Sean Paul Spencer, MD,PhD

All Publications

• Profiling the human intestinal environment under physiological conditions. Nature Shalon, D., Culver, R. N., Grembi, J. A., Folz, J., Treit, P. V., Shi, H., Rosenberger, F. A., Dethlefsen, L., Meng, X., Yaffe, E., Aranda-Diaz, A., Geyer, P. E., Mueller-Reif, J. B., Spencer, S., Patterson, A. D., Triadafilopoulos, G., Holmes, S. P., Mann, M., Fiehn, O., Relman, D. A., Huang, K. C. 2023

  Abstract

  The spatiotemporal structure of the human microbiome1,2, proteome3 and metabolome4,5 reflects and determines regional intestinal physiology and may have implications for disease6. Yet, little is known about the distribution of microorganisms, their environment and their biochemical activity in the gut because of reliance on stool samples and limited access to only some regions of the gut using endoscopy in fasting or sedated individuals7. To address these deficiencies, we developed an ingestible device that collects samples from multiple regions of the human intestinal tract during normal digestion. Collection of 240 intestinal samples from 15 healthy individuals using the device and subsequent multi-omics analyses identified significant differences between bacteria, phages, host proteins and metabolites in the intestines versus stool. Certain microbial taxa were differentially enriched and prophage induction was more prevalent in the intestines than in stool. The host proteome and bile acid profiles varied along the intestines and were highly distinct from those of stool. Correlations between gradients in bile acid concentrations and microbial abundance predicted species that altered the bile acid pool through deconjugation. Furthermore, microbially conjugated bile acid concentrations exhibited amino acid-dependent trends that were not apparent in stool. Overall, non-invasive, longitudinal profiling of microorganisms, proteins and bile acids along the intestinal tract under physiological conditions can help elucidate the roles of the gut microbiome and metabolome in human physiology and disease.

  View details for DOI 10.1038/s41586-023-05989-7

  View details for PubMedID 37165188

• Impact of a 7-day homogeneous diet on interpersonal variation in human gut microbiomes and metabolomes. Cell host & microbe Guthrie, L., Spencer, S. P., Perelman, D., Van Treuren, W., Han, S., Yu, F. B., Sonnenburg, E. D., Fischbach, M. A., Meyer, T. W., Sonnenburg, J. L. 2022

  Abstract

  Gut microbiota metabolism of dietary compounds generates a vast array of microbiome-dependent metabolites (MDMs), which are highly variable between individuals. The uremic MDMs (uMDMs) phenylacetylglutamine (PAG), p-cresol sulfate (PCS), and indoxyl sulfate (IS) accumulate during renal failure and are associated with poor outcomes. Targeted dietary interventions may reduce toxic MDM generation; however, it is unclear if inter-individual differences in diet or gut microbiome dominantly contribute to MDM variance. Here, we use a 7-day homogeneous average American diet to standardize dietary precursor availability in 21 healthy individuals. During dietary homogeneity, the coefficient of variation in PAG, PCS, and IS (primary outcome) did not decrease, nor did inter-individual variation in most identified metabolites; other microbiome metrics showed no or modest responses to the intervention. Host identity and age are dominant contributors to variability in MDMs. These results highlight the potential need to pair dietary modification with microbial therapies to control MDM profiles.

  View details for DOI 10.1016/j.chom.2022.05.003

  View details for PubMedID 35643079

• Pursuing Human-Relevant Gut Microbiota-Immune Interactions. Immunity Spencer, S. P., Fragiadakis, G. K., Sonnenburg, J. L. 2019; 51 (2): 225–39

  Abstract

  The gut microbiota is a complex and plastic network of diverse organisms intricately connected with human physiology. Recent advances in profiling approaches of both the microbiota and the immune system now enable a deeper exploration of immunity-microbiota connections. An important next step is to elucidate a human-relevant "map" of microbial-immune wiring while focusing on animal studies to probe a prioritized subset of interactions. Here, we provide an overview of this field's current status and discuss two approaches for establishing priorities for detailed investigation: (1) longitudinal intervention studies in humans probing the dynamics of both the microbiota and the immune system and (2) the study of traditional populations to assess lost features of human microbial identity whose absence may be contributing to the rise of immunological disorders. These human-centered approaches offer a judicious path forward to understand the impact of the microbiota in immune development and function.

