Advances in Human Microbiome Science

Agenda

* Presentation titles and times are subject to change.

Abstracts

Gut Microbiome Richness in Health and Disease
Stanislav Dusko Ehrlich, PhD, Institut National de la Recherche Agronomique (INRA) & King’s College London

We have developed an approach, named quantitative metagenomics, to assess presence and abundance of microbial genes of the gastrointestinal tract communities. The approach is based on high throughput DNA sequencing in conjunction with an extensive catalog of microbial genes, the latest having >9.9 million genes. A large proportion of the catalog genes encoded by the same microbial species or sub-species genetic elements (viruses, plasmids, CRISPR, etc) have been clustered by an innovative method, based on covariance of gene abundances.  This approach has revealed two types of individuals in populations from Europe, US and Asia, differing by the richness of their gut microbiome. Microbiome poor individuals have a less healthy metabolic and inflammatory profile and an increased risk to develop metabolic syndrome associated chronic diseases, such as diabetes, hepatic & cardiovascular complications. Nutritional interventions can correct, in parallel, metabolic parameters and microbiome richness opening avenues for prevention of chronic diseases. Factors that impact microbial richness will be presented and discussed.

Illuminating the Role of Microbiome in Disease Through Metabolomics
Jonathan Braun, MD, PhD, David Geffen School of Medicine at the University of California, Los Angeles

The composition of the enteric microbiome is increasingly implicated in the threshold and phenotype of local and systemic developmental inflammatory, and neoplastic diseases.  Mechanistically, a simplifying concept is that at-risk microbial communities deleteriously affect host physiology by key bioactive products (primary or secondary small molecules and peptides) they make or fail to make. This concept dictates a shift of microbiome assessment from composition to high-throughput metagenomics, transcription, and metabolomics. It also requires a human systems biology framework, bioinformatically and experimentally, to efficiently screen and validate microbial metabolic candidates that target host traits critical to disease state.  Using such approaches, the landmark bioactive microbial metabolites (short chain fatty acids and secondary bile acids) have been augmented by several new classes of molecules with unexpected host pathophysiologic mechanisms in host traits ranging from mucosal inflammatory disease and autism-like developmental neurobiologic disorders. Microbial communities also organize into one of 3 or 4 modes of metabolic output, termed metabotypes, that may provide a link between environmental and functional states of the microbiome. An important prediction is that pharmacologic targeting of these microbial metabolite pathways may provide a non-ecologic strategy to “treat” the microbiome to improve human health. 

Small Molecules from the Human Microbiota
Michael Fischbach, PhD, University of California, San Francisco

The discovery of natural products – small molecules from microbes often used as drugs – has been an ad hoc pursuit for almost a century. The rapidly growing database of microbial genome sequences offers new opportunities to leverage genomics and bioinformatics toward discovering natural products and characterizing their roles in mediating interspecies interactions. This seminar will describe two convergent, ongoing lines of research: our use of genomics and bioinformatics to identify biosynthetic gene clusters and predict the structures of their small molecule products, and our efforts to identify and characterize small molecules produced by the human microbiota.

Causes and consequences of interpersonal microbial variation
Andy Goodman, PhD, Yale University, New Haven

The human gut provides a habitat for enormous bacterial communities associated with health and resistance to disease. These communities result from a complex process of bacterial cooperation and competition that is not understood. I will describe how new genetic approaches for gut anaerobes can be combined with germfree animal husbandry to identify and characterize inter-bacterial and host-bacterial interactions during health and disease. These approaches shed new light on the balance between invading enteropathogens and resident commensal microbes, revealing new commensal-encoded mechanisms for resilience during inflammation. Mechanistic insights into microbiome dynamics will facilitate predictive and intervention approaches for maximizing the contribution of the microbiome to health.

