Publications by authors named "J Tyler Faith"

112 Publications

Maternal infection programmes offspring immunity.

Nat Rev Immunol 2021 Apr;21(4):207

OxMS Preprint Journal Club, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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http://dx.doi.org/10.1038/s41577-021-00532-zDOI Listing
April 2021

Intestinal Host Response to SARS-CoV-2 Infection and COVID-19 Outcomes in Patients With Gastrointestinal Symptoms.

Gastroenterology 2021 Mar 4. Epub 2021 Mar 4.

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; The Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Background & Aims: Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of COVID-19, we investigated intestinal infection with SARS-CoV-2, its effect on pathogenesis, and clinical significance.

Methods: Human intestinal biopsy tissues were obtained from patients with COVID-19 (n =19) and uninfected control individuals (n = 10) for microscopic examination, cytometry by time of flight analyses, and RNA sequencing. Additionally, disease severity and mortality were examined in patients with and without GI symptoms in 2 large, independent cohorts of hospitalized patients in the United States (n = 634) and Europe (n = 287) using multivariate logistic regressions.

Results: COVID-19 case patients and control individuals in the biopsy cohort were comparable for age, sex, rates of hospitalization, and relevant comorbid conditions. SARS-CoV-2 was detected in small intestinal epithelial cells by immunofluorescence staining or electron microscopy in 14 of 16 patients studied. High-dimensional analyses of GI tissues showed low levels of inflammation, including down-regulation of key inflammatory genes including IFNG, CXCL8, CXCL2, and IL1B and reduced frequencies of proinflammatory dendritic cells compared with control individuals. Consistent with these findings, we found a significant reduction in disease severity and mortality in patients presenting with GI symptoms that was independent of sex, age, and comorbid illnesses and despite similar nasopharyngeal SARS-CoV-2 viral loads. Furthermore, there was reduced levels of key inflammatory proteins in circulation in patients with GI symptoms.

Conclusions: These data highlight the absence of a proinflammatory response in the GI tract despite detection of SARS-CoV-2. In parallel, reduced mortality in patients with COVID-19 presenting with GI symptoms was observed. A potential role of the GI tract in attenuating SARS-CoV-2-associated inflammation needs to be further examined.
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http://dx.doi.org/10.1053/j.gastro.2021.02.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931673PMC
March 2021

Ecosystem engineering in the Quaternary of the West Coast of South Africa.

Evol Anthropol 2021 Jan 18;30(1):50-62. Epub 2021 Feb 18.

Department of Archaeology, University of Cape Town, Cape Town, South Africa.

Despite advances in our understanding of the geographic and temporal scope of the Paleolithic record, we know remarkably little about the evolutionary and ecological consequences of changes in human behavior. Recent inquiries suggest that human evolution reflects a long history of interconnections between the behavior of humans and their surrounding ecosystems (e.g., niche construction). Developing expectations to identify such phenomena is remarkably difficult because it requires understanding the multi-generational impacts of changes in behavior. These long-term dynamics require insights into the emergent phenomena that alter selective pressures over longer time periods which are not possible to observe, and are also not intuitive based on observations derived from ethnographic time scales. Generative models show promise for probing these potentially unexpected consequences of human-environment interaction. Changes in the uses of landscapes may have long term implications for the environments that hominins occupied. We explore other potential proxies of behavior and examine how modeling may provide expectations for a variety of phenomena.
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http://dx.doi.org/10.1002/evan.21886DOI Listing
January 2021

A global environmental crisis 42,000 years ago.

Science 2021 02;371(6531):811-818

Institute of Geography, Friedrich-Schiller-University Jena, 07743 Jena, Germany.

Geological archives record multiple reversals of Earth's magnetic poles, but the global impacts of these events, if any, remain unclear. Uncertain radiocarbon calibration has limited investigation of the potential effects of the last major magnetic inversion, known as the Laschamps Excursion [41 to 42 thousand years ago (ka)]. We use ancient New Zealand kauri trees () to develop a detailed record of atmospheric radiocarbon levels across the Laschamps Excursion. We precisely characterize the geomagnetic reversal and perform global chemistry-climate modeling and detailed radiocarbon dating of paleoenvironmental records to investigate impacts. We find that geomagnetic field minima ~42 ka, in combination with Grand Solar Minima, caused substantial changes in atmospheric ozone concentration and circulation, driving synchronous global climate shifts that caused major environmental changes, extinction events, and transformations in the archaeological record.
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http://dx.doi.org/10.1126/science.abb8677DOI Listing
February 2021

Identifying the true number of specimens of the extinct blue antelope (Hippotragus leucophaeus).

Sci Rep 2021 Jan 22;11(1):2100. Epub 2021 Jan 22.

Natural History Museum Vienna, Burgring 7, 1010, Vienna, Austria.