  View details for DOI 10.1016/j.immuni.2019.08.002

  View details for PubMedID 31433970

• The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan. Nature Kotzin, J. J., Spencer, S. P., McCright, S. J., Kumar, D. B., Collet, M. A., Mowel, W. K., Elliott, E. N., Uyar, A., Makiya, M. A., Dunagin, M. C., Harman, C. C., Virtue, A. T., Zhu, S., Bailis, W., Stein, J., Hughes, C., Raj, A., Wherry, E. J., Goff, L. A., Klion, A. D., Rinn, J. L., Williams, A., Flavell, R. A., Henao-Mejia, J. 2016; 537 (7619): 239-243

  Abstract

  Neutrophils, eosinophils and 'classical' monocytes collectively account for about 70% of human blood leukocytes and are among the shortest-lived cells in the body. Precise regulation of the lifespan of these myeloid cells is critical to maintain protective immune responses and minimize the deleterious consequences of prolonged inflammation. However, how the lifespan of these cells is strictly controlled remains largely unknown. Here we identify a long non-coding RNA that we termed Morrbid, which tightly controls the survival of neutrophils, eosinophils and classical monocytes in response to pro-survival cytokines in mice. To control the lifespan of these cells, Morrbid regulates the transcription of the neighbouring pro-apoptotic gene, Bcl2l11 (also known as Bim), by promoting the enrichment of the PRC2 complex at the Bcl2l11 promoter to maintain this gene in a poised state. Notably, Morrbid regulates this process in cis, enabling allele-specific control of Bcl2l11 transcription. Thus, in these highly inflammatory cells, changes in Morrbid levels provide a locus-specific regulatory mechanism that allows rapid control of apoptosis in response to extracellular pro-survival signals. As MORRBID is present in humans and dysregulated in individuals with hypereosinophilic syndrome, this long non-coding RNA may represent a potential therapeutic target for inflammatory disorders characterized by aberrant short-lived myeloid cell lifespan.

  View details for DOI 10.1038/nature19346

  View details for PubMedID 27525555

  View details for PubMedCentralID PMC5161578

• Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science (New York, N.Y.) Spencer, S. P., Wilhelm, C., Yang, Q., Hall, J. A., Bouladoux, N., Boyd, A., Nutman, T. B., Urban, J. F., Wang, J., Ramalingam, T. R., Bhandoola, A., Wynn, T. A., Belkaid, Y. 2014; 343 (6169): 432-7

  Abstract

  How the immune system adapts to malnutrition to sustain immunity at barrier surfaces, such as the intestine, remains unclear. Vitamin A deficiency is one of the most common micronutrient deficiencies and is associated with profound defects in adaptive immunity. Here, we found that type 3 innate lymphoid cells (ILC3s) are severely diminished in vitamin A-deficient settings, which results in compromised immunity to acute bacterial infection. However, vitamin A deprivation paradoxically resulted in dramatic expansion of interleukin-13 (IL-13)-producing ILC2s and resistance to nematode infection in mice, which revealed that ILCs are primary sensors of dietary stress. Further, these data indicate that, during malnutrition, a switch to innate type 2 immunity may represent a powerful adaptation of the immune system to promote host survival in the face of ongoing barrier challenges.