Diet-Microbiome-Health Interactions in Older People
Paul W. O'Toole, PhD, University College Cork

The fecal microbiota composition of 500 subjects in the ELDERMET cohort differed significantly between individuals; correlated with habitual diet; was directly proportional in diversity to the Healthy Food Diversity index. Gradients in microbiota composition correlated with gradients in several health parameters, after adjustment for possible confounders. Subjects in long-term residential care had the lowest microbiota diversity, and we now show by analysis of microbiota composition over 6 months that a low initial microbiota diversity level is associated with greater composition shift during 6 month follow-up. Residence in a long-term care facility was not required for a low-diversity microbiota, because subjects living in their own homes and consuming a low-diversity diet also acquired a low diversity microbiota. These individuals had lower scores for a number of health parameters. Shotgun metagenome sequencing in 223 subjects indicated that the low diversity microbiota of frailer subjects harbored significantly lower gene counts than the microbiome of subjects consuming a high Healthy Food Diversity index diet, especially for carbohydrate fermentation, amino acid metabolism, and nucleotide metabolism. We also noted differential abundance of sub-groups of a recently discovered order of archaeal methanogens. Application of an iterative bi-clustering algorithm (iBBiG) to microbiota composition data from 732 faecal samples from 371 ELDERMET cohort subjects identified distinctive microbiota configurations associated with ageing in both community and long-stay residential care elderly subjects. These data provide a framework for analysing microbiota-health associations, distinguishing correlation from causation, and developing microbiota-based health surveillance for older adults.

Quantifying Horizontal Gene Transfer from Metagenomic Sequences
Mingzhi Lin, MS, New York University

Microorganisms live in ecologically diverse communities and interact in multiple ways, including horizontal gene transfer (HGT). The biological and evolutionary significance of HGT has broad implications for our understanding of microbial communities, not only in terms of structure, evolution and functions, but also in terms of human health – HGT has been responsible for the dissemination of numerous antibiotic-resistance determinants across diverse bacterial species. Quantification of HGT from microbial sequences sampled from complex environments is thus a critical step to study the impacts of HGT on microbial communities and their interactions with environments, which, however, is still a challenge. To fill this gap, we developed a novel method based on mutational correlation to detect and quantify host- and environment-associated variation of HGT rates from whole-genome shotgun metagenomic sequences. Analysis on samples in human oral cavity from Human Microbiome Project shows HGT rates for some opportunistic pathogens varying widely, even among healthy subjects, with strong niche specialization. Comparing to quantification using genomic sequences, we also observed significantly elevated HGT rates in local microbial communities, underscoring the power of using metagenomic sequences for studying HGT.

Discordant Temporal Development of Bacterial Phyla and the Emergence of Core in the Fecal Microbiota of Young Children
Tamar Ringel-Kulka MD, MPH^3#

The colonization pattern of intestinal microbiota during childhood may impact health later in life, but children older than 1 year are poorly studied. We followed healthy children aged 1-4 years (n=28) for up to 12 months, during which a symbiotic intervention and occasional antibiotics intake occurred, and compared them with adults from the same region. Microbiota was quantified with the HITChip phylogenetic microarray and analyzed with linear mixed effects model and other statistical approaches. Synbiotic administration increased the stability of Actinobacteria and antibiotics decreased Clostridium cluster XIVa abundance. Bacterial diversity did not increase in 1-5-year old children and remained significantly lower than in adults. Actinobacteria, Bacilli and Clostridium cluster IV retained child-like abundances, whereas some other groups were converting to adult-like profiles. Microbiota stability increased, with Bacteroidetes being the main contributor. The common core of microbiota in children increased with age from 18 to 25 highly abundant genus-level taxa, including several butyrate-producing organisms, and developed towards an adult like composition. In conclusion, intestinal microbiota is not established before 5 years of age and diversity, core microbiota and different taxa are still developing towards adult type configuration. Discordant development patterns of bacterial phyla may reflect physiological development steps in children.
 
