in order to infer scenarios whereby terrestrial microbiomes may produce essential lipids for higher trophic levels. In doing so, I aim to look for not only particular pathways that suggest the potential for synthesis of ω-3 LC-HUFA, but also for the selective ecological forces in which these pathways can exist. The end goal of this research is to learn whether ω-3 LC-HUFA synthesis pathways are found within the soil or gut microbiome of terrestrial ecosystems, including animal hosts, and therefore use these results as a basis for sustainable production of LC-HUFA by leveraging microbial ecosystem activities to aggregate essential lipids that are the building blocks for complex nervous systems, such as the human brain. This research will identify and experimentally test ecological factors that induce microbial LC-HUFA biosynthesis using in-vitro microbiomes, which incorporate orders of magnitude greater genomic diversity than can culture isolates. Not only will these results help inform the circumstances surrounding terrestrial support of higher-order mammals, but they also have great potential to influence current biotechnological approaches to sustainably produce LC-HUFAs for the human food industry. Omega-3 LC-HUFA supplementation is effective at reducing systemic inflammation implicated in non-communicable disease proliferation due to aging, poor nutrition, and sedentary lifestyles [1]. Therefore, improving our knowledge about the context and source of LC-HUFA production in microbial ecosystems has major implications for combating the most pernicious disease burdens on modern healthcare.