Native to southern Africa, the blue antelope (Hippotragus leucophaeus) is the only large African mammal species known to have become extinct in historical times. However, it was poorly documented prior to its extinction ~ 1800 AD, and many of the small number of museum specimens attributed to it are taxonomically contentious. This places limitations on our understanding of its morphology, ecology, and the mechanisms responsible for its demise. We retrieved genetic information from ten of the sixteen putative blue antelope museum specimens using both shotgun sequencing and mitochondrial genome target capture in an attempt to resolve the uncertainty surrounding the identification of these specimens. We found that only four of the ten investigated specimens, and not a single skull, represent the blue antelope. This indicates that the true number of historical museum specimens of the blue antelope is even smaller than previously thought, and therefore hardly any reference material is available for morphometric, comparative and genetic studies. Our study highlights how genetics can be used to identify rare species in natural history collections where other methods may fail or when records are scarce. Additionally, we present an improved mitochondrial reference genome for the blue antelope as well as one complete and two partial mitochondrial genomes. A first analysis of these mitochondrial genomes indicates low levels of maternal genetic diversity in the 'museum population', possibly confirming previous results that blue antelope population size was already low at the time of the European colonization of South Africa.
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http://dx.doi.org/10.1038/s41598-020-80142-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822880PMC
January 2021

Modeling dysbiosis of human NASH in mice: Loss of gut microbiome diversity and overgrowth of Erysipelotrichales.

PLoS One 2021 4;16(1):e0244763. Epub 2021 Jan 4.

Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.

Background & Aim: Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD) that is responsible for a growing fraction of cirrhosis and liver cancer cases worldwide. Changes in the gut microbiome have been implicated in NASH pathogenesis, but the lack of suitable murine models has been a barrier to progress. We have therefore characterized the microbiome in a well-validated murine NASH model to establish its value in modeling human disease.

Methods: The composition of intestinal microbiota was monitored in mice on a 12- or 24-week NASH protocol consisting of high fat, high sugar Western Diet (WD) plus once weekly i.p injection of low-dose CCl4. Additional mice were subjected to WD-only or CCl4-only conditions to assess the independent effect of these variables on the microbiome.

Results: There was substantial remodeling of the intestinal microbiome in NASH mice, characterized by declines in both species diversity and bacterial abundance. Based on changes to beta diversity, microbiota from NASH mice clustered separately from controls in principal coordinate analyses. A comparison between WD-only and CCl4-only controls with the NASH model identified WD as the primary driver of early changes to the microbiome, resulting in loss of diversity within the 1st week. A NASH signature emerged progressively at weeks 6 and 12, including, most notably, a reproducible bloom of the Firmicute order Erysipelotrichales.

Conclusions: We have established a valuable model to study the role of gut microbes in NASH, enabling us to identify a new NASH gut microbiome signature.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244763PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781477PMC
January 2021

Increased ecological resource variability during a critical transition in hominin evolution.

Sci Adv 2020 Oct 21;6(43). Epub 2020 Oct 21.

Lamont-Doherty Earth Observatory, Columbia University, Palisades, NY 10964, USA.

Although climate change is considered to have been a large-scale driver of African human evolution, landscape-scale shifts in ecological resources that may have shaped novel hominin adaptations are rarely investigated. We use well-dated, high-resolution, drill-core datasets to understand ecological dynamics associated with a major adaptive transition in the archeological record ~24 km from the coring site. Outcrops preserve evidence of the replacement of Acheulean by Middle Stone Age (MSA) technological, cognitive, and social innovations between 500 and 300 thousand years (ka) ago, contemporaneous with large-scale taxonomic and adaptive turnover in mammal herbivores. Beginning ~400 ka ago, tectonic, hydrological, and ecological changes combined to disrupt a relatively stable resource base, prompting fluctuations of increasing magnitude in freshwater availability, grassland communities, and woody plant cover. Interaction of these factors offers a resource-oriented hypothesis for the evolutionary success of MSA adaptations, which likely contributed to the ecological flexibility typical of foragers.
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http://dx.doi.org/10.1126/sciadv.abc8975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577727PMC
October 2020

Investigating Biotic Interactions in Deep Time.

Trends Ecol Evol 2021 01 13;36(1):61-75. Epub 2020 Oct 13.

School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, NE, USA.

Recent renewed interest in using fossil data to understand how biotic interactions have shaped the evolution of life is challenging the widely held assumption that long-term climate changes are the primary drivers of biodiversity change. New approaches go beyond traditional richness and co-occurrence studies to explicitly model biotic interactions using data on fossil and modern biodiversity. Important developments in three primary areas of research include analysis of (i) macroevolutionary rates, (ii) the impacts of and recovery from extinction events, and (iii) how humans (Homo sapiens) affected interactions among non-human species. We present multiple lines of evidence for an important and measurable role of biotic interactions in shaping the evolution of communities and lineages on long timescales.
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http://dx.doi.org/10.1016/j.tree.2020.09.001DOI Listing
January 2021

Gastrointestinal involvement attenuates COVID-19 severity and mortality.

medRxiv 2020 Sep 9. Epub 2020 Sep 9.

Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of coronavirus disease 2019 (COVID-19), we investigated the impact of GI infection on disease pathogenesis in three large cohorts of patients in the United States and Europe. Unexpectedly, we observed that GI involvement was associated with a significant reduction in disease severity and mortality, with an accompanying reduction in key inflammatory proteins including IL-6, CXCL8, IL-17A and CCL28 in circulation. In a fourth cohort of COVID-19 patients in which GI biopsies were obtained, we identified severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) within small intestinal enterocytes for the first time in vivo but failed to obtain culturable virus. High dimensional analyses of GI tissues confirmed low levels of cellular inflammation in the GI lamina propria and an active downregulation of key inflammatory genes including IFNG, CXCL8, CXCL2 and IL1B among others. These data draw attention to organ-level heterogeneity in disease pathogenesis and highlight the role of the GI tract in attenuating SARS-CoV-2-associated inflammation with related mortality benefit.
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http://dx.doi.org/10.1101/2020.09.07.20187666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491532PMC
September 2020

SARS-CoV-2-specific IgA and limited inflammatory cytokines are present in the stool of select patients with acute COVID-19.

medRxiv 2020 Sep 5. Epub 2020 Sep 5.

Background And Aims: Immune dysregulation caused by SARS-CoV-2 infection is thought to play a pathogenic role in COVID-19. SARS-CoV-2 can infect a variety of host cells, including intestinal epithelial cells. We sought to characterize the role of the gastrointestinal immune system in the pathogenesis of the inflammatory response associated with COVID-19.

Methods: We measured cytokines, inflammatory markers, viral RNA, microbiome composition and antibody responses in stool and serum samples from a prospectively enrolled cohort of 44 hospitalized COVID-19 patients.

Results: SARS-CoV-2 RNA was detected in stool of 41% of patients and was found more frequently in patients with diarrhea than those without (16[44%] vs 5[19%], p=0.06). Patients who survived had lower median viral genome copies than those who did not (p=0.021). Compared to uninfected controls, COVID-19 patients had higher median fecal levels of IL-8 (166.5 vs 286.5 pg/mg; p=0.05) and lower levels of fecal IL-10 (678 vs 194 pg/mg; p<0.001) compared to uninfected controls. Stool IL-23 was higher in patients with more severe COVID-19 disease (223.8 vs 86.6 pg/mg; p=0.03) and we find evidence of intestinal virus-specific IgA responses, which was associated with more severe disease. Fecal cytokines and calprotectin levels were not correlated with gastrointestinal symptoms or with the level of virus detected.

Conclusions: Although SARS-CoV-2 RNA was detectable in the stools of COVID-19 patients and select individuals had evidence for a specific mucosal IgA response, intestinal inflammation was limited, even in patients presenting with gastrointestinal symptoms.
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http://dx.doi.org/10.1101/2020.09.03.20183947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480054PMC
September 2020

Defined microbiota transplant restores Th17/RORγt regulatory T cell balance in mice colonized with inflammatory bowel disease microbiotas.

Proc Natl Acad Sci U S A 2020 09 18;117(35):21536-21545. Epub 2020 Aug 18.

The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;

The building evidence for the contribution of microbiota to human disease has spurred an effort to develop therapies that target the gut microbiota. This is particularly evident in inflammatory bowel diseases (IBDs), where clinical trials of fecal microbiota transplantation have shown some efficacy. To aid the development of novel microbiota-targeted therapies and to better understand the biology underpinning such treatments, we have used gnotobiotic mice to model microbiota manipulations in the context of microbiotas from humans with inflammatory bowel disease. Mice colonized with IBD donor-derived microbiotas exhibit a stereotypical set of phenotypes, characterized by abundant mucosal Th17 cells, a deficit in the tolerogenic RORγt regulatory T (Treg) cell subset, and susceptibility to disease in colitis models. Transplanting healthy donor-derived microbiotas into mice colonized with human IBD microbiotas led to induction of RORγt Treg cells, which was associated with an increase in the density of the microbiotas following transplant. Microbiota transplant reduced gut Th17 cells in mice colonized with a microbiota from a donor with Crohn's disease. By culturing strains from this microbiota and screening them in vivo, we identified a specific strain that potently induces Th17 cells. Microbiota transplants reduced the relative abundance of this strain in the gut microbiota, which was correlated with a reduction in Th17 cells and protection from colitis.
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http://dx.doi.org/10.1073/pnas.1922189117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474624PMC
September 2020

A Late Pleistocene human humerus from Rusinga Island, Lake Victoria, Kenya.

J Hum Evol 2020 09 8;146:102855. Epub 2020 Aug 8.

Department of Anthropology, University of Connecticut, 354 Mansfield Road, Storrs, CT, 06269, USA.

