Sarkis K. Mazmanian

Complex microbial communities are found throughout terrestrial, aquatic, and animal-associated ecosystems. Genetic modification of discrete microbial taxa within native communities represents a powerful tool to study and augment microbiome functions. Herein, we develop Synthetic Phage Assisted Reprogrammable and Targetable Addition (SPARTA) as a one-step strategy for packaging, delivering, and integrating large synthetic DNA into a broad range of native microbiomes. SPARTA leverages a broad-spectrum synthetic phage particle for in situ genome engineering within complex soil, freshwater, and mammalian fecal microbiomes, reprogramming 59 native species across 16 families. By modulating SPARTA components, we further demonstrated tunability of SPARTA towards targeted microbiome population. Additionally, we built a novel companion tool to quantitatively identify engineered taxa, named “16S crRNA-guided inference of bacterial engineering sequencing” or ScRibe-seq. The SPARTA-ScRibe-seq pipeline delivered and validated functional synthetic gene clusters in diverse native microbiomes while preserving the original microbial community structure. Together, this novel genome engineering framework constitutes an end-to-end programmable platform for rational and customizable reprogramming of native microbiomes.

Gut microbiome composition is altered in Parkinson’s disease (PD), the fastest-growing neurological condition, that is characterized by neurodegeneration, motor dysfunction, and is frequently accompanied by gastrointestinal (GI) symptoms. Notably, microbial taxa with anti-inflammatory properties are consistently depleted in PD patients compared to controls. To explore whether specific gut bacteria may be disease-protective, we assembled a microbial consortium of 8 human-associated taxa that are reduced in individuals with PD. Treatment of α-synuclein overexpressing (Thy1-ASO) mice, an animal model of PD, with this consortium improved motor and GI deficits. A single bacterial species from this consortium, Faecalibacterium prausnitzii , was sufficient to correct gut microbiome deviations in Thy1-ASO mice, induce anti-inflammatory immune responses, and promote protective colonic gene expression profiles. Accordingly, oral treatment with F. prausnitzii robustly ameliorated motor and GI deficits and reduced α-synuclein aggregates in the brain. These findings support the emerging hypothesis of functional contributions by the microbiome to PD outcomes, and embolden the development of potential probiotic therapies to treat motor and non-motor symptoms.

The gut microbiome has profound influences on brain activity and complex behaviours. Research across diverse animal species, in both natural environments and laboratory settings, has identified biological mechanisms that underlie gut–brain interactions. An emerging central theme is that the gut microbiome is shaped by, and actively contributes to, sociability throughout the lifespan. In this Review, we highlight recent literature revealing the effects of the microbiome on early neurodevelopment, immune modulation, stress responses and microorganism-mediated metabolism that affect social behaviour. Studies investigating the cellular and molecular pathways that underlie microbial influences on social behaviour have implicated brain regions and circuits that mediate critical aspects of animal behaviours, including bonding, mating, defence, aggression and social learning. Gut microbiome–brain research using animal models of social deficits and ecological studies in the wild, as well as investigations of human conditions comorbid with impaired social behaviour, could offer new and natural avenues for improved quality of life in individuals and social groups.

The pathophysiology of Parkinson’s disease (PD) involves gene-environment interactions that impair various cellular processes including mitochondrial dysfunction. Mitochondria-associated mutations increase PD risk, respiration is altered in the PD brain, and mitochondria-damaging toxicants cause PD-like motor and gastrointestinal symptoms in animal models. The gut microbiome is altered in PD, representing an environmental risk, however a relationship between mitochondrial function and the microbiome in PD has not been previously established. Herein, we discover that dysregulation of mitochondria-associated genes and hyperactive striatal mitochondria are induced by the microbiome in α-synuclein-overexpressing (Thy1-ASO) mice. Thy1-ASO mice elaborate increased reactive oxygen species in the striatum whereas germ-free counterparts express increased oxygen scavenging proteins. Indeed, treatment with an antioxidant drug improves motor performance in Thy1-ASO mice and blocking oxidant scavenging in germ-free mice enhances motor deficits in an α-synuclein dependent manner. Thus, the gut microbiome promotes motor symptoms in a mouse model of PD via increased mitochondrial respiration and oxidative stress in the brain.

Gut microbiome composition is altered in Parkinson’s disease (PD), a neurodegenerative disorder characterized by motor dysfunction and frequently accompanied by gastrointestinal (GI) symptoms. Notably, microbial taxa with anti-inflammatory properties are consistently depleted in PD patients compared to controls. To explore whether specific gut bacteria may be disease-protective, we assembled a microbial consortium of 8 human-associated taxa that are reduced in individuals with PD across multiple cohorts and geographies. Treatment of α-synuclein overexpressing (Thy1-ASO) mice, an animal model of PD, with this consortium improved motor and GI deficits. A single bacterial species from this consortium, Faecalibacterium prausnitzii , was sufficient to correct gut microbiome deviations in Thy1-ASO mice, induce anti-inflammatory immune responses, and promote protective colonic gene expression profiles. Accordingly, oral treatment with F. prausnitzii robustly ameliorated motor and GI symptoms and reduced α-synuclein aggregates in the brain. These findings support the emerging hypothesis of functional contributions by the microbiome to PD and embolden development of potential probiotic therapies.