The Human Microbiome in Precision Medicine
by prof. Jack Gilbert
The human microbiome is a high dimensional and dynamic part of our physiology that plays a key role in managing health and individualized responses to diet and medicine. The immune system controls our interaction with the microbial world, and the microbial communities in our bodies are central to modulating the immune response. Changes in the human microbiome and their metabolism have substantial influence on atopy, neurological disorders, metabolic disorders, and a range of complex conditions and disease states. Diet is incredibly important in shaping human health and the microbiome, altering both composition and metabolic activity, resulting in changes in immune, endocrine, and neurological systems. Microbiome-Wide Association Studies (MWAS) combined with novel quantitative multi-omic approaches are enabling us to use AI techniques to determine personalized responses to nutrition that drive diseases states and treatment efficacy. Through these innovations, we are finally realizing the paradigm of precision medicine for facilitating patient care.
Professor Jack A Gilbert earned his Ph.D. from Unilever and Nottingham University, UK in 2002, and received his postdoctoral training at Queens University, Canada. From 2005-2010 he was a senior scientist at Plymouth Marine Laboratory, UK; and from 2010-2018 he was Group Leader for Microbial Ecology at Argonne National Laboratory, a Professor of Surgery, and Director of The Microbiome Center at University of Chicago. In 2019 he moved to University of California San Diego, where he is a Professor in Pediatrics and the Scripps Institution of Oceanography, Associate Vice Chancellor for Marine Science, and Director of both the Microbiome and Metagenomics Center and the Microbiome Core Facility. Dr. Gilbert uses molecular analysis to test fundamental hypotheses in microbial ecology.
He cofounded the Earth Microbiome Project and American Gut Project. He has authored more than 450 peer reviewed publications and book chapters on microbial ecology. He is the founding Editor in Chief of mSystems journal. In 2014 he was recognized on Crain’s Business Chicago’s 40 Under 40 List, and in 2015 he was listed as one of the 50 most influential scientists by Business Insider, and in the Brilliant Ten by Popular Scientist. In 2016 he won the Altemeier Prize from the Surgical Infection Society, and the WH Pierce Prize from the Society for Applied Microbiology for research excellence. In 2017 he co- authored “Dirt is Good”, a popular science guide to the microbiome and children’s health. In 2018, he founded BiomeSense Inc to produce automated microbiome sensors. In 2021 Dr Gilbert became the UCSD PI for the National institutes of Health’s $175M Nutrition for Precision Medicine program. In 2023 he became President of Applied Microbiology International, and won the 2023 IFF Microbiome Science Prize.
Seizure modulation by the gut microbiota and tryptophan-kynurenine metabolism in an animal model of infantile spasms
Infantile epileptic spasms syndrome (IESS) is a devastating early-onset epileptic encephalopathy with a poor neurodevelopmental prognosis. Accumulating evidence proposes an important role of gut microbiota in neurodevelopmental disorders via microbiota-gut-brain axis. In a neonatal rat model of IESS, we show both the ketogenic diet and antibiotic administration to reduce seizure frequency and to be associated with improved developmental outcomes. Seizure reductions were accompanied by specific gut microbial alterations including increases in Streptococcus thermophilus and Lactococcus lactis. Mimicking the fecal microbial alterations in a targeted probiotic, we administered these species in a 5:1 ratio. Probiotic administration reduced seizures and improved locomotor activities in control diet-fed animals, similar to KD-fed animals while a negative control (Ligilactobacillus salivarius) had no impact. These results suggest that a targeted microbiota manipulation could improve behavior outcome in infantile epilepsy and provides new insights into microbiota manipulation as a therapeutic avenue for neurodevelopmental disorders.
