Bio


Sean Spencer, MD,PhD is a Gastroenterologist and Physician Scientist at Stanford University working with Justin Sonennburg,PhD to uncover the role of dietary intake on the gut microbiome and mucosal immune system. Sean obtained his medical degree University of Pennsylvania, earning his PhD studying nutritional immunology with Yasmine Belkaid,PhD at the National Institutes of Health (NIH), after which he moved to Boston for residency training at Massachusetts General Hospital and completed his Gastroenterology training at Stanford University. Sean’s career goal is to study mechanisms by which dietary intake influences our microbiome and immune system to better understand and treat gastrointestinal disease.

Clinical Focus


  • Gastroenterology
  • Neurogastroenterology & Motility
  • Gastrointestinal Microbiota
  • Diet

Academic Appointments


Honors & Awards


  • A.P. Giannini Postdoctoral Fellow, AP Giannini Foundation (2021-2023)
  • Training Grant in Academic Gastroenterology (T32), National Institute of Diabetes and Digestive and Kidney Diseases (2019-2021)
  • Ruth L. Kirschstein NRSA Individual Predoctoral MD/PhD fellowship (F30), National Institute of Diabetes and Digestive and Kidney Disease (2011-2014)
  • Medical Scientist Training Program (T32), National Institute of General Medical Sciences (2007-2009)

Program Affiliations


Professional Education


  • Bachelor of Science, University of Wisconsin Madison (2007)
  • PhD, University of Pennsylvania, Immunology (2013)
  • Doctor of Medicine, University of Pennsylvania (2015)
  • Residency: Massachusetts General Hospital Internal Medicine Residency (2017) MA
  • Fellowship: Stanford University Gastroenterology Fellowship (2021) CA
  • Board Certification: American Board of Internal Medicine, Internal Medicine (2018)

Graduate and Fellowship Programs


  • Gastroenterology & Hepatology (Fellowship Program)

All Publications


  • 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

  • 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