Strain-specific gene function prediction and the Human Microbiome Bioactives Resource
by prof. Curtis Huttenhower
Abstract
Most genetic material encountered in microbial communities - including the human microbiome - remains both uncharacterized and, often, strain-specific. This leaves a tremendous gap in translating microbiome science to personalized biomarkers and therapies. While multi-omic studies represent a promising means of prioritizing leads for validation, this still leaves thousands of molecular targets for most phenotypes of interest. The Human Microbiome Bioactives Resource (HMBR) provides a set of computational and experimental protocols for accelerating these tasks, including the identification of “bioactive” strains, microbial proteins, and chemical products from the human gut, as well as newly predicting function for uncharacterized genes and metabolites. These have proven effective in applications as diverse as the inflammatory bowel diseases (IBD, in a meta-analysis spanning over 8,700 metagenomes) or companion animal nutrition (employing almost 2,500 canine and feline gut samples). In an end-to-end example linking metagenomics, metatranscriptomics, metabolomics, inflammation phenotypes, and drug treatment, we have specifically identified a subset of microbial gene families responsible for 5-ASA inactivation, the leading cause of progression to second-line treatments in IBD. Together, this family of approaches provides multiple new avenues for identifying molecular activities responsible for microbiome-phenotype associations.
Short Bio
Curtis Huttenhower, PhD, is a Professor of Computational Biology and Bioinformatics in the Departments of Biostatistics and Immunology and Infectious Diseases at the Harvard T.H. Chan School of Public Health, where he co-directs the Harvard Chan Microbiome in Public Health Center. He is an Associate Member at the Broad Institute's Microbiome Program. His lab focuses on computational methods for functional analysis of microbial communities and molecular epidemiology of the human microbiome. This includes systems biology reconstructions integrating metagenomic, metatranscriptomic, and other microbial community 'omics, microbiome ecology in health and disease, and its potential as a diagnostic tool and point of therapeutic intervention.
Short talks
Achieving pan-microbiome biological insights via the dbBact knowledge base
Microbiome 16S rRNA studies have examined diverse habitats, including oceans, soil, plants, animals, and large cross-sectional human studies. However, finding commonalities between different experiments, habitats, or conditions is very difficult due to technical issues related to using different primer pairs and relying on taxonomy for scientific reporting. Hence, grosso modo, the 16S rRNA microbiome literature has not been integrated into a collaborative body of knowledge. It often comprises effectively isolated studies, where researchers may be completely unaware of commonalities between their findings and those in other studies, especially across different niches or habitats. In the past five years, we have created dbBact (www.dbbact.org), a knowledge base, to bridge this gap and lay the groundwork for gaining core pan-microbiome insights. Briefly, amplicon sequence variants (ASVs) from datasets of published papers are manually analyzed, and bacterial sequences associated with experimental conditions are uploaded to dbBact, together with ontology-based characterizations (e.g., “the abundance of sequence ACTGGA… was higher in fecal samples of horses with colitis compared to healthy controls in California”). To date, dbBact contains data from more than 1000 published studies across diverse habitats, spanning ~370,000 unique 16S rRNA ASVs, with approximately 1,500,000 sequence-to-phenotype associations. We demonstrated how dbBact provides many types of novel hypotheses that cannot be formulated by standard methods (Amir et al., Nucleic Acids Research, 2023). We will show how dbBact may be (1) applied as part of microbiome research in any niche; (2) allow a new type of meta-analysis; and (3) be harnessed to answer ecological questions.
Noam Shental, The Open University of Israel, Israel
Link to publication: https://academic.oup.com/nar/article/51/13/6593/7199329?login=true
Establishment of a non-Westernized gut microbiota in men who have sex with men is associated with sexual practices
The human gut microbiota is influenced by various factors, including health status and environmental conditions, yet considerable inter-individual differences remain unexplained. Previous studies identified that the gut microbiota of men who have sex with men (MSM) is distinct from that of non-MSM. Here, we reveal through species-level microbiota analysis using shotgun metagenomics that the gut microbiota of many MSM with Western origin resembles gut microbial communities of non-Westernized populations. Specifically, MSM gut microbiomes are frequently dominated by members of the Prevotellaceae family, including co-colonization of species from the Segatella copri complex and unknown Prevotellaceae members. Questionnaire-based analysis exploring inter-individual differences in MSM links specific sexual practices to microbiota composition. Moreover, machine learning identifies microbial features associated with sexual activities in MSM. Together, this study shows associations of sexual activities with gut microbiome alterations in MSM, which may have a large impact on population-based microbiota studies.