In 2010, a hominin right humerus fragment (KNM-RU 58330) was surface collected in a small gully at Nyamita North in the Late Pleistocene Wasiriya Beds of Rusinga Island, Kenya. A combination of stratigraphic and geochronological evidence suggests the specimen is likely between ∼49 and 36 ka in age. The associated fauna is diverse and dominated by semiarid grassland taxa. The small sample of associated Middle Stone Age artifacts includes Levallois flakes, cores, and retouched points. The 139 mm humeral fragment preserves the shaft from distal to the lesser tubercle to 14 mm below the distal end of the weakly projecting deltoid tuberosity. Key morphological features include a narrow and weakly marked pectoralis major insertion and a distinctive medial bend in the diaphysis at the deltoid insertion. This bend is unusual among recent human humeri but occurs in a few Late Pleistocene humeri. The dimensions of the distal end of the fragment predict a length of 317.9 ± 16.4 mm based on recent samples of African ancestry. A novel method of predicting humeral length from the distance between the middle of the pectoralis major and the bottom of the deltoid insertion predicts a length of 317.3 mm ± 17.6 mm. Cross-sectional geometry at the midshaft shows a relatively high percentage of cortical bone and a moderate degree of flattening of the shaft. The Nyamita humerus is anatomically modern in its morphology and adds to the small sample of hominins from the Late Pleistocene associated with Middle Stone Age artifacts known from East Africa. It may sample a population closely related to the people of the out-of-Africa migration.
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http://dx.doi.org/10.1016/j.jhevol.2020.102855DOI Listing
September 2020

Gut T cell-independent IgA responses to commensal bacteria require engagement of the TACI receptor on B cells.

Sci Immunol 2020 07;5(49)

Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

The gut mounts secretory immunoglobulin A (SIgA) responses to commensal bacteria through nonredundant T cell-dependent (TD) and T cell-independent (TI) pathways that promote the establishment of mutualistic host-microbiota interactions. SIgAs from the TD pathway target penetrant bacteria, and their induction requires engagement of CD40 on B cells by CD40 ligand on T follicular helper cells. In contrast, SIgAs from the TI pathway bind a larger spectrum of bacteria, but the mechanism underpinning their production remains elusive. Here, we show that the intestinal TI pathway required CD40-independent B cell-activating signals from TACI, a receptor for the innate CD40 ligand-like factors BAFF and APRIL. TACI-induced SIgA responses targeted a fraction of the gut microbiota without shaping its overall composition. Of note, TACI was dispensable for TD induction of IgA in gut-associated lymphoid organs. Thus, BAFF/APRIL signals acting on TACI orchestrate commensal bacteria-specific SIgA responses through an intestinal TI program.
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http://dx.doi.org/10.1126/sciimmunol.aat7117DOI Listing
July 2020

Fungal Trans-kingdom Dynamics Linked to Responsiveness to Fecal Microbiota Transplantation (FMT) Therapy in Ulcerative Colitis.

Cell Host Microbe 2020 05 15;27(5):823-829.e3. Epub 2020 Apr 15.

Gastroenterology and Hepatology Division, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA; The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA. Electronic address:

Fecal microbiota transplantation (FMT) targeting gut microbiota has recently been successfully applied to ulcerative colitis. However, only a subset of patients responds to FMT, and there is a pressing need for biomarkers of responsiveness. Fungi (the mycobiota) represent a highly immunologically reactive component of the gut microbiota. We analyzed samples from a large randomized controlled trial of FMT for ulcerative colitis (UC). High Candida abundance pre-FMT was associated with a clinical response, whereas decreased Candida abundance post-FMT was indicative of ameliorated disease severity. High pre-FMT Candida was associated with increased bacterial diversity post-FMT, and the presence of genera was linked to FMT responsiveness. Although we detected elevated anti-Candida antibodies in placebo recipients, this increase was abrogated in FMT recipients. Our data suggest that FMT might reduce Candida to contain pro-inflammatory immunity during intestinal disease and highlight the utility of mycobiota-focused approaches to identify FMT responders prior to therapy initiation.
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http://dx.doi.org/10.1016/j.chom.2020.03.006DOI Listing
May 2020

Fecal IgA Levels Are Determined by Strain-Level Differences in Bacteroides ovatus and Are Modifiable by Gut Microbiota Manipulation.

Cell Host Microbe 2020 Mar 18;27(3):467-475.e6. Epub 2020 Feb 18.

