Specialized Metabolites from the Microbiome in Health and Disease

The microbiota, and the genes that comprise its microbiome, play key roles in human health. Host-microbe interactions affect immunity, metabolism, development, and behavior, and dysbiosis of gut bacteria contributes to disease. Despite advances in correlating changes in the microbiota with various conditions, specific mechanisms of host-microbiota signaling remain largely elusive. We discuss the synthesis of microbial metabolites, their absorption, and potential physiological effects on the host. We propose that the effects of specialized metabolites may explain present knowledge gaps in linking the gut microbiota to biological host mechanisms during initial colonization, and in health and disease

A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice

Amyloids are a class of protein with unique self-aggregation properties, and their aberrant accumulation can lead to cellular dysfunctions associated with neurodegenerative diseases. While genetic and environmental factors can influence amyloid formation, molecular triggers and/or facilitators are not well defined. Growing evidence suggests that non-identical amyloid proteins may accelerate reciprocal amyloid aggregation in a prion-like fashion. While humans encode ~30 amyloidogenic proteins, the gut microbiome also produces functional amyloids. For example, curli are cell surface amyloid proteins abundantly expressed by certain gut bacteria. In mice overexpressing the human amyloid α-synuclein (αSyn), we reveal that colonization with curli-producing Escherichia coli promotes αSyn pathology in the gut and the brain. Curli expression is required for E. coli to exacerbate αSyn-induced behavioral deficits, including intestinal and motor impairments. Purified curli subunits accelerate αSyn aggregation in biochemical assays, while oral treatment of mice with a gut-restricted amyloid inhibitor prevents curli-mediated acceleration of pathology and behavioral abnormalities. We propose that exposure to microbial amyloids in the gastrointestinal tract can accelerate αSyn aggregation and disease in the gut and the brain

American Gut: An Open Platform For Citizen Science Microbiome Research

Copyright © 2018 McDonald et al. Although much work has linked the human microbiome to specific phenotypes and lifestyle variables, data from different projects have been challenging to integrate and the extent of microbial and molecular diversity in human stool remains unknown. Using standardized protocols from the Earth Microbiome Project and sample contributions from over 10,000 citizen-scientists, together with an open research network, we compare human microbiome specimens primarily from the United States, United Kingdom, and Australia to one another and to environmental samples. Our results show an unexpected range of beta-diversity in human stool microbiomes compared to environmental samples; demonstrate the utility of procedures for removing the effects of overgrowth during room-temperature shipping for revealing phenotype correlations; uncover new molecules and kinds of molecular communities in the human stool metabolome; and examine emergent associations among the microbiome, metabolome, and the diversity of plants that are consumed (rather than relying on reductive categorical variables such as veganism, which have little or no explanatory power). We also demonstrate the utility of the living data resource and cross-cohort comparison to confirm existing associations between the microbiome and psychiatric illness and to reveal the extent of microbiome change within one individual during surgery, providing a paradigm for open microbiome research and education. IMPORTANCE We show that a citizen science, self-selected cohort shipping samples through the mail at room temperature recaptures many known microbiome results from clinically collected cohorts and reveals new ones. Of particular interest is integrating n = 1 study data with the population data, showing that the extent of microbiome change after events such as surgery can exceed differences between distinct environmental biomes, and the effect of diverse plants in the diet, which we confirm with untargeted metabolomics on hundreds of samples

American Gut: an Open Platform for Citizen Science Microbiome Research

McDonald D, Hyde E, Debelius JW, et al. American Gut: an Open Platform for Citizen Science Microbiome Research. mSystems. 2018;3(3):e00031-18

Enhancement of Fc-receptor mediated phagocytosis by macrophage colony stimulating factor

Phagocytosis by macrophages is critical for defense against extracellular pathogens. While the phagocytic machinery for Fe-mediated phagocytosis is well characterized, our understanding of particle capture via binding to the Fey receptor is poor. The Fey receptors are a family of single-pass transmembrane receptors with variable affinity for IgG. Initiation of signaling through these receptors is mediated by clustering in response to particle-associated IgG. A growing body of evidence implicates the cytoskeleton as a regulator of transmembrane receptor motion. This work suggests that actiri may influence particle binding and the initiation of Fe receptor signaling. Macrophage Colony Stimulating Factor (MCSF or CSF-1), a macrophage growth factor and chemo-attractant has been implicated as a regulator of phagocytosis. Early work suggested that MCSF regulated phagocytosis by increasing Fe receptor expression. Here, we demonstrate that MCSF is able to transiently increase macrophage phagocytic capacity through independent of receptor expression. Three possible mechanisms were investigated: changes in receptor diffusion, enhancement of membrane convection, or allostery-induced changes in receptor affinity. Actin disruption by drug treatment or fixation prevents MCSF enhancement of capture. MCSF transiently increased protrusive activity of the macrophage plasma membrane without increasing the rate of receptor diffusion, suggesting a model in which MCSF increases particle engagement by stimulation of micro-probing of the local environment. Furthermore, a novel biophysical mechanism for inter-receptor sensitization mediated by the actin cytoskeleton is proposed

Turning Participatory Microbiome Research into Usable Data: Lessons from the American Gut Project

The role of the human microbiome is the subject of continued investigation resulting in increased understanding. However, current microbiome research has only scratched the surface of the variety of healthy microbiomes. Public participation in science through crowdsourcing and crowdfunding microbiome research provides a novel opportunity for both participants and investigators. However, turning participatory science into publishable data can be challenging. Clear communication with the participant base and among researchers can ameliorate some challenges. Three major aspects need to be considered: recruitment and ongoing interaction, sample collection, and data analysis. Usable data can be maximized through diligent participant interaction, careful survey design, and maintaining an open source pipeline. While participatory science will complement rather than replace traditional avenues, it presents new opportunities for studies in the microbiome and beyond

Turning Participatory Microbiome Research into Usable Data: Lessons from the American Gut Project.

The role of the human microbiome is the subject of continued investigation resulting in increased understanding. However, current microbiome research has only scratched the surface of the variety of healthy microbiomes. Public participation in science through crowdsourcing and crowdfunding microbiome research provides a novel opportunity for both participants and investigators. However, turning participatory science into publishable data can be challenging. Clear communication with the participant base and among researchers can ameliorate some challenges. Three major aspects need to be considered: recruitment and ongoing interaction, sample collection, and data analysis. Usable data can be maximized through diligent participant interaction, careful survey design, and maintaining an open source pipeline. While participatory science will complement rather than replace traditional avenues, it presents new opportunities for studies in the microbiome and beyond

The microbiome and human biology

Over the past few years, microbiome research has dramatically reshaped our understanding of human biology. New insights range from an enhanced understanding of how microbes mediate digestion and disease processes (e.g., in inflammatory bowel disease) to surprising associations with Parkinson's disease, autism, and depression. In this review, we describe how new generations of sequencing technology, analytical advances coupled to new software capabilities, and the integration of animal model data have led to these new discoveries. We also discuss the prospects for integrating studies of the microbiome, metabolome, and immune system, with the goal of elucidating mechanisms that govern their interactions. This systems-level understanding will change how we think about ourselves as organisms