Kun D. Huang, Helmholtz Centre for Infection Research, Germany
Link to publication: https://www.sciencedirect.com/science/article/pii/S2666379124000491
Deep genomic characterization of the gut microbiome: A novel space for biomarker discovery
Eric J.C. Gálvez, Bioinformatician | Data Scientist, Roche, Switzerland
Highlights
Gut microbiota patterns associated with duration of diarrhea in children under five years of age in Ethiopia
Introduction: Diarrhea claims about 500,000 lives annually among children under five years of age and about 90% of those deaths occur in Sub-Saharan Africa and South Asia. Childhood mortality due to acute diarrhea (AD; < 7 days of duration) is decreasing, but prolonged (ProD; 7-13 days of duration) and persistent (PD; ≥ 14 days of duration) diarrhea combined (ProPD) are responsible for increased morbidity and mortality in low- and middle- income countries (LMICs).
Objectives: This study aimed to characterize the gut microbiota (GM) composition of children with acute diarrhea (AD) and prolonged or persistent diarrhea (ProPD) by comparing GM composition between these two groups and with non-diarrheal controls in a case-control study.
Methods: The study included fecal samples from 1321 children 0-59 months old. After preprocessing based on sequencing depth, we analyzed the GM of 1313 children comparing 554 AD cases, 95 ProPD cases, and 663 frequency matched, non-diarrheal controls. All children were enrolled from Jimma, Ethiopia. The GM composition was determined using 16S rRNA gene (V4 region) amplicon sequencing. The observed zero-radius Operational Taxonomic Units (zOTUs) and Shannon diversity index were assessed, and Bray-Curtis dissimilarity metrics were generated and differences between groups evaluated by PERMANOVA. DESeq2 was used to determine taxa being differentially abundant between diarrhea subcategories and non-diarrheal controls.
Results: All diarrhea cases (AD and ProPD) combined and each group separately were associated with a decrease in bacterial diversity compared to non-diarrheal controls. Relative to non-diarrheal controls, the GM of children with AD or ProPD was enriched in Escherichia spp., Campylobacter spp., and Streptococcus spp. The GM of children with AD or ProPD was characterized by a decreased relative abundance of Prevotella copri, Faecalibacterium prausnitzii and Dialister succinatiphilus compared to non-diarrheal controls. Similarly, compared to AD cases, ProPD cases were characterized by a decreased relative abundance of important gut commensals such as F. prausnitzii, Akkermansia muciniphila, Eubacterium hadrum and Blautia spp.
Conclusion: The GM of children with AD and ProPD was enriched in putative pathogens as well as facultative anaerobes, while obligate anaerobes were reduced. The GM of children with ProPD was characterized by a more pronounced reduction of obligate anaerobic gut commensals compared to AD, suggesting that prolonged duration of diarrhea is accompanied by a depletion of healthy gut commensals. This indicates a potential role for targeted dietary supplements to restore gut eubiosis and/ or the use of next generation probiotics to improve ProPD treatment.
Getnet Tesfaw, School of Medical Laboratory Sciences, Jimma University, Ethiopia; and Department of Food Science, University of Copenhagen, Denmark
A three strain postbiotic mix improves the immune system function after oral intake for 28-days
Background: Dietary selenium complements are known to improve overall health and enhance different aspects of the immune response, participating in the function of the immune cells, cytokine secretion regulation of chronic inflammation and control of excessive immune responses. In this study, our objective was to evaluate whether a selenium-rich postbiotic composed of whole-cell Saccharomyces cerevisiae ABB S12, Kluyveromyces marxianus ABB S8 and Saccharomyces boulardii ABB S3 yeast strains, can act as provider of selenium to enhance the function of the human immune system after oral intake.
Methods and findings: A total of 15 volunteers were enrolled in a 28-day clinical study in which they complemented their normal diets with a daily dose of a novel selenium food supplement, “postbiotic immune”. Selenium levels in plasma were quantified by ELISA (Enzyme Linked Immuno Sorbent Assay), and the proliferation and activation of different subsets of lymphocytes isolated from PBMC’s (Peripheral Blood Mononuclear Cells) were assessed by flow cytometry using different cell markers. At the end of the study, we observed a higher proliferative capacity of total lymphocytes and specifically, of CD16+ lymphocytes (natural killer cells), upon stimulation with the CD3 and CD28 antibodies mimicking cell activation in vitro. Interestingly, we did not observe an increase in the activation of the lymphocyte subsets CD4+ (T helper cells) but CD16+, indicating that that there was a specific activation of natural killer cells.
Conclusions: Altogether, our results suggest that orally ingested ”Postbiotic immune” primes the human immune system to elicit a faster and more efficient immune response through the specific activation of natural killer cells.
Jordi Cuñé Castellana, AB Biotek HNH, UK
Link to publication: https://nutraceuticals.imedpub.com/a-three-strain-postbiotic-mix-improves-the-immune-system-function-after-oral-intake-for-28days.php?aid=52017