  View details for DOI 10.1126/science.1247606

  View details for PubMedID 24458645

  View details for PubMedCentralID PMC4313730

• Dietary and commensal derived nutrients: shaping mucosal and systemic immunity. Current opinion in immunology Spencer, S. P., Belkaid, Y. 2012; 24 (4): 379-84

  Abstract

  The intestine serves as the primary site of nutrient absorption in the body while also harboring the highest burden of commensal microflora and representing a major portal of pathogen exposure. As such, the immune network of the intestine relies on both dietary and commensal derived signals to guide appropriate function. Recent advances highlight the role of dietary derived nutrients and commensal derived metabolites in shaping gastrointestinal immunity. In particular, vitamin A has been shown to have dominant and pleiotropic effects in the intestine. In addition, dietary derived AHR ligands and commensal derived metabolites are now emerging as important players in mucosal immunity. Thus nutrition, commensal microflora and the mucosal immune system are all intimately connected.

  View details for DOI 10.1016/j.coi.2012.07.006

  View details for PubMedID 22857854

  View details for PubMedCentralID PMC3431603

• CH4, H2S, and H2O: How Do They Relate to Microbiome-Driven IBS Pathogenesis? Digestive diseases and sciences Spencer, S. 2023

  View details for DOI 10.1007/s10620-023-08198-4

  View details for PubMedID 38060166

• Metagenomic Immunoglobulin Sequencing (MIG-Seq) Exposes Patterns of IgA Antibody Binding in the Healthy Human Gut Microbiome. bioRxiv : the preprint server for biology Olm, M. R., Spencer, S. P., Silva, E. L., Sonnenburg, J. L. 2023

  Abstract

  IgA, the most highly produced human antibody, is continually secreted into the gut to shape the intestinal microbiota. Methodological limitations have critically hindered defining which microbial strains are targeted by IgA and why. Here, we develop a new technique, Metagenomic Immunoglobulin Sequencing (MIG-Seq), and use it to determine IgA coating levels for thousands of gut microbiome strains in healthy humans. We find that microbes associated with both health and disease have higher levels of coating, and that microbial genes are highly predictive of IgA binding levels, with mucus degradation genes especially correlated with high binding. We find a significant reduction in replication rates among microbes bound by IgA, and demonstrate that IgA binding is more correlated with host immune status than traditional microbial abundance measures. This study introduces a powerful technique for assessing strain-level IgA binding in human stool, paving the way for deeper understanding of IgA-based host microbe interactions.

  View details for DOI 10.1101/2023.11.21.568153

  View details for PubMedID 38045399

• Cromolyn Reduces Symptoms in Patients With Irritable Bowel Syndrome, Functional Dyspepsia, or Gastroparesis Karhu, E., Linda Anh Nguyen, Sonu, I., Neshatian, L., Gottfried-Blackmore, A., Fernandez-Becker, N., Spencer, S. LIPPINCOTT WILLIAMS & WILKINS. 2023: S492

  View details for Web of Science ID 001091849301218

• Ultra-deep sequencing of Hadza hunter-gatherers recovers vanishing gut microbes. Cell Carter, M. M., Olm, M. R., Merrill, B. D., Dahan, D., Tripathi, S., Spencer, S. P., Yu, F. B., Jain, S., Neff, N., Jha, A. R., Sonnenburg, E. D., Sonnenburg, J. L. 2023

  Abstract

  The gut microbiome modulates immune and metabolic health. Human microbiome data are biased toward industrialized populations, limiting our understanding of non-industrialized microbiomes. Here, we performed ultra-deep metagenomic sequencing on 351 fecal samples from the Hadza hunter-gatherers of Tanzania and comparative populations in Nepal and California. We recovered 91,662 genomes of bacteria, archaea, bacteriophages, and eukaryotes, 44% of which are absent from existing unified datasets. We identified 124 gut-resident species vanishing in industrialized populations and highlighted distinct aspects of the Hadza gut microbiome related to in situ replication rates, signatures of selection, and strain sharing. Industrialized gut microbes were found to be enriched in genes associated with oxidative stress, possibly a result of microbiome adaptation to inflammatory processes. This unparalleled view of the Hadza gut microbiome provides a valuable resource, expands our understanding of microbes capable of colonizing the human gut, and clarifies the extensive perturbation induced by the industrialized lifestyle.

