Pathobiont-triggered induction of epithelial IDO1 drives regional susceptibility to Inflammatory Bowel Disease.

The structure and function of the mammalian gut vary by region, yet why inflammatory diseases manifest in specific regions and not others remains unclear. We use a TNF-overexpressing Crohn's disease (CD) model (Tnf ), which typically presents in the terminal ileum (TI), to investigate how environmental factors interact with the host's immune susceptibility to drive region-specific disease. We identified , an intracellular bacterium and murine counterpart to the human sexually transmitted , as necessary and sufficient to trigger disease manifestation in the ascending colon (AC), another common site of human CD.

in the gastrointestinal tract as a modifier of human health.

are common members of the human gut microbiota. Multiple reports have emerged linking the abundance of to health benefits and disease risk in humans and animals. This review highlights findings linking species in the gastrointestinal (GI) tract to health outcomes across a spectrum of disorders, encompassing those that affect the digestive, respiratory, urinary, and central nervous systems.

The acetylase activity of Cdu1 regulates bacterial exit from infected cells by protecting effectors from degradation.

Many cellular processes are regulated by ubiquitin-mediated proteasomal degradation. Pathogens can regulate eukaryotic proteolysis through the delivery of proteins with de-ubiquitinating (DUB) activities. The obligate intracellular pathogen secretes Cdu1 (ChlaDUB1), a dual deubiquitinase and Lys-acetyltransferase, that promotes Golgi remodeling and survival of infected host cells presumably by regulating the ubiquitination of host and bacterial proteins.

Mechanism of 2'-fucosyllactose degradation by human-associated .

Among the first microorganisms to colonize the human gut of breastfed infants are bacteria capable of fermenting human milk oligosaccharides (HMOs). One of the most abundant HMOs, 2'-fucosyllactose (2'-FL), may specifically drive bacterial colonization of the intestine. Recently, differential growth has been observed across multiple species of on various HMOs including 2'-FL.

Mechanism of 2'-Fucosyllactose degradation by Human-Associated .

Unlabelled: Among the first microorganisms to colonize the human gut of breastfed infants are bacteria capable of fermenting human milk oligosaccharides (HMOs). One of the most abundant HMOs, 2'-fucosyllactose (2'-FL), may specifically drive bacterial colonization of the intestine. Recently, differential growth has been observed across multiple species of on various HMOs including 2'FL.

A genetic system for Akkermansia muciniphila reveals a role for mucin foraging in gut colonization and host sterol biosynthesis gene expression.

Akkermansia muciniphila, a mucophilic member of the gut microbiota, protects its host against metabolic disorders. Because it is genetically intractable, the mechanisms underlying mucin metabolism, gut colonization and its impact on host physiology are not well understood. Here we developed and applied transposon mutagenesis to identify genes important for intestinal colonization and for the use of mucin.

The emerging complexity of Chlamydia trachomatis interactions with host cells as revealed by molecular genetic approaches.

Chlamydia trachomatis (Ct) is an intracellular bacterial pathogen that relies on the activity of secreted proteins known as effectors to promote replication and avoidance of immune clearance. Understanding the contribution of Ct effectors to pathogenesis has proven to be challenging, given that these proteins often perform multiple functions during intracellular infection. Recent advances in molecular genetic analysis of Ct have provided valuable insights into the multifaceted nature of secreted effector proteins and their impact on the interaction between Ct and host cells and tissues.

The acetylase activity of Cdu1 regulates bacterial exit from infected cells by protecting effectors from degradation.

Many cellular processes are regulated by ubiquitin-mediated proteasomal degradation. Pathogens can regulate eukaryotic proteolysis through the delivery of proteins with de-ubiquitinating (DUB) activities. The obligate intracellular pathogen secretes Cdu1 (ChlaDUB1), a dual deubiquitinase and Lys-acetyltransferase, that promotes Golgi remodeling and survival of infected host cells presumably by regulating the ubiquitination of host and bacterial proteins.

Chlamydia repurposes the actin-binding protein EPS8 to disassemble epithelial tight junctions and promote infection.

Invasive microbial pathogens often disrupt epithelial barriers, yet the mechanisms used to dismantle tight junctions are poorly understood. Here, we show that the obligate pathogen Chlamydia trachomatis uses the effector protein TepP to transiently disassemble tight junctions early during infection. TepP alters the tyrosine phosphorylation status of host proteins involved in cytoskeletal regulation, including the filamentous actin-binding protein EPS8.

Diet-derived metabolites and mucus link the gut microbiome to fever after cytotoxic cancer treatment.

Not all patients with cancer and severe neutropenia develop fever, and the fecal microbiome may play a role. In a single-center study of patients undergoing hematopoietic cell transplant ( = 119), the fecal microbiome was characterized at onset of severe neutropenia. A total of 63 patients (53%) developed a subsequent fever, and their fecal microbiome displayed increased relative abundances of , a species of mucin-degrading bacteria ( = 0.

Mucus-degrading Bacteroides link carbapenems to aggravated graft-versus-host disease.

The intestinal microbiota is an important modulator of graft-versus-host disease (GVHD), which often complicates allogeneic hematopoietic stem cell transplantation (allo-HSCT). Broad-spectrum antibiotics such as carbapenems increase the risk for intestinal GVHD, but mechanisms are not well understood. In this study, we found that treatment with meropenem, a commonly used carbapenem, aggravates colonic GVHD in mice via the expansion of Bacteroides thetaiotaomicron (BT).

The bacterial effector GarD shields Chlamydia trachomatis inclusions from RNF213-mediated ubiquitylation and destruction.

