About

Laurie Comstock, PhD, is a Professor of Microbiology at the University of Chicago, affiliated with the Department of Microbiology, Committee on Microbiology, and Committee on Molecular Metabolism and Nutrition. Her research focuses on the human intestinal microbiota, a complex and dynamic community of microbes crucial for human health and disease prevention. Her lab studies the interactions among bacterial members of this ecosystem, exploring how they cooperate and antagonize each other to form health-promoting communities. The research employs microbiological, genetic, biochemical, and gnotobiotic mouse analyses, along with genomic, metagenomic, and computational approaches to understand these complex interactions. Key contributions include the discovery of numerous classes of antimicrobial proteins used by bacteria to compete within their ecosystem, and investigations into their mechanisms of action, ecological properties, and potential applications for human health. Additionally, her work examines the evolution of microbes in the human gut, focusing on how horizontally transferred genetic elements personalize individual gut microbiota and influence community benefits.

Research topics

• Biology
• Ecology
• Evolutionary biology
• Biochemistry
• Genetics

Selected publications

• Antagonism by the Type VI secretion system of <i>Bacteroides fragilis</i> is controlled by a TetR family regulator and released small molecule

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-20 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Antagonistic systems of bacteria are often tightly regulated. The human gut Bacteroidales harbor three distinct antagonistic Type VI secretion systems (T6SS), one of which is present only in Bacteroides fragilis , known as the GA3 T6SS. Although this is the best studied of the three T6SSs, little is known about how it is regulated. The gene upstream of the GA3 T6SS locus encodes a TetR family transcriptional regulator (TetR GA3 ), which we show represses expression of the GA3 T6SS locus. The gene immediately upstream and divergently transcribed from tetR GA3 , designated here as lgs GA3 , encodes a product of the α-oxoamine synthase family of pyridoxal phosphate-dependent enzymes with structural homology to the CqsA autoinducer synthase of the CAI-1 quorum sensing system of Vibrio spp . When lgs GA3 is deleted, transcription of the GA3 T6SS locus is repressed in a TetR-dependent manner. Strains synthesizing Lgs GA3 produce a molecule present in the supernatant that likely serves as the TetR GA3 ligand, overcoming TetR transcriptional repression of the GA3 T6SS. We show that GA3 T6SS-specific immunity genes present on two acquired immunity defense islands are also regulated by Lgs GA3 coordinating expression of GA3 T6SS antagonism with protection from competitor’s GA3 T6SS toxins. Production and firing of the GA3 T6SS and subsequent antagonism occurs in bacteria deleted for lgs GA3 when grown with bacteria containing this gene or their supernatants. These data show that the GA3 T6SS is regulated by a small molecule acting through TetR GA3 allowing the bacteria to coordinate antagonistic and protective systems. Significance statement There are numerous external and intrinsic signals that dictate when bacteria become aggressive and when they activate their defensive systems. We show that B. fragilis strains with a GA3 T6SS synthesize a small molecule released from bacterial cells that acts through TetR family regulators to coordinate transcription of both the antagonistic GA3 T6SS and arrays of immunity genes to competitor’s GA3 T6SS toxins. Bacteria can respond to this molecule when released from non-kin bacteria, allowing them to sense and respond to a threat from a nearby competitor. The coordinated regulation of the GA3 T6SS and arrays of immunity genes is the second example of regulatory crosstalk between the GA3 T6SS and genes of MGEs through TetR family regulators.

  PublisherOA PDFDOI

• Mechanisms of bacterial immunity, protection, and survival during interbacterial warfare

  Cell Host & Microbe · 2024-06-01 · 25 citations

  reviewOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• A cryptic plasmid is among the most numerous genetic elements in the human gut

  Cell · 2024-02-01 · 59 citations

  articleOpen accessCorresponding

  Plasmids are extrachromosomal genetic elements that often encode fitness-enhancing features. However, many bacteria carry "cryptic" plasmids that do not confer clear beneficial functions. We identified one such cryptic plasmid, pBI143, which is ubiquitous across industrialized gut microbiomes and is 14 times as numerous as crAssphage, currently established as the most abundant extrachromosomal genetic element in the human gut. The majority of mutations in pBI143 accumulate in specific positions across thousands of metagenomes, indicating strong purifying selection. pBI143 is monoclonal in most individuals, likely due to the priority effect of the version first acquired, often from one's mother. pBI143 can transfer between Bacteroidales, and although it does not appear to impact bacterial host fitness in vivo, it can transiently acquire additional genetic content. We identified important practical applications of pBI143, including its use in identifying human fecal contamination and its potential as an alternative approach to track human colonic inflammatory states.

