Learning Mucosal Immunity from Gut Microbes
by Ramnik Xavier
Short Bio
Ramnik Xavier is a core institute member of the Broad Institute of MIT and Harvard, where he serves as director of the Klarman Cell Observatory. He is also director of the Broad’s Immunology Program and co-director of the Broad’s Infectious Disease and Microbiome Program. He is the Kurt J. Isselbacher Professor of Medicine at Harvard Medical School; director of the Center for Computational and Integrative Biology and professor in the Department of Molecular Biology at Massachusetts General Hospital (MGH); and co-director of the Center for Microbiome Informatics and Therapeutics at MIT.
His laboratory focuses on systematic characterization of genetic variants to understand the regulation of barrier defense, innate and adaptive immunity; chemical biology to control cellular disease phenotypes suggested by human genetics; molecular mechanisms to determine roles of the microbiome in health and disease; and development of computational approaches to uncover patterns of human and microbial pathway regulation during disease and treatment.
Xavier has spent his academic career at MGH, where he served as chief of gastroenterology for nine years and is currently director of the NIH-funded Center for the Study of Inflammatory Bowel Disease.
Short talks
Questioning the fetal microbiome illustrates pitfalls of low-biomass microbial studies
Whether the human fetus and the prenatal intrauterine environment (amniotic fluid and placenta) are stably colonized by microbial communities in a healthy pregnancy remains a subject of debate. Here we evaluate recent studies that characterized microbial populations in human fetuses from the perspectives of reproductive biology, microbial ecology, bioinformatics, immunology, clinical microbiology and gnotobiology, and assess possible mechanisms by which the fetus might interact with microorganisms. Our analysis indicates that the detected microbial signals are likely the result of contamination during the clinical procedures to obtain fetal samples or during DNA extraction and DNA sequencing. Furthermore, the existence of live and replicating microbial populations in healthy fetal tissues is not compatible with fundamental concepts of immunology, clinical microbiology and the derivation of germ-free mammals. These conclusions are important to our understanding of human immune development and illustrate common pitfalls in the microbial analyses of many other low-biomass environments. The pursuit of a fetal microbiome serves as a cautionary example of the challenges of sequence-based microbiome studies when biomass is low or absent, and emphasizes the need for a trans-disciplinary approach that goes beyond contamination controls by also incorporating biological, ecological and mechanistic concepts.
Katherine M Kennedy & Marcus C. de Goffau
McMaster University, Canada
Twitter summary: https://twitter.com/KateKennedy/status/1618407336619692034
Gut microorganisms and their genes are associated with cognition and neuroanatomy in children
The gastrointestinal tract, its resident microorganisms, and the central nervous system are connected by biochemical signaling, also known as the ”microbiome-gut-brain-axis.” Both the human brain and the gut microbiome have critical developmental windows in the first years of life, raising the possibility that their development is co-occurring and likely co-dependent. Emerging evidence implicates gut microorganisms and microbiota composition in cognitive outcomes and neurodevelopmental disorders (e.g., autism and anxiety), but the influence of gut microbial metabolism on typical neurodevelopment has not been explored in detail. We investigated the relationship of the microbiome with the neuroanatomy and cognitive function of 361 healthy children, demon- strating that differences in gut microbial taxa and gene functions are associated with overall cognitive function and with differences in the size of multiple brain regions. Using a combination of multivariate linear and machine learning (ML) models, we showed that many species, including Gordonibacter pamelae and Blautia wexlerae, were significantly associated with higher cognitive function, while some species such as Ruminococcus gnavus were more commonly found in children with low cognitive scores after controlling for sociodemographic factors. Microbial genes for enzymes involved in the metabolism of neuroactive compounds, particularly short-chain fatty acids such as acetate and propionate, were also associated with cognitive function. In addition, ML models were able to use microbial taxa to predict the volume of brain regions, and many taxa that were identified as important in predicting cognitive function also dominated the feature importance metric for individual brain regions. For example, B. wexlerae was the most important species in models predicting the size of the parahippocampal region in both the left and right hemispheres, while several species from the phylum Bacteroidetes, including GABA-producing B. ovatus, were important for predicting the size of the left accumbens area, but not the right. These findings provide potential biomarkers of neurocognition and brain development and may lead to the future development of targets for early detection and early intervention.
Link to OA paper: https://doi.org/10.1101/2020.02.13.944181
Kevin Scott Bonham, Ghuilherme Fahur Bottino, Shelley Hoeft McCann, Vanja Klepac-Ceraj
Presenting author’s affiliation: Wellesley College, USA
Detailed Social Network Interactions and Gut Microbiome Strain-Sharing Within Isolated Honduras Villages
When humans assemble into face-to-face social networks, they create an extended environment that permits exposure to the microbiome of other members of a population. Social network interactions may thereby also shape the composition and diversity of the microbiome at individual and population levels. Here, we use comprehensive social network and detailed microbiome sequencing data in 1,098 adults across 9 isolated villages in Honduras to investigate the relationship between social network structure and microbiome composition. Using both species-level and strain-level data, we show that microbial sharing occurs between many relationship types, notably including non-familial and non-household connections. Using strain-sharing data alone, we can confidently predict a wide variety of relationship types (AUC ~0.73). This strain-level sharing extends to second-degree social connections in a network, suggesting the importance of the extended network with respect to microbiome composition. We also observe that socially central individuals are more microbially similar to the overall village than those on the social periphery. Finally, we observe that clusters of microbiome species and strains occur within clusters of people in the village social networks, providing the social niches in which microbiome biology and phenotypic impact are manifested.