  View details for DOI 10.1016/j.cell.2023.05.046

  View details for PubMedID 37348505

• Ultra-deep Sequencing of Hadza Hunter-Gatherers Recovers Vanishing Gut Microbes. bioRxiv : the preprint server for biology Merrill, B. D., Carter, M. M., Olm, M. R., Dahan, D., Tripathi, S., Spencer, S. P., Yu, B., Jain, S., Neff, N., Jha, A. R., Sonnenburg, E. D., Sonnenburg, J. L. 2022

  Abstract

  The gut microbiome is a key modulator of immune and metabolic health. Human microbiome data is biased towards industrialized populations, providing limited understanding of the distinct and diverse non-industrialized microbiomes. Here, we performed ultra-deep metagenomic sequencing and strain cultivation on 351 fecal samples from the Hadza, hunter-gatherers in Tanzania, and comparative populations in Nepal and California. We recover 94,971 total genomes of bacteria, archaea, bacteriophages, and eukaryotes, 43% of which are absent from existing unified datasets. Analysis of in situ growth rates, genetic pN/pS signatures, high-resolution strain tracking, and 124 gut-resident species vanishing in industrialized populations reveals differentiating dynamics of the Hadza gut microbiome. Industrialized gut microbes are enriched in genes associated with oxidative stress, possibly a result of microbiome adaptation to inflammatory processes. This unparalleled view of the Hadza gut microbiome provides a valuable resource that expands our understanding of microbes capable of colonizing the human gut and clarifies the extensive perturbation brought on by the industrialized lifestyle.

  View details for DOI 10.1101/2022.03.30.486478

  View details for PubMedID 36238714

• The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans. Science (New York, N.Y.) Jones, R. C., Karkanias, J., Krasnow, M. A., Pisco, A. O., Quake, S. R., Salzman, J., Yosef, N., Bulthaup, B., Brown, P., Harper, W., Hemenez, M., Ponnusamy, R., Salehi, A., Sanagavarapu, B. A., Spallino, E., Aaron, K. A., Concepcion, W., Gardner, J. M., Kelly, B., Neidlinger, N., Wang, Z., Crasta, S., Kolluru, S., Morri, M., Pisco, A. O., Tan, S. Y., Travaglini, K. J., Xu, C., Alcántara-Hernández, M., Almanzar, N., Antony, J., Beyersdorf, B., Burhan, D., Calcuttawala, K., Carter, M. M., Chan, C. K., Chang, C. A., Chang, S., Colville, A., Crasta, S., Culver, R. N., Cvijović, I., D'Amato, G., Ezran, C., Galdos, F. X., Gillich, A., Goodyer, W. R., Hang, Y., Hayashi, A., Houshdaran, S., Huang, X., Irwin, J. C., Jang, S., Juanico, J. V., Kershner, A. M., Kim, S., Kiss, B., Kolluru, S., Kong, W., Kumar, M. E., Kuo, A. H., Leylek, R., Li, B., Loeb, G. B., Lu, W. J., Mantri, S., Markovic, M., McAlpine, P. L., de Morree, A., Morri, M., Mrouj, K., Mukherjee, S., Muser, T., Neuhöfer, P., Nguyen, T. D., Perez, K., Phansalkar, R., Pisco, A. O., Puluca, N., Qi, Z., Rao, P., Raquer-McKay, H., Schaum, N., Scott, B., Seddighzadeh, B., Segal, J., Sen, S., Sikandar, S., Spencer, S. P., Steffes, L. C., Subramaniam, V. R., Swarup, A., Swift, M., Travaglini, K. J., Van Treuren, W., Trimm, E., Veizades, S., Vijayakumar, S., Vo, K. C., Vorperian, S. K., Wang, W., Weinstein, H. N., Winkler, J., Wu, T. T., Xie, J., Yung, A. R., Zhang, Y., Detweiler, A. M., Mekonen, H., Neff, N. F., Sit, R. V., Tan, M., Yan, J., Bean, G. R., Charu, V., Forgó, E., Martin, B. A., Ozawa, M. G., Silva, O., Tan, S. Y., Toland, A., Vemuri, V. N., Afik, S., Awayan, K., Botvinnik, O. B., Byrne, A., Chen, M., Dehghannasiri, R., Detweiler, A. M., Gayoso, A., Granados, A. A., Li, Q., Mahmoudabadi, G., McGeever, A., de Morree, A., Olivieri, J. E., Park, M., Pisco, A. O., Ravikumar, N., Salzman, J., Stanley, G., Swift, M., Tan, M., Tan, W., Tarashansky, A. J., Vanheusden, R., Vorperian, S. K., Wang, P., Wang, S., Xing, G., Xu, C., Yosef, N., Alcántara-Hernández, M., Antony, J., Chan, C. K., Chang, C. A., Colville, A., Crasta, S., Culver, R., Dethlefsen, L., Ezran, C., Gillich, A., Hang, Y., Ho, P. Y., Irwin, J. C., Jang, S., Kershner, A. M., Kong, W., Kumar, M. E., Kuo, A. H., Leylek, R., Liu, S., Loeb, G. B., Lu, W. J., Maltzman, J. S., Metzger, R. J., de Morree, A., Neuhöfer, P., Perez, K., Phansalkar, R., Qi, Z., Rao, P., Raquer-McKay, H., Sasagawa, K., Scott, B., Sinha, R., Song, H., Spencer, S. P., Swarup, A., Swift, M., Travaglini, K. J., Trimm, E., Veizades, S., Vijayakumar, S., Wang, B., Wang, W., Winkler, J., Xie, J., Yung, A. R., Artandi, S. E., Beachy, P. A., Clarke, M. F., Giudice, L. C., Huang, F. W., Huang, K. C., Idoyaga, J., Kim, S. K., Krasnow, M., Kuo, C. S., Nguyen, P., Quake, S. R., Rando, T. A., Red-Horse, K., Reiter, J., Relman, D. A., Sonnenburg, J. L., Wang, B., Wu, A., Wu, S. M., Wyss-Coray, T. 2022; 376 (6594): eabl4896