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

Fecal IgA production depends on colonization by a gut microbiota. However, the bacterial strains that drive gut IgA production remain largely unknown. Here, we assessed the IgA-inducing capacity of a diverse set of human gut microbial strains by monocolonizing mice with each strain. We identified Bacteroides ovatus as the species that best induced gut IgA production. However, this induction varied bimodally across different B. ovatus strains. The high IgA-inducing B. ovatus strains preferentially elicited more IgA production in the large intestine through the T cell-dependent B cell-activation pathway. Remarkably, a low-IgA phenotype in mice could be robustly and consistently converted into a high-IgA phenotype by transplanting a multiplex cocktail of high IgA-inducing B. ovatus strains but not individual ones. Our results highlight the critical importance of microbial strains in driving phenotype variation in the mucosal immune system and provide a strategy to robustly modify a gut immune phenotype, including IgA production.
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http://dx.doi.org/10.1016/j.chom.2020.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213796PMC
March 2020

Reply to Weihmann: Fifty gazelles do not equal an elephant, and other ecological misunderstandings.

Proc Natl Acad Sci U S A 2020 02 4;117(7):3370-3371. Epub 2020 Feb 4.

Department of Anthropology and Geography, Colorado State University, Fort Collins, CO 80523.

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http://dx.doi.org/10.1073/pnas.1920565117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035609PMC
February 2020

Human Primordial Germ Cells Are Specified from Lineage-Primed Progenitors.

Cell Rep 2019 12;29(13):4568-4582.e5

Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

In vitro gametogenesis is the process of making germline cells from human pluripotent stem cells. The foundation of this model is the quality of the first progenitors called primordial germ cells (PGCs), which in vivo are specified during the peri-implantation window of human development. Here, we show that human PGC (hPGC) specification begins at day 12 post-fertilization. Using single-cell RNA sequencing of hPGC-like cells (hPGCLCs) differentiated from pluripotent stem cells, we discovered that hPGCLC specification involves resetting pluripotency toward a transitional state with shared characteristics between naive and primed pluripotency, followed by differentiation into lineage-primed TFAP2A progenitors. Applying the germline trajectory to TFAP2C mutants reveals that TFAP2C functions in the TFAP2A progenitors upstream of PRDM1 to regulate the expression of SOX17. This serves to protect hPGCLCs from crossing the Weismann's barrier to adopt somatic cell fates and, therefore, is an essential mechanism for successfully initiating in vitro gametogenesis.
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http://dx.doi.org/10.1016/j.celrep.2019.11.083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939677PMC
December 2019

Micro Methods for Megafauna: Novel Approaches to Late Quaternary Extinctions and Their Contributions to Faunal Conservation in the Anthropocene.

Bioscience 2019 Nov 2;69(11):877-887. Epub 2019 Oct 2.

Department of Archaeology, Max Planck Institute for the Science of Human History, Jena, Germany.

Drivers of Late Quaternary megafaunal extinctions are relevant to modern conservation policy in a world of growing human population density, climate change, and faunal decline. Traditional debates tend toward global solutions, blaming either dramatic climate change or dispersals of Homo sapiens to new regions. Inherent limitations to archaeological and paleontological data sets often require reliance on scant, poorly resolved lines of evidence. However, recent developments in scientific technologies allow for more local, context-specific approaches. In the present article, we highlight how developments in five such methodologies (radiocarbon approaches, stable isotope analysis, ancient DNA, ancient proteomics, microscopy) have helped drive detailed analysis of specific megafaunal species, their particular ecological settings, and responses to new competitors or predators, climate change, and other external phenomena. The detailed case studies of faunal community composition, extinction chronologies, and demographic trends enabled by these methods examine megafaunal extinctions at scales appropriate for practical understanding of threats against particular species in their habitats today.
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http://dx.doi.org/10.1093/biosci/biz105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829010PMC
November 2019

Reorganization of surviving mammal communities after the end-Pleistocene megafaunal extinction.

Science 2019 09;365(6459):1305-1308

Department of Biological Sciences, Macquarie University, New South Wales 2109, Australia.

Large mammals are at high risk of extinction globally. To understand the consequences of their demise for community assembly, we tracked community structure through the end-Pleistocene megafaunal extinction in North America. We decomposed the effects of biotic and abiotic factors by analyzing co-occurrence within the mutual ranges of species pairs. Although shifting climate drove an increase in niche overlap, co-occurrence decreased, signaling shifts in biotic interactions. Furthermore, the effect of abiotic factors on co-occurrence remained constant over time while the effect of biotic factors decreased. Biotic factors apparently played a key role in continental-scale community assembly before the extinctions. Specifically, large mammals likely promoted co-occurrence in the Pleistocene, and their loss contributed to the modern assembly pattern in which co-occurrence frequently falls below random expectations.
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http://dx.doi.org/10.1126/science.aaw1605DOI Listing
September 2019

Early hominins evolved within non-analog ecosystems.

Proc Natl Acad Sci U S A 2019 10 7;116(43):21478-21483. Epub 2019 Oct 7.

Department of Anthropology and Geography, Colorado State University, Fort Collins, CO 80523.