Coauthors: Jing Cheng MSc^1,2#, Ineke Heikamp-de Jong⁴ , Yehuda Ringel MD^5,6, Ian Carroll PhD⁵, Willem M. de Vos PhD^1,2,4, Jarkko Salojärvi PhD¹ and Reetta Satokari PhD^1,2
1 Department of Bacteriology and Immunology, University of Helsinki, Finland
2 Department of Veterinary Biosciences, University of Helsinki, Finland
3 Department of Maternal and Child Health, The University of North Carolina at Chapel Hill
4 Laboratory of Microbiology, Wageningen University, The Netherlands
5 Division of Gastroenterology and Hepatology, The University of North Carolina at Chapel Hill
6 Division of Gastroenterology, Beilinson Hospital, Israel
# Equal contribution

Unintended Consequences of Early-life Antibiotic Administration on the Intestinal Microbiota and Host Immunity
Victoria Ruiz, PhD, NYU Langone Medical Center

Broad-spectrum antibiotics are frequently prescribed for children and in cases of viral infection, provide no clinical benefit. However, early-life antibiotic use may affect the host microbiota, promoting long-term metabolic and immunologic alterations. We hypothesized that early-life therapeutic doses [or pulsed antibiotic treatment (PAT)] would perturb the intestinal microbiota leading to alterations in tissue-specific and systemic immunity. To test this hypothesis, C57BL/6 mice were exposed to the β-lactam, amoxicillin, or the macrolide, tylosin. Therapeutic doses of both agents altered expression profiles of intestinal genes including those involved in lymphocyte function and antimicrobial defenses. Flow cytometric analysis demonstrated that mice exposed to tylosin at day 5 of life had a decreased frequency of specific splenic and ileal T-cell populations, whereas exposure post-weaning had minimal effects. Although even a single tylosin course had multiple immunological alterations in conventional mice, essentially none were detected in germ-free animals; indicating that an antibiotic-perturbed microbiota is required for the observed effects. Transfer of PAT-perturbed microbiota to germ-free recipients led to impaired IgA expression and decreased splenic T cells in the now-conventionalized recipients. Alterations in the frequency of splenic and intestinal T cells and sIgA production were associated with decreased bacterial richness (β-diversity), altered community structure (β-diversity), and microbial compositional changes. These results provide evidence that early-life alterations of the intestinal microbiota by PAT modulate systemic and mucosal cellular and humoral immune phenotypes that may persist long after the exposure has ceased.
 
Coauthors: Thomas Battaglia, Isak Engstrand, Amy Ou, Kenneth H. Cadwell, and Martin J. Blaser, NYU Langone Medical Center

Exploiting the immune response to illuminate host-microbiota interactions
Noah W. Palm, Yale University School of Medicine, New Haven, CT, USA

The composition of the gut microbiota is thought to have dramatic effects on the development and progression of a variety of diseases, including Inflammatory Bowel Disease (IBD), autoimmunity, and metabolic syndrome.  However, identifying the specific bacteria that preferentially affect disease susceptibility and severity in humans remains a major challenge. In response to this problem, we developed a novel technology that uses the host’s own immune response to the microbiota as a guide to identify specific members of the gut microbiota that preferentially modulate disease development. This approach specifically identified known disease-causing intestinal bacteria in a mouse model of microbiota-driven colitis. Furthermore, we were able to use this approach to identify specific bacterial strains from IBD patients that selectively conferred susceptibility to severe colitis when transplanted into germ-free mice. These studies thus: (i) establish a new strategy for the identification of disease- and immune-modulating members of the microbiota in humans; (ii) identify potentially disease-driving members of the intestinal microbiota in humans with IBD; and (iii) begin to establish causal, rather than correlative, connections between specific changes in the microbiota and human disease. Future studies using similar approaches will allow us to elucidate the full spectrum of reciprocal interactions between the microbiota and the host immune system. These studies will lead to a more complete understanding of the role of microbiota composition in human health and disease and will eventually enable the development of novel and specific microbiota-targeted therapeutics.