Link to OA paper: https://www.biorxiv.org/content/10.1101/2023.04.06.535875v1
Jackson Pullman, Francesco Beghini, Marcus Alexander, Shivkumar Vishnempet, Drew Prinster, Ilana Brito, Nicholas Christakis
Presenting author’s affiliation: Yale University, New Haven, USA
Tips and Tricks for DNA isolation from stool samples
Julie Sean, Sr Global Product Manager at QIAGEN, Germany
Highlights
Worldwide presence of Blastocystis in the human gut microbiome is linked to healthier dietary regimes and lower body mass index
The human body is inhabited by a community of diverse bacteria, archaea, viruses, fungi, and microeukaryotes, collectively called the human microbiome, that impact human health. Shotgun metagenomic sequencing enables high-resolution profiling of all members of the community. While the bacterial constituents have been investigated extensively, organisms from other domains, such as eukaryotes, are currently underexplored. Blastocystis spp. is a common eukaryotic protist that lives in the gastrointestinal tract of humans and other animals. The ecological and clinical significance of Blastocystis is still controversial, as it has been associated both with gastrointestinal symptoms and has been found in asymptomatic individuals. We performed a large-scale data harmonization and analysis of more than 50,000 metagenomic samples (34,687 from the ZOE PREDICT Studies, 13,928 from 68 public studies on humans, and 4,623 animal samples from 50 public studies) to investigate Blastocystis presence in the gut microbiome. Our results suggest a potentially favorable role for Blastocystis. We observed a worldwide presence of Blastocystis among healthy individuals with prevalence variability linked to host age, lifestyle, and geographical provenance. We established a dose-dependent coupling of Blastocystis carriage and diet quality, showing that Blastocystis-positive individuals tended to consume healthier, less-processed, fiber-enriched foods. Moreover, we show that the presence of Blastocystis was associated with favorable near-term fasting and postprandial cardiometabolic markers, such as lower GlycA and higher HDL. Finally, we reveal through meta-analysis a robust and reproducible association between the presence of Blastocystis and a lower body mass index, as well as reduced risk for inflammatory bowel diseases, colorectal cancer, and diabetes. Overall, the widespread presence of Blastocystis among healthy individuals suggests that, although associated with disease in certain conditions, it could be a non-pathogenic member of the gut microbiome. Further genomic studies are needed to unravel the specific role of Blastocystis subspecies in human health and disease. Finally, our work serves as an example of how shotgun metagenomic datasets can help investigate the non-bacterial components of the human microbiome.
Elisa Piperni, Long H. Nguyen, Paolo Manghi, Hanseul Kim, Edoardo Pasolli, Alberto Arrè, Kate M. Bermingham, Aitor Blanco-Míguez, Richard Davies, Francesca Giordano, George Hadjigeorgiou, Emily Leeming, Lauren J. McIver, Jonathan Wolf, Simone M. Cacciò, Sarah E. Berry, Danilo Ercolini, Andrew T. Chan, Curtis Huttenhower, Tim D. Spector, Nicola Segata, Francesco Asnicar
Presenting author’s affiliation: Department CIBIO, University of Trento, Italy; IEO, Istituto Europeo di Oncologia IRCSS, Milan, Italy
Co-diversification of an intestinal Mycoplasma and its salmonid host
Understanding the evolutionary relationships between a host and its intestinal resident bacteria can transform how we understand adaptive phenotypic traits. The interplay between hosts and their resident bacteria inevitably affects the intestinal environment and, thereby, the living conditions of both the host and the microbiota. Thereby this co-existence likely influences the fitness of both bacteria and host. Whether this co-existence leads to evolutionary co-diversification in animals is largely unexplored, mainly due to the complexity of the environment and microbial communities and the often low host selection. We present the gut metagenome from wild Atlantic salmon (Salmo salar), a new wild organism model with an intestinal microbiota of low complexity and a well-described population structure, making it well-suited for investigating co-evolution. Our data reveal a strong host selection of a core gut microbiota dominated by a single Mycoplasma species. We found a clear co-diversification between the population structure of Atlantic salmon and nucleotide variability of the intestinal Mycoplasma populations conforming to expectations from co-evolution between host and resident bacteria. Our results show that the stable microbiota of Atlantic salmon has evolved with its salmonid host populations while potentially providing adaptive traits to the salmon host populations, including defence mechanisms, biosynthesis of essential amino acids, and metabolism of B vitamins. We highlight Atlantic salmon as a novel model for studying co-evolution between vertebrate hosts and their resident bacteria.
Link to OA paper: https://www.nature.com/articles/s41396-023-01379-z
Jacob Agerbo Rasmussen, Morten T. Limborg
Center for Evolutionary Hologenomics, University of Copenhagen, Denmark