  Abstract

  Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, identification of the tissue-specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type-specific RNA splicing was discovered and analyzed across tissues within an individual.

  View details for DOI 10.1126/science.abl4896

  View details for PubMedID 35549404

• Environmental enteric dysfunction induces regulatory T cells that inhibit local CD4+T cell responses and impair oral vaccine efficacy IMMUNITY Bhattacharjee, A., Burr, A. P., Overacre-Delgoffe, A. E., Tometich, J. T., Yang, D., Huckestein, B. R., Linehan, J. L., Spencer, S. P., Hall, J. A., Harrison, O. J., da Fonseca, D., Norton, E. B., Belkaid, Y., Hand, T. W. 2021; 54 (8): 1745-+

  Abstract

  Environmental enteric dysfunction (EED) is a gastrointestinal inflammatory disease caused by malnutrition and chronic infection. EED is associated with stunting in children and reduced efficacy of oral vaccines. To study the mechanisms of oral vaccine failure during EED, we developed a microbiota- and diet-dependent mouse EED model. Analysis of E. coli-labile toxin vaccine-specific CD4+ T cells in these mice revealed impaired CD4+ T cell responses in the small intestine and but not the lymph nodes. EED mice exhibited increased frequencies of small intestine-resident RORγT+FOXP3+ regulatory T (Treg) cells. Targeted deletion of RORγT from Treg cells restored small intestinal vaccine-specific CD4 T cell responses and vaccine-mediated protection upon challenge. However, ablation of RORγT+FOXP3+ Treg cells made mice more susceptible to EED-induced stunting. Our findings provide insight into the poor efficacy of oral vaccines in EED and highlight how RORγT+FOXP3+ Treg cells can regulate intestinal immunity while leaving systemic responses intact.