Cumming School of Medicine, University of Calgary, Calgary, Canada
Wastewater sequencing reveals community and variant dynamics of the collective human virome
Wastewater is a discarded human by-product, but its analysis may help us understand the health of populations. Epidemiologists first analyzed wastewater to track outbreaks of poliovirus decades ago, but so-called wastewater-based epidemiology was reinvigorated to monitor SARS-CoV-2 levels while bypassing the difficulties and pit falls of individual testing. Current approaches overlook the activity of most human viruses and preclude a deeper understanding of human virome community dynamics. Here, we conduct a comprehensive sequencing-based analysis of 363 longitudinal wastewater samples from ten distinct sites in two major cities. Critical to detection is the use of a viral probe capture set targeting thousands of viral species or variants. Over 450 distinct pathogenic viruses from 28 viral families are observed, most of which have never been detected in such samples. Sequencing reads of established pathogens and emerging viruses correlate to clinical data sets of SARS-CoV-2, influenza virus, and monkeypox viruses, outlining the public health utility of this approach. Viral communities are tightly organized by space and time. Finally, the most abundant human viruses yield sequence variant information consistent with regional spread and evolution. We reveal the viral landscape of human wastewater and its potential to improve our understanding of outbreaks, transmission, and its effects on overall population health.
Link to OA paper: https://www.nature.com/articles/s41467-023-42064-1
Baylor College of Medicine, Houston, TX, USA
Analyzing microbial evolution through gene and genome phylogenies
Microbiome scientists critically need modern tools to explore and analyze microbial evolution. Often this involves studying the evolution of microbial genomes as a whole. However, different genes in a single genome can be subject to different evolutionary pressures, which can result in distinct gene-level evolutionary histories. To address this challenge, we propose to treat estimated gene-level phylogenies as data objects, and present an interactive method for the analysis of a collection of gene phylogenies. We use a local linear approximation of phylogenetic tree space to visualize estimated gene trees as points in low-dimensional Euclidean space, and address important practical limitations of existing related approaches, allowing an intuitive visualization of complex data objects. We demonstrate the utility of our proposed approach through microbial data analyses, including by identifying outlying gene histories in strains of Prevotella, and by contrasting Streptococcus phylogenies estimated using different gene sets. Our method is available as an open-source R package, and assists with estimating, visualizing, and interacting with a collection of bacterial gene phylogenies.
Link to OA paper: https://doi.org/10.1093/biostatistics/kxad025
University of Washington, Department of Statistics, Seattle, WA, USA
Metabolic diversity in commensal protists regulates intestinal immunity and trans-kingdom competition
Commensal protists have historically been overlooked as members of the gut microbiota, but recent studies have highlighted the dominant effects of these commensals on the gut ecosystem. In particular, protists in the Parabasalia phylum reshape the intestinal immune landscape and influence host susceptibility to both infectious and inflammatory diseases. However, the mechanisms used by these protists to shape the gut environment remain poorly understood. Here, we identify a new species of commensal parabasalid in the mouse intestine, Tritrichomonas casperi. We find that metabolic differences between T. casperi and the closely related species Tritrichomonas musculis modulate their effects on host immunity and determine their ecological niche within the microbiota. First, we investigate metabolic output of these commensal parabasalids using genomic and metabolomic analysis. This reveals species-level differences in excretion of the tuft cell activating metabolite succinate, which causes differential remodeling of the immune system in the small intestine. Next, we investigate protist metabolic input by manipulating dietary fiber intake, as well as developing in vitro culture. This reveals that whereas T. musculis preferentially relies on dietary polysaccharides, T. casperi uses host mucus glycans as a carbon source. These carbon source preferences lead to differential competition with commensal bacteria in the intestine, including Bacteroidales spp. and Akkermansia muciniphila. These trans-kingdom interactions can in turn suppress protist-induced intestinal immune responses in a diet-dependent manner. Finally, we explore the diversity of commensal protists in humans by examining parabasalids in the microbiomes of both industrialized and non-industrialized populations. We identify multiple new species of commensal parabasalids in the microbiomes of non-industrialized populations, including novel human-associated tritrichomonads that are closely related T. musculis and T. casperi. Altogether, our findings elucidate how commensal parabasalid metabolism acts as a focal point for complex interactions with the host immune system, commensal bacteria, and diet, to impact intestinal immunity and host health.
Link to OA paper: https://www.biorxiv.org/content/10.1101/2022.08.26.505490v2
Stanford School of Medicine, Stanford, CA, USA