About

Marco Jost is a professor at Harvard Medical School, leading the Jost Lab in the Department of Microbiology. His research focuses on decoding the molecular language of host-microbiome communication through systematic CRISPR technologies and chemically defined in vitro and in vivo experiments. The goal of his work is to define the causal contributions of the microbiome to basic human biology and to provide mechanistic insights into the pathophysiology of human diseases, including diabetes and inflammatory disorders. His lab aims to lay the groundwork for the development of microbiome-based therapeutics. The lab was established in April 2021 and is located on the Longwood Campus of Harvard Medical School.

Research topics

• Biology
• Genetics
• Computational biology
• Cartography
• Evolutionary biology

Selected publications

• <i>Blautia wexlerae</i> Transforms Dietary Fatty Acids to Activate Enteroendocrine Signaling and Improve Metabolic Health in Mice and Humans

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-14

  articleOpen access

  ABSTRACT Metabolites produced by the gut microbiome influence host metabolic health, but how this occurs remains incompletely defined. Here, we report that a common human gut commensal, Blautia wexlerae , converts dietary fats into bioactive metabolites that induce gut hormone production to affect glucose metabolism and suppress appetite. We found that colonization with Blautia wexlerae correlated with healthier eating behaviors in humans. Blautia wexlerae encodes a unique acyl transferase and is capable of producing acyl amines from nutrient substrates. These Blautia acyl amines stimulated human enteroendocrine cells to secrete GLP-1 and other gut peptide hormones more potently than endogenously produced acyl amines. When fed to mice, acyl amines improved glycemic control and decreased appetite. In humans, higher stool levels of Blautia DNA encoding acyl amine synthesis genes correlated with leanness and decreased dietary fat intake. These results define a mechanism of action for how Blautia wexlerae affects host metabolic control.

  PublisherOA PDFDOI

• 33: COMMENSALS DEPLETED IN OBESITY ACTIVATE ENTEROENDOCRINE CELLS AND IMPROVE HOST METABOLISM

  Gastroenterology · 2025-05-01

  article
  PublisherDOI

• Comprehensive interrogation of synthetic lethality in the DNA damage response

  Nature · 2025-04-09 · 44 citations

  articleOpen access

  Abstract The DNA damage response (DDR) is a multifaceted network of pathways that preserves genome stability 1,2 . Unravelling the complementary interplay between these pathways remains a challenge 3,4 . Here we used CRISPR interference (CRISPRi) screening to comprehensively map the genetic interactions required for survival during normal human cell homeostasis across all core DDR genes. We captured known interactions and discovered myriad new connections that are available online. We defined the molecular mechanism of two of the strongest interactions. First, we found that WDR48 works with USP1 to restrain PCNA degradation in FEN1/LIG1-deficient cells. Second, we found that SMARCAL1 and FANCM directly unwind TA-rich DNA cruciforms, preventing catastrophic chromosome breakage by the ERCC1–ERCC4 complex. Our data yield fundamental insights into genome maintenance, provide a springboard for mechanistic investigations into new connections between DDR factors and pinpoint synthetic vulnerabilities that could be exploited in cancer therapy.

  PublisherOA PDFDOI

• A DNA-gated molecular guard controls bacterial Hailong anti-phage defence

  Nature · 2025-04-30 · 13 citations

  articleOpen access
  PublisherOA PDFDOI

• Systematic identification and characterization of regulators of aryl hydrocarbon receptor signaling

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-16 · 1 citations

  preprintOpen accessSenior authorCorresponding

  The human aryl hydrocarbon receptor (AHR) integrates chemical signals derived from the environment, gut microbes, and endogenous sources to regulate processes ranging from intestinal barrier integrity to xenobiotic detoxification. Despite strong evidence that dysregulation of AHR signaling is a causal factor in metabolic and autoimmune disorders, we currently lack a comprehensive understanding of the factors that regulate AHR activity in human cells. Here, we use genome-scale CRISPR screening to systematically identify regulators of AHR signaling in hepatocytes. The resulting datasets recapitulate the core AHR signaling pathway and identify a large network of regulators. Many of these factors have roles beyond AHR signaling, reflecting that AHR signaling is deeply integrated into human cell biology. We further dissect this network to reveal novel modes of regulation of AHR expression, protein levels, and signaling. For example, we find that the E3 ubiquitin ligase UBR5 sustains AHR signaling by counteracting degradation of ligand-bound AHR. Finally, we identify components of the AHR regulatory network that are specific to cell types and ligands as potential nodes to manipulate AHR signaling in a targeted manner for therapeutic benefit. Overall, our results define the regulatory network that underpins AHR activation, with implications for our understanding of host-microbe interactions and integrative chemosensation and the etiology of metabolic and inflammatory disorders.