Present-day African ecosystems serve as referential models for conceptualizing the environmental context of early hominin evolution, but the degree to which modern ecosystems are representative of those in the past is unclear. A growing body of evidence from eastern Africa's rich and well-dated late Cenozoic fossil record documents communities of large-bodied mammalian herbivores with ecological structures differing dramatically from those of the present day, implying that modern communities may not be suitable analogs for the ancient ecosystems of hominin evolution. To determine when and why the ecological structure of eastern Africa's herbivore faunas came to resemble those of the present, here we analyze functional trait changes in a comprehensive dataset of 305 modern and fossil herbivore communities spanning the last ∼7 Myr. We show that nearly all communities prior to ∼700 ka were functionally non-analog, largely due to a greater richness of non-ruminants and megaherbivores (species >1,000 kg). The emergence of functionally modern communities precedes that of taxonomically modern communities by 100,000s of years, and can be attributed to the combined influence of Plio-Pleistocene C grassland expansion and pulses of aridity after ∼1 Ma. Given the disproportionate ecological impacts of large-bodied herbivores on factors such as vegetation structure, hydrology, and fire regimes, it follows that the vast majority of early hominin evolution transpired in the context of ecosystems that functioned unlike any today. Identifying how past ecosystems differed compositionally and functionally from those today is key to conceptualizing ancient African environments and testing ecological hypotheses of hominin evolution.
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http://dx.doi.org/10.1073/pnas.1909284116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815188PMC
October 2019

Interleukin 22 disrupts pancreatic function in newborn mice expressing IL-23.

Nat Commun 2019 10 4;10(1):4517. Epub 2019 Oct 4.

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Neonatal inflammatory diseases are associated with severe morbidity, but the inflammatory factors underlying them and their potential effector mechanisms are poorly defined. Here we show that necrotizing enterocolitis in neonate mice is accompanied by elevation of IL-23 and IL-22 and decreased production of pancreatic enzymes. These phenotypes are mirrored in neonate mice overexpressing IL-23 in CX3CR1 myeloid cells or in keratinocytes. The mice fail to grow and die prematurely, displaying systemic inflammation, nutrient malabsorption and decreased expression of intestinal and pancreatic genes mediating digestion and absorption of carbohydrates, proteins, and lipids. Germ-free environment improves, and genetic ablation of IL-22 restores normal growth in mice overexpressing IL-23. Mechanistically, IL-22 acts directly at the level of pancreatic acinar cells to decrease expression of the pancreas associated transcription factor 1a (PTF1a). These results show that augmented production of IL-23 and IL-22 in early life has a negative impact on pancreatic enzyme secretion and food absorption.
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http://dx.doi.org/10.1038/s41467-019-12540-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778080PMC
October 2019

Challenges in IBD Research: Preclinical Human IBD Mechanisms.

Inflamm Bowel Dis 2019 05;25(Suppl 2):S5-S12

University of Chicago, Chicago, IL, USA.

Preclinical human IBD mechanisms is part of five focus areas of the Challenges in IBD research document, which also include environmental triggers, novel technologies, precision medicine and pragmatic clinical research. The Challenges in IBD research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of a multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the preclinical human IBD mechanisms manuscript is focused on highlighting the main research gaps in the pathophysiological understanding of human IBD. These research gap areas include: 1) triggers of immune responses; 2) intestinal epithelial homeostasis and wound repair; 3) age-specific pathophysiology; 4) disease complications; 5) heterogeneous response to treatments; and 6) determination of disease location. As an approach to address these research gaps, the prioritization of reverse translation studies is proposed in which clinical observations are the foundation for experimental IBD research in the lab, and for the identification of new therapeutic targets and biomarkers. The use of human samples in validating basic research findings and development of precision medicine solutions is also proposed. This prioritization aims to put emphasis on relevant biochemical pathways and humanized in vitro and in vivo models that extrapolate meaningfully to human IBD, to eventually yield first-in-class and effective therapies.
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http://dx.doi.org/10.1093/ibd/izz075DOI Listing
May 2019

Small intestinal microbial dysbiosis underlies symptoms associated with functional gastrointestinal disorders.

Nat Commun 2019 05 1;10(1):2012. Epub 2019 May 1.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55902, USA.

Small intestinal bacterial overgrowth (SIBO) has been implicated in symptoms associated with functional gastrointestinal disorders (FGIDs), though mechanisms remain poorly defined and treatment involves non-specific antibiotics. Here we show that SIBO based on duodenal aspirate culture reflects an overgrowth of anaerobes, does not correspond with patient symptoms, and may be a result of dietary preferences. Small intestinal microbial composition, on the other hand, is significantly altered in symptomatic patients and does not correspond with aspirate culture results. In a pilot interventional study we found that switching from a high fiber diet to a low fiber, high simple sugar diet triggered FGID-related symptoms and decreased small intestinal microbial diversity while increasing small intestinal permeability. Our findings demonstrate that characterizing small intestinal microbiomes in patients with gastrointestinal symptoms may allow a more targeted antibacterial or a diet-based approach to treatment.
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http://dx.doi.org/10.1038/s41467-019-09964-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494866PMC
May 2019

Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice.