Chlamydia trachomatis is the leading cause of sexually transmitted bacterial infections and a major threat to women's reproductive health in particular. This obligate intracellular pathogen resides and replicates within a cellular compartment termed an inclusion, where it is sheltered by unknown mechanisms from gamma-interferon (IFNγ)-induced cell-autonomous host immunity. Through a genetic screen, we uncovered the Chlamydia inclusion membrane protein gamma resistance determinant (GarD) as a bacterial factor protecting inclusions from cell-autonomous immunity.

Human genetic diversity regulating the locus confers increased cytokines in response to .

Human genetic diversity can have profound effects on health outcomes upon exposure to infectious agents. For infections with (), the wide range of genital and ocular disease manifestations are likely influenced by human genetic differences that regulate interactions between and host cells. We leveraged this diversity in cellular responses to demonstrate the importance of variation at the Toll-like receptor 1 (), , and locus to cytokine production in response to .

Genotypic and Phenotypic Diversity among Human Isolates of Akkermansia muciniphila.

The mucophilic anaerobic bacterium is a prominent member of the gastrointestinal (GI) microbiota and the only known species of the phylum in the mammalian gut. A high prevalence of in adult humans is associated with leanness and a lower risk for the development of obesity and diabetes. Four distinct phylogenetic groups have been described, but little is known about their relative abundance in humans or how they impact human metabolic health.

Application of a expression system to identify proteins translocated into host cells.

is a Gram-negative, obligate intracellular pathogen that causes community-acquired respiratory infections. uses a cell contact-dependent type-III secretion (T3S) system to translocate pathogen effector proteins that manipulate host cellular functions. While several T3S effectors have been proposed, few have been experimentally confirmed in In this study, we expressed 382 genes in as fusion proteins to an epitope tag derived from glycogen synthase kinase 3β (GSK3β) which is the target of phosphorylation by mammalian kinases.

The Pediatric Obesity Microbiome and Metabolism Study (POMMS): Methods, Baseline Data, and Early Insights.

Objective: The purpose of this study was to establish a biorepository of clinical, metabolomic, and microbiome samples from adolescents with obesity as they undergo lifestyle modification.

Methods: A total of 223 adolescents aged 10 to 18 years with BMI ≥95th percentile were enrolled, along with 71 healthy weight participants. Clinical data, fasting serum, and fecal samples were collected at repeated intervals over 6 months.

An endometrial organoid model of interactions between and epithelial and immune cells.

Our understanding of how the obligate intracellular bacterial pathogen reprograms the function of infected cells in the upper genital tract is largely based on observations made in cell culture with transformed epithelial cell lines. Here, we describe a primary organoid system derived from endometrial tissue to recapitulate epithelial cell diversity, polarity and ensuing responses to infection. Using high-resolution and time-lapse microscopy, we catalog the infection process in organoids from invasion to egress, including the reorganization of the cytoskeleton and positioning of intracellular organelles.

Modeling of variables in cellular infection reveals CXCL10 levels are regulated by human genetic variation and the Chlamydia-encoded CPAF protease.

Susceptibility to infectious diseases is determined by a complex interaction between host and pathogen. For infections with the obligate intracellular bacterium Chlamydia trachomatis, variation in immune activation and disease presentation are regulated by both host genetic diversity and pathogen immune evasion. Previously, we discovered a single nucleotide polymorphism (rs2869462) associated with absolute abundance of CXCL10, a pro-inflammatory T-cell chemokine.

Bacterial genetics and molecular pathogenesis in the age of high throughput DNA sequencing.

When Stanley Falkow introduced Molecular Koch's Postulates (Falkow, 1988) as a conceptual framework to identify microbial factors that contributed to disease, he reaffirmed the prominent role that the basic principles of genetic analysis should play in defining genotype-phenotype associations in microbial pathogens. In classical bacterial genetics the nature of mutations is inferred through cis-trans complementation and by indirectly mapping their relative position and physical distance through recombination frequencies - all of which were made possible by the genetic tools of the day: natural transformations, conjugation and transduction. Unfortunately, many of these genetic tools are not always available to study pathogenic bacteria.

Insertional mutagenesis in the zoonotic pathogen Chlamydia caviae.

The ability to introduce targeted genetic modifications in microbial genomes has revolutionized our ability to study the role and mode of action of individual bacterial virulence factors. Although the fastidious lifestyle of obligate intracellular bacterial pathogens poses a technical challenge to such manipulations, the last decade has produced significant advances in our ability to conduct molecular genetic analysis in Chlamydia trachomatis, a major bacterial agent of infertility and blindness. Similar approaches have not been established for the closely related veterinary Chlamydia spp.

Insights into the Autoproteolytic Processing and Catalytic Mechanism of the Virulence-Associated Protease CPAF.

CPAF (chlamydial protease-like activity factor) is a protease that is translocated into the host cytosol during infection. CPAF activity results in dampened host inflammation signaling, cytoskeletal remodeling, and suppressed neutrophil activation. Although CPAF is an emerging antivirulence target, its catalytic mechanism has been unexplored to date.

A renewed tool kit to explore pathogenesis: from molecular genetics to new infection models.

is the most prevalent sexually transmitted bacterial pathogen and the leading cause of preventable blindness in the developing world. invades the epithelium of the conjunctiva and genital tract and replicates within an intracellular membrane-bound compartment termed the inclusion. To invade and replicate in mammalian cells, remodels epithelial surfaces by reorganizing the cytoskeleton and cell-cell adhesions, reprograms membrane trafficking, and modulates cell signaling to dampen innate immune responses.