  PublisherOA PDFDOI

• Vaginal lactobacilli produce anti-inflammatory β-carboline compounds

  Cell Host & Microbe · 2024-10-17 · 39 citations

  articleOpen access
  PublisherOA PDFDOI

• Dissecting host–microbe interactions with modern functional genomics

  Current Opinion in Microbiology · 2024-10-04 · 4 citations

  reviewOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• Comprehensive Interrogation of Synthetic Relationships in the Human DNA Damage Response

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-08-19 · 6 citations

  preprintOpen access

  Abstract The DNA damage response (DDR) is a multi-faceted network of pathways that preserves genome stability. Unraveling the complementary interplay between these pathways remains a challenge. Here, we comprehensively mapped genetic interactions for all core DDR genes using combinatorial CRISPRi screening. We discovered myriad new connections, including interactions between cancer genes and small molecule targets. We focused on two of the strongest interactions: FEN1 / LIG1 : WDR48 and FANCM : SMARCAL1 . First, we found that WDR48 works with USP1 to restrain overactive translesion synthesis in FEN1/LIG1-deficient cells, and that a preclinical inhibitor of USP1 specifically kills FEN1-deficient cells. Second, we found that SMARCAL1 and FANCM suppress DNA double-strand break (DSB) formation at TA-rich repeats in late replicating regions that otherwise escape into mitosis and cause nuclear fragmentation. We present fundamental insights into genome maintenance processes and our dataset provides a springboard for mechanistic investigations into connections between DDR factors and suggests multiple interactions that could be exploited in cancer therapy.

  PublisherOA PDFDOI

• Microfluidics-free single-cell genomics with templated emulsification

  Nature Biotechnology · 2023-03-06 · 204 citations

  articleOpen access

  Current single-cell RNA-sequencing approaches have limitations that stem from the microfluidic devices or fluid handling steps required for sample processing. We develop a method that does not require specialized microfluidic devices, expertise or hardware. Our approach is based on particle-templated emulsification, which allows single-cell encapsulation and barcoding of cDNA in uniform droplet emulsions with only a vortexer. Particle-templated instant partition sequencing (PIP-seq) accommodates a wide range of emulsification formats, including microwell plates and large-volume conical tubes, enabling thousands of samples or millions of cells to be processed in minutes. We demonstrate that PIP-seq produces high-purity transcriptomes in mouse-human mixing studies, is compatible with multiomics measurements and can accurately characterize cell types in human breast tissue compared to a commercial microfluidic platform. Single-cell transcriptional profiling of mixed phenotype acute leukemia using PIP-seq reveals the emergence of heterogeneity within chemotherapy-resistant cell subsets that were hidden by standard immunophenotyping. PIP-seq is a simple, flexible and scalable next-generation workflow that extends single-cell sequencing to new applications.

  PublisherOA PDFDOI

• Structural insight into G-protein chaperone-mediated maturation of a bacterial adenosylcobalamin-dependent mutase

  Journal of Biological Chemistry · 2023-07-28 · 3 citations

  articleOpen access

  G-protein metallochaperones are essential for the proper maturation of numerous metalloenzymes. The G-protein chaperone MMAA in humans (MeaB in bacteria) uses GTP hydrolysis to facilitate the delivery of adenosylcobalamin (AdoCbl) to AdoCbl-dependent methylmalonyl-CoA mutase, an essential metabolic enzyme. This G-protein chaperone also facilitates the removal of damaged cobalamin (Cbl) for repair. Although most chaperones are standalone proteins, isobutyryl-CoA mutase fused (IcmF) has a G-protein domain covalently attached to its target mutase. We previously showed that dimeric MeaB undergoes a 180° rotation to reach a state capable of GTP hydrolysis (an active G-protein state), in which so-called switch III residues of one protomer contact the G-nucleotide of the other protomer. However, it was unclear whether other G-protein chaperones also adopted this conformation. Here, we show that the G-protein domain in a fused system forms a similar active conformation, requiring IcmF oligomerization. IcmF oligomerizes both upon Cbl damage and in the presence of the nonhydrolyzable GTP analog, guanosine-5'-[(β,γ)-methyleno]triphosphate, forming supramolecular complexes observable by mass photometry and EM. Cryo-EM structural analysis reveals that the second protomer of the G-protein intermolecular dimer props open the mutase active site using residues of switch III as a wedge, allowing for AdoCbl insertion or damaged Cbl removal. With the series of structural snapshots now available, we now describe here the molecular basis of G-protein-assisted AdoCbl-dependent mutase maturation, explaining how GTP binding prepares a mutase for cofactor delivery and how GTP hydrolysis allows the mutase to capture the cofactor.

  PublisherOA PDFDOI

Recent grants

• Deciphering the logic of glycolipid signaling at the host-microbiome interface

  NIH · $200k · 2019–2021

• Systematic Genome-Wide Characterization of Iron Homeostasis

  NIH · $162k · 2015–2018

Frequent coauthors

• Jonathan S. Weissman

  Whitehead Institute for Biomedical Research

  213 shared

• Max A. Horlbeck

  University of California, San Francisco

  70 shared

• Joseph M. Replogle

  Whitehead Institute for Biomedical Research

  68 shared

• Thomas M. Norman

  Memorial Sloan Kettering Cancer Center

  64 shared

• Jeffrey A. Hussmann

  Whitehead Institute for Biomedical Research

  58 shared

• Luke A. Gilbert

  University of California, San Francisco

  54 shared

• Ivo Buschmann

  Brandenburg University of Technology Cottbus-Senftenberg

  54 shared

• Imo E. Hoefer

  University Medical Center Utrecht

  50 shared

Labs

• Jost LabPI

Education

• Ph.D., Microbiology

  Harvard University

  2008

• M.S., Microbiology

  University of California, San Diego

  2003

• B.S., Microbiology

  University of California, San Diego

  2001