Gut 2020 01 29;69(1):42-51. Epub 2019 Apr 29.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.

Background And Aims: Prenatal and early life bacterial colonisation is thought to play a major role in shaping the immune system. Furthermore, accumulating evidence links early life exposures to the risk of developing IBD later in life. We aimed to assess the effect of maternal IBD on the composition of the microbiome during pregnancy and on the offspring's microbiome.

Methods: We prospectively examined the diversity and taxonomy of the microbiome of pregnant women with and without IBD and their babies at multiple time points. We evaluated the role of maternal IBD diagnosis, the mode of delivery, antibiotic use and feeding behaviour on the microbiome composition during early life. To assess the effects of IBD-associated maternal and infant microbiota on the enteric immune system, we inoculated germ-free mice (GFM) with the respective stool and profiled adaptive and innate immune cell populations in the murine intestines.

Results: Pregnant women with IBD and their offspring presented with lower bacterial diversity and altered bacterial composition compared with control women and their babies. Maternal IBD was the main predictor of the microbiota diversity in the infant gut at 7, 14, 30, 60 and 90 days of life. Babies born to mothers with IBD demonstrated enrichment in and depletion in . Finally, GFM inoculated with third trimester IBD mother and 90-day infant stools showed significantly reduced microbial diversity and fewer class-switched memory B cells and regulatory T cells in the colon.

Conclusion: Aberrant gut microbiota composition persists during pregnancy with IBD and alters the bacterial diversity and abundance in the infant stool. The dysbiotic microbiota triggered abnormal imprinting of the intestinal immune system in GFM.
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http://dx.doi.org/10.1136/gutjnl-2018-317855DOI Listing
January 2020

Microbial Engraftment and Efficacy of Fecal Microbiota Transplant for Clostridium Difficile in Patients With and Without Inflammatory Bowel Disease.

Inflamm Bowel Dis 2019 05;25(6):969-979

Icahn Institute for Genomics & Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York NY, USA.

Background: Recurrent and severe Clostridium difficile infections (CDI) are treated with fecal microbiota transplant (FMT). Uncertainty exists regarding FMT effectiveness for CDI with underlying inflammatory bowel disease (IBD) and regarding its effects on disease activity and effectiveness in transferring the donor microbiota to patients with and without IBD.

Methods: Subjects with and without IBD who underwent FMT for recurrent or severe CDI between 2013 and 2016 at The Mount Sinai Hospital were followed for up to 6 months. The primary outcome was CDI recurrence 6 months after FMT. Secondary outcomes were (1) CDI recurrence 2 months after FMT; (2) frequency of IBD flare after FMT; (3) microbiota engraftment after FMT; (and 4) predictors of CDI recurrence.

Results: One hundred thirty-four patients, 46 with IBD, were treated with FMT. Follow-up was available in 83 and 118 patients at 6 and 2 months, respectively. There was no difference in recurrence in patients with and without IBD at 6 months (38.7% vs 36.5%; P > 0.99) and 2 months (22.5% vs 17.9%; P = 0.63). Proton pump inhibitor use, severe CDI, and comorbid conditions were predictors of recurrence. Pre-FMT microbiota was not predictive of CDI recurrence. Subjects with active disease requiring medication escalation had reduced engraftment, with no difference in engraftment based on CDI recurrence or IBD endoscopic severity at FMT.

Conclusions: Inflammatory bowel disease did not affect CDI recurrence rates 6 months after FMT. Pre-FMT microbiota was not predictive of recurrence, and microbial engraftment was impacted in those requiring IBD treatment escalation, though not by CDI recurrence or IBD disease severity.
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http://dx.doi.org/10.1093/ibd/izy398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499938PMC
May 2019

The gut microbiota composition affects dietary polyphenols-mediated cognitive resilience in mice by modulating the bioavailability of phenolic acids.

Sci Rep 2019 03 5;9(1):3546. Epub 2019 Mar 5.

Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, 10029, New York, USA.

Dietary polyphenols promote memory in models of sleep deprivation (SD), stress, and neurodegeneration. The biological properties of dietary polyphenols greatly depend upon the bioavailability of their phenolic metabolites derivatives, which are modulated by gut microbiota. We recently demonstrated that supplementation with grape-derived bioactive dietary polyphenol preparation (BDPP) improves SD-induced cognitive impairment. This study examined the role of the gut microbiota in the ability of BDPP to prevent memory impairment in response to SD. C57BL6/J mice, treated with antibiotics mix (ABX) or BDPP or both, were sleep-deprived at the end of a fear conditioning training session and fear memory was assessed the next day. Gut microbiota composition was analyzed in fecal samples and BDPP-driven phenolic acid metabolites extraction was measured in plasma. We report that the beneficial effect of BDPP on memory in SD is attenuated by ABX-induced dysbiosis. We identified specific communities of fecal microbiota that are associated with the bioavailability of BDPP-derived phenolic acids, which in turn, are associated with memory promotion. These results suggest the gut microbiota composition significantly affects the bioavailability of phenolic acids that drive the dietary polyphenols' cognitive resilience property. Our findings provide a preclinical model with which to test the causal association of gut microbiota-polyphenols, with the ultimate goal of potential developing dietary polyphenols for the prevention/treatment of cognitive impairment.
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http://dx.doi.org/10.1038/s41598-019-39994-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401062PMC
March 2019

Gut microbiota density influences host physiology and is shaped by host and microbial factors.