  PublisherOA PDFDOI

• <i>Bacteroides</i> expand the functional versatility of a universal transcription factor and transcribed DNA to program capsule diversity

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-06-21 · 6 citations

  preprintOpen access

  SUMMARY Human gut Bacteroides species encode numerous (eight or more) tightly regulated capsular polysaccharides (CPS). Specialized paralogs of the universal transcription elongation factor NusG, called UpxY (Y), and an anti-Y UpxZ (Z) are encoded by the first two genes of each CPS operon. The Y-Z regulators combine with promoter inversions to limit CPS transcription to a single operon in most cells. Y enhances transcript elongation whereas Z inhibits noncognate Ys. How Y distinguishes among cognate CPS operons and how Z inhibits only noncognate Ys are unknown. Using in-vivo nascent-RNA sequencing and p romoter-less in v itr o transcription (PIVoT), we establish that Y recognizes a paused RNA polymerase via sequences in both the exposed non-template DNA and the upstream duplex DNA. Y association is aided by novel ‘pause-then-escape’ nascent RNA hairpins. Z binds non-cognate Ys to directly inhibit Y association. This Y-Z hierarchical regulatory program allows Bacteroides to create CPS subpopulations for optimal fitness.

  PublisherOA PDFDOI

• Inflammation and bacteriophages affect DNA inversion states and functionality of the gut microbiota

  Cell Host & Microbe · 2024-02-28 · 53 citations

  articleOpen access

  Reversible genomic DNA inversions control the expression of numerous gut bacterial molecules, but how this impacts disease remains uncertain. By analyzing metagenomic samples from inflammatory bowel disease (IBD) cohorts, we identified multiple invertible regions where a particular orientation correlated with disease. These include the promoter of polysaccharide A (PSA) of Bacteroides fragilis, which induces regulatory T cells (Tregs) and ameliorates experimental colitis. The PSA promoter was mostly oriented "OFF" in IBD patients, which correlated with increased B. fragilis-associated bacteriophages. Similarly, in mice colonized with a healthy human microbiota and B. fragilis, induction of colitis caused a decline of PSA in the "ON" orientation that reversed as inflammation resolved. Monocolonization of mice with B. fragilis revealed that bacteriophage infection increased the frequency of PSA in the "OFF" orientation, causing reduced PSA expression and decreased Treg cells. Altogether, we reveal dynamic bacterial phase variations driven by bacteriophages and host inflammation, signifying bacterial functional plasticity during disease.

  PublisherDOI

• Comprehensive analyses of a large human gut Bacteroidales culture collection reveal species and strain level diversity and evolution

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-03-09 · 7 citations

  preprintOpen accessSenior authorCorresponding

  Species of the Bacteroidales order are among the most abundant and stable bacterial members of the human gut microbiome with diverse impacts on human health. While Bacteroidales strains and species are genomically and functionally diverse, order-wide comparative analyses are lacking. We cultured and sequenced the genomes of 408 Bacteroidales isolates from healthy human donors representing nine genera and 35 species and performed comparative genomic, gene-specific, mobile gene, and metabolomic analyses. Families, genera, and species could be grouped based on many distinctive features. However, we also show extensive DNA transfer between diverse families, allowing for shared traits and strain evolution. Inter- and intra-specific diversity is also apparent in the metabolomic profiling studies. This highly characterized and diverse Bacteroidales culture collection with strain-resolved genomic and metabolomic analyses can serve as a resource to facilitate informed selection of strains for microbiome reconstitution.

  PublisherOA PDFDOI

• A pervasive large conjugative plasmid mediates multispecies biofilm formation in the intestinal microbiota increasing resilience to perturbations

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-04-29 · 5 citations

  preprintOpen accessSenior authorCorresponding

  Although horizontal gene transfer is pervasive in the intestinal microbiota, we understand only superficially the roles of most exchanged genes and how the mobile repertoire affects community dynamics. Similarly, little is known about the mechanisms underlying the ability of a community to recover after a perturbation. Here, we identified and functionally characterized a large conjugative plasmid that is one of the most frequently transferred elements among Bacteroidales species and is ubiquitous in diverse human populations. This plasmid encodes both an extracellular polysaccharide and fimbriae, which promote the formation of multispecies biofilms in the mammalian gut. We use a hybridization-based approach to visualize biofilms in clarified whole colon tissue with unprecedented 3D spatial resolution. These biofilms increase bacterial survival to common stressors encountered in the gut, increasing strain resiliency, and providing a rationale for the plasmid's recent spread and high worldwide prevalence.

  PublisherOA PDFDOI

• Phosphorothioate DNA modification by BREX Type 4 systems in the human gut microbiome

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-06-03 · 4 citations

  preprintOpen access

  Abstract Among dozens of microbial DNA modifications regulating gene expression and host defense, phosphorothioation (PT) is the only known backbone modification, with sulfur inserted at a non-bridging oxygen by dnd and ssp gene families. Here we explored the distribution of PT genes in 13,663 human gut microbiome genomes, finding that 6.3% possessed dnd or ssp genes predominantly in Bacillota, Bacteroidota, and Pseudomonadota. This analysis uncovered several putative new PT synthesis systems, including Type 4 Bacteriophage Exclusion (BREX) brx genes, which were genetically validated in Bacteroides salyersiae. Mass spectrometric analysis of DNA from 226 gut microbiome isolates possessing dnd , ssp , and brx genes revealed 8 PT dinucleotide settings confirmed in 6 consensus sequences by PT-specific DNA sequencing. Genomic analysis showed PT enrichment in rRNA genes and depletion at gene boundaries. These results illustrate the power of the microbiome for discovering prokaryotic epigenetics and the widespread distribution of oxidation-sensitive PTs in gut microbes. One-sentence Summary Application of informatic, mass spectrometric, and sequencing-based mapping tools to human gut bacteria revealed new phosphorothioate epigenetic systems widespread in the gut microbiome.