  View details for DOI 10.1016/j.immuni.2021.07.005

  View details for Web of Science ID 000684589700013

  View details for PubMedID 34348118

• When Gut Microbiota Creep into Fat, the Fat Creeps Back. Cell Spencer, S. P., Sonnenburg, J. L. 2020; 183 (3): 589–91

  Abstract

  Ha and colleagues describe a previously unappreciated diversity of microbes in the mesenteric adipose tissue (MAT) surrounding the GI tract. Viable bacteria that are mislocalized from the gut microbiota and metabolically adapted to the MAT contribute to the "creeping fat" of Crohn's disease.

  View details for DOI 10.1016/j.cell.2020.10.008

  View details for PubMedID 33125887

• Colons or semi-colons: punctuating the regional variation of intestinal microbial-immune interactions. Nature reviews. Gastroenterology & hepatology Culver, R. N., Spencer, S. P., Huang, K. C. 2020

  View details for DOI 10.1038/s41575-020-0302-z

  View details for PubMedID 32322050

• High Prevalence of Concurrent Gastrointestinal Manifestations in Patients with SARS-CoV-2: Early Experience from California. Gastroenterology Cholankeril, G., Podboy, A., Aivaliotis, V. I., Tarlow, B., Pham, E. A., Spencer, S., Kim, D., Hsing, A., Ahmed, A. 2020

  View details for DOI 10.1053/j.gastro.2020.04.008

  View details for PubMedID 32283101

• Association of Digestive Symptoms and Hospitalization in Patients With SARS-CoV-2 Infection. The American journal of gastroenterology Cholankeril, G. n., Podboy, A. n., Aivaliotis, V. I., Pham, E. A., Spencer, S. P., Kim, D. n., Ahmed, A. n. 2020; 115 (7): 1129–32

  Abstract

  High rates of concurrent gastrointestinal manifestations have been noted in patients with corona virus disease 2019 (COVID-19); however, the association between these digestive manifestations and need for hospitalization has not been established.This is a retrospective review of consecutive patients diagnosed with COVID-19. A total of 207 patients were identified; 34.5% of patients noted concurrent gastrointestinal symptoms, with 90% of gastrointestinal symptoms being mild.In a multivariate regression model controlled for demographics and disease severity, an increased risk of hospitalization was noted in patients with any digestive symptom (adjusted odds ratio 4.84, 95% confidence interval: 1.68-13.94).The presence of digestive symptoms in COVID-19 is associated with a need for hospitalization.

  View details for DOI 10.14309/ajg.0000000000000712

  View details for PubMedID 32618665

  View details for PubMedCentralID PMC7302101

• The long noncoding RNA Morrbid regulates CD8 T cells in response to viral infection PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Kotzin, J. J., Iseka, F., Wright, J., Basavappa, M. G., Clark, M. L., Ali, M., Abdel-Hakeem, M. S., Robertson, T. F., Mowel, W. K., Joannas, L., Neal, V. D., Spencer, S. P., Syrett, C. M., Anguera, M. C., Williams, A., Wherry, E., Henao-Mejia, J. 2019; 116 (24): 11916–25

  Abstract

  The transcriptional programs that regulate CD8 T-cell differentiation and function in the context of viral infections or tumor immune surveillance have been extensively studied; yet how long noncoding RNAs (lncRNAs) and the loci that transcribe them contribute to the regulation of CD8 T cells during viral infections remains largely unexplored. Here, we report that transcription of the lncRNA Morrbid is specifically induced by T-cell receptor (TCR) and type I IFN stimulation during the early stages of acute and chronic lymphocytic choriomeningitis virus (LCMV) infection. In response to type I IFN, the Morrbid RNA and its locus control CD8 T cell expansion, survival, and effector function by regulating the expression of the proapoptotic factor, Bcl2l11, and by modulating the strength of the PI3K-AKT signaling pathway. Thus, our results demonstrate that inflammatory cue-responsive lncRNA loci represent fundamental mechanisms by which CD8 T cells are regulated in response to pathogens and potentially cancer.

  View details for DOI 10.1073/pnas.1819457116

  View details for Web of Science ID 000471039700057

  View details for PubMedID 31138702