Group 3 Innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells
Matthew R. Hepworth, Weill Cornell Medical College, NYC, USA

Inflammatory CD4+ T cell responses to self or commensal bacteria underlie the pathogenesis of autoimmunity and inflammatory bowel disease (IBD), respectively. While selection of self-specific T cells in the thymus limits responses to mammalian tissue antigens, the mechanisms that control selection of commensal bacteria-specific T cells remain poorly understood. Here we demonstrate that group 3 innate lymphoid cell (ILC3)-intrinsic expression of major histocompatibility complex class II (MHCII) is regulated similarly to thymic epithelial cells, and that MHCII+ ILC3s directly induce cell death of activated commensal bacteria-specific T cells. Further, MHCII on colonic ILC3s was reduced in pediatric IBD patients. These results define a selection pathway for commensal bacteria-specific CD4+ T cells in the intestine and suggest that this process is dysregulated in human IBD.

Metagenomics of the Gut Microbiome: A New Source of Innovative Drugs
Rodolphe Clerval, MS, ENTEROME

The role of the gut microbiota in the pathogenesis of various disorders is nowadays undisputed. Translation of recent scientific discoveries into healthcare innovation has been limited so far. This is partially attributable to our limited knowledge of the gut microbiota composition and the nature of the complexity of interactions between the microbiome and the host. Modern metagenomic tools, such as whole metagenome sequencing and functional metagenomic screening platforms are opening a new era that will lead to identification of new targets and drug candidates.

Gene-Environment Interactions Mediate Microbiome Control of Mucosal Immunology
Sarkis K Mazmanian, PhD, California Institute of Technology, Pasadena

Advances in genomic technologies have empowered unprecedented analysis of the human genome and the gut microbiome in conditions such inflammatory bowel disease (IBD). Despite a wealth of sequence-based data identifying risk variants in the genome and dysbiosis in the microbiome during IBD, molecular mechanisms unifying gene-microbiome interactions remain unknown. Bacteroides fragilis ameliorates experimental colitis via production of Polysaccharide A, a microbial symbiosis factor delivered to the gut immune system by outer membrane vesicles (OMVs). We reveal herein that OMVs require ATG16L1, a primary IBD-risk gene, to promote regulatory T cell (TREG) activity during protection from colitis. NOD2, a bacterial pattern receptor and the most common gene variant in IBD, interacts with ATG16L1 during clearance of pathogenic gut bacteria. OMVs activate a novel NOD2-ATG16L1 pathway in intestinal dendritic cells that results in anti-inflammatory responses. Finally, immune cells from IBD patients with the T300A risk variant in ATG16L1 do not promote Foxp3+ TREG development OMVs. These findings suggest that variants in ATG16L1 and NOD2 may disrupt ‘sensing’ of the beneficial signals from the gut microbiome, revealing entirely new insights into the etiology of IBD.

Immunology Relevant Microbiome Control of Mucosal Immunology
Randy Longman, MD, PhD

Joint inflammation causes significant morbidity in up to 30% of the 2 million people in the U.S. suffering from inflammatory bowel disease (IBD), but our ability to diagnostically identify, and therapeutically target these symptoms remain limited. IBD-associated joint inflammation or spondyloarthropathy (SpA) is part of a larger group of seronegative SpA with overlapping genetic and clinical features in which the gut is the putative port of entry for microbial triggers of systemic cellular inflammation which ultimately result in joint disease. We have recently shown that specific taxa expand in patients with new-onset rheumatoid arthritis and that intestinal colonization can promote immune cell activation. While several studies have identified marked alterations in the microbiota of patients with inflammatory bowel disease (IBD), the microbial and immune cell contribution to the underlying pathogenesis of IBD-associated SpA (IBD-SpA) remains poorly characterized. This seminar will explore the hypothesis that microbial dysbiosis in IBD-SpA underlies a break in immune tolerance to gut commensals and causes local and systemic expansion of Th17 cells that support joint inflammation.

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