  PublisherOA PDFDOI

• A highly conserved and globally prevalent cryptic plasmid is among the most numerous mobile genetic elements in the human gut

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-03-25 · 6 citations

  preprintOpen access

  ABSTRACT Plasmids are extrachromosomal genetic elements that often encode fitness enhancing features. However, many bacteria carry ‘cryptic’ plasmids that do not confer clear beneficial functions. We identified one such cryptic plasmid, pBI143, which is ubiquitous across industrialized gut microbiomes, and is 14 times as numerous as crAssphage, currently established as the most abundant genetic element in the human gut. The majority of mutations in pBI143 accumulate in specific positions across thousands of metagenomes, indicating strong purifying selection. pBI143 is monoclonal in most individuals, likely due to the priority effect of the version first acquired, often from one’s mother. pBI143 can transfer between Bacteroidales and although it does not appear to impact bacterial host fitness in vivo , can transiently acquire additional genetic content. We identified important practical applications of pBI143, including its use in identifying human fecal contamination and its potential as an inexpensive alternative for detecting human colonic inflammatory states.

  PublisherOA PDFDOI

• Untangling the Role of Pathobionts from Bacteroides Species in Inflammatory Bowel Diseases

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-10-29

  preprintOpen access

  Abstract Inflammatory bowel diseases (IBD) arise from a convergence of underlying genetic susceptibility, environmental factors, and shifts in gut microbiota function and membership. Although the latter may trigger and contribute to IBD, there is little consensus on a specific causative pathogen. In this study, we demonstrate that commensal Bacteroides fragilis strains from ulcerative colitis (UC) patients before and during the development of ileal pouchitis engraft and promote colitis in specific pathogen free (SPF) IL-10 deficient (IL-10 -/- ) mice, but not in wild type SPF mice or when mono-associated in germ free mice. The colitis in IL-10 -/- mice was also associated with significant alterations in commensal microbiota potentially important for maintaining intestinal and immune homeostasis. UC pouchitis B. fragilis also engrafts in DSS-induced colitis in WT SPF mice, indicating a fitness advantage under conditions of mucosal inflammation over other commensals in the gut microbiota. These findings show that gut inflammation promotes the expansion and fitness of UC-derived Bacteroides species that is associated with changes in the SPF gut microbiota and may be promote colitis in genetically susceptible hosts. Importance This study supports the notion that human inflammatory bowel diseases arise from the emergence of indigenous pathobionts in genetically-prone subjects. Colitis-promoting pathobionts are well-suited to establish themselves in the host inflammatory environment and outcompete endogenous microbiota. Once engrafted, the pathobiont can further aggravate inflammation in a genetically-susceptible host. Such complex interplay among several factors creates a vicious pro-inflammatory cycle and promotes disease development. These findings are consistent with our previous clinical observation that B. fragilis , an otherwise low-abundance commensal species, expands prior to the development of UC pouchitis. We believe these findings are relevant to the pathogenesis of UC pouchitis and possibly human inflammatory bowel diseases in general, underscoring the role of commensal to pathobiont transitions, rather than classical pathogens, in promoting and exacerbating the onset of human IBD.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01AI067711

  NIH · $1.4M · 2012

• NIH Grant R56AI044193

  NIH · $344k · 2009

• NIH Grant R01AI044193

  NIH · $2.9M · 2011

• Protective mechanisms of the gut Bacteroidales

  NIH · $5.1M · 2012–2028

• Contact-Dependent Antagonism in Gut Bacteroidales

  NIH · $2.1M · 2015–2021

Frequent coauthors

• Michael J. Coyne

  121 shared

• Maria Chatzidaki‐Livanis

  Harvard University

  49 shared

• D D Thomas

  The University of Texas Health Science Center at San Antonio

  31 shared

• Dennis L. Kasper

  27 shared

• Leonor García-Bayona

  University of Chicago

  19 shared

• Valentina Laclare McEneany

  Brigham and Women's Hospital

  18 shared

• C. Mark Fletcher

  Harvard University

  17 shared

• Katja G. Weinacht

  Stanford Medicine

  17 shared

Labs

• Laurie ComstockPI

Education

• Ph.D., Microbiology and Immunology

  Wake Forest University Medical Center / Bowman Gray School of Medicine

  1991

• B.S., Biology

  Rensselaer Polytechnic Institute

  1987

• Other, Bacteroides fragilis genetics

  Brigham and Women's Hospital / Harvard Medical School

  1996

• Other, Vibrio cholerae pathogenesis

  University of Maryland Medical Center / Center for Vaccine Development

  1995