Elife 2019 01 22;8. Epub 2019 Jan 22.

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, United States.

To identify factors that regulate gut microbiota density and the impact of varied microbiota density on health, we assayed this fundamental ecosystem property in fecal samples across mammals, human disease, and therapeutic interventions. Physiologic features of the host (carrying capacity) and the fitness of the gut microbiota shape microbiota density. Therapeutic manipulation of microbiota density in mice altered host metabolic and immune homeostasis. In humans, gut microbiota density was reduced in Crohn's disease, ulcerative colitis, and ileal pouch-anal anastomosis. The gut microbiota in recurrent infection had lower density and reduced fitness that were restored by fecal microbiota transplantation. Understanding the interplay between microbiota and disease in terms of microbiota density, host carrying capacity, and microbiota fitness provide new insights into microbiome structure and microbiome targeted therapeutics.

Editorial Note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
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http://dx.doi.org/10.7554/eLife.40553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342524PMC
January 2019

Microbiotas from Humans with Inflammatory Bowel Disease Alter the Balance of Gut Th17 and RORγt Regulatory T Cells and Exacerbate Colitis in Mice.

Immunity 2019 01;50(1):212-224.e4

Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Microbiota are thought to influence the development and progression of inflammatory bowel disease (IBD), but determining generalizable effects of microbiota on IBD etiology requires larger-scale functional analyses. We colonized germ-free mice with intestinal microbiotas from 30 healthy and IBD donors and determined the homeostatic intestinal T cell response to each microbiota. Compared to microbiotas from healthy donors, transfer of IBD microbiotas into germ-free mice increased numbers of intestinal Th17 cells and Th2 cells and decreased numbers of RORγt Treg cells. Colonization with IBD microbiotas exacerbated disease in a model where colitis is induced upon transfer of naive T cells into Rag1 mice. The proportions of Th17 and RORγt Treg cells induced by each microbiota were predictive of human disease status and accounted for disease severity in the Rag1 colitis model. Thus, an impact on intestinal Th17 and RORγt Treg cell compartments emerges as a unifying feature of IBD microbiotas, suggesting a general mechanism for microbial contribution to IBD pathogenesis.
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http://dx.doi.org/10.1016/j.immuni.2018.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512335PMC
January 2019

Heterogeneity in gut microbiota drive polyphenol metabolism that influences α-synuclein misfolding and toxicity.

J Nutr Biochem 2019 02 14;64:170-181. Epub 2018 Nov 14.

Department of Neurology, Icahn School of Medicine at Mount Sinai, NY, New York, USA 10029; Geriatric Research, Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, Bronx, New York, USA 10468. Electronic address:

The intestinal microbiota actively converts dietary flavanols into phenolic acids, some of which are bioavailable in vivo and may promote resilience to select neurological disorders by interfering with key pathologic mechanisms. Since every person harbors a unique set of gut bacteria, we investigated the influence of the gut microbiota's interpersonal heterogeneity on the production and bioavailability of flavonoid metabolites that may interfere with the misfolding of alpha (α)-synuclein, a process that plays a central role in Parkinson's disease and other α-synucleinopathies. We generated two experimental groups of humanized gnotobiotic mice with compositionally diverse gut bacteria and orally treated the mice with a flavanol-rich preparation (FRP). The two gnotobiotic mouse groups exhibited distinct differences in the generation and bioavailability of FRP-derived microbial phenolic acid metabolites that have bioactivity towards interfering with α-synuclein misfolding or inflammation. We also demonstrated that these bioactive phenolic acids are effective in modulating the development and progression of motor dysfunction in a Drosophila model of α-synucleinopathy. Lastly, through in vitro bacterial fermentation studies, we identified select bacteria that are capable of supporting the generation of these bioavailable and bioactive phenolic acids. Outcomes from our studies provide a better understanding of how interpersonal heterogeneity in the gut microbiota differentially modulates the efficacy of dietary flavanols to protect against select pathologic mechanisms. Collectively, our findings provide the basis for future developments of probiotic, prebiotic, or synbiotic approaches for modulating the onset and/or progression of α-synucleinopathies and other neurological disorders involving protein misfolding and/or inflammation.
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http://dx.doi.org/10.1016/j.jnutbio.2018.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363841PMC
February 2019