Biology subjects

Flynn, K. J.

Publications and source records attributed to Flynn, K. J..

4 recordsLinked to original sources

bioRxiv2022

The gut bacterial community potentiates Clostridioides difficile infection severity

The severity of Clostridioides difficile infections (CDI) has increased over the last few decades. Patient age, white blood cell count, creatinine levels as well as C. difficile ribotype and toxin genes have been associated with disease severity. However, it is unclear whether there is an association between members of the gut microbiota and disease severity. The gut microbiota is known to interact with C. difficile during infection. Perturbations to the gut microbiota are necessary for C. difficile to colonize the gut. The gut microbiota can inhibit C. difficile colonization through bile acid metabolism, nutrient consumption and bacteriocin production. Here we sought to demonstrate that members of the gut bacterial communities can also contribute to disease severity. We derived diverse gut communities by colonizing germ-free mice with different human fecal communities. The mice were then infected with a single C. difficile ribotype 027 clinical isolate which resulted in moribundity and histopathologic differences. The variation in severity was associated with the human fecal community that the mice received. Generally, bacterial populations with pathogenic potential, such as Escherichia, Helicobacter, and Klebsiella, were associated with more severe outcomes. Bacterial groups associated with fiber degradation, bile acid metabolism and lantibiotic production, such as Anaerostipes and Coprobacillus, were associated with less severe outcomes. These data indicate that, in addition to the host and C. difficile, populations of gut bacteria can influence CDI disease severity. ImportanceClostridioides difficile colonization can be asymptomatic or develop into an infection, ranging in severity from mild diarrhea to toxic megacolon, sepsis, and death. Models that predict severity and guide treatment decisions are based on clinical factors and C. difficile characteristics. Although the gut microbiome plays a role in protecting against CDI, its effect on CDI disease severity is unclear and has not been incorporated into disease severity models. We demonstrated that variation in the microbiome of mice colonized with human feces yielded a range of disease outcomes. These results revealed groups of bacteria associated with both severe and mild C. difficile infection outcomes. Gut bacterial community data from patients with CDI could improve our ability to identify patients at risk of developing more severe disease and improve interventions which target C. difficile and the gut bacteria to reduce host damage.

microbiology↗

bioRxiv2021

Permutational immune analysis reveals architectural similarities between inflammaging, Down syndrome and autoimmunity

People with Down syndrome show cellular and clinical features of dysregulated aging of the immune system, including naive-memory shift in the T cell compartment and increased incidence of autoimmunity. However, a quantitative understanding of how various immune compartments change with age in Down syndrome remains lacking. Here we performed deep immunophenotyping of a cohort of individuals with Down syndrome across the lifespan, selecting for individuals not affected by autoimmunity. We simultaneously interrogated age- and sex-matched healthy neurotypical controls and people with type 1 diabetes, as a representative autoimmune disease. We built a new analytical software, IMPACD, that enabled us to rapidly identify many features of immune dysregulation in Down syndrome that are recapitulated in other autoimmune diseases. We found significant quantitative and qualitative dysregulation of naive CD4+ and CD8+ T cells in Down syndrome and identified IL-6 as a candidate driver of some of these changes, thus extending the consideration of immunopathologic cytokines in Down syndrome beyond interferons. Notably, we successfully used immune cellular composition to generate three quantitative models of aging (i.e. immune clocks) trained on control subjects. All three immune clocks demonstrated significantly advanced immune aging in people with Down syndrome. Notably, one of these clocks, informed by Down syndrome-relevant biology, also showed advanced immune aging in people with type 1 diabetes. Together, our findings demonstrate a novel approach to studying immune aging in Down syndrome which may have implications in the context of other autoimmune diseases. One Sentence SummaryPermutational analysis of immune landscape reveals advanced immune aging in people with Down syndrome and in people with type 1 diabetes.

immunology↗

bioRxiv2019

DCA promotes a novel tolerogenic program in CD4+ T cells by inhibiting CDK8

Immune health requires innate and adaptive immune cells to engage precisely balanced pro- and anti-inflammatory forces. We employ the concept of chemical immunophenotypes to classify small molecules functionally or mechanistically according to their patterns of effects on primary innate and adaptive immune cells. The high-specificity, low-toxicity cyclin dependent kinase 8 (CDK8) inhibitor DCA exerts a distinct tolerogenic profile in both innate and adaptive immune cells. DCA promotes Treg and Th2 differentiation, while inhibiting Th1 and Th17 differentiation, in both murine and human cells. This unique chemical immunophenotype led to mechanistic studies showing that DCA promotes Treg differentiation in part by regulating a previously undescribed CDK8-GATA3-FOXP3 pathway that regulates early pathways of Foxp3 expression. These results highlight previously unappreciated links between Treg and Th2 differentiation and extend our understanding of the transcription factors that regulate Treg differentiation and their temporal sequencing. These findings have significant implications for future mechanistic and translational studies of CDK8 and CDK8 inhibitors.

immunology↗

bioRxiv2017

Spatial variation of the native colon microbiota in healthy adults

The microbiome has been implicated in the development of colorectal cancer (CRC) and inflammatory bowel diseases (IBD). The specific traits of these diseases vary along the axis of the digestive tract. Further, variation in the structure of the gut microbiota has been associated with both diseases. Here we profiled the microbiota of the healthy proximal and distal mucosa and lumen to better understand how bacterial populations vary along the colon. We used a two-colonoscope approach to sample proximal and distal mucosal and luminal contents from the colons of 20 healthy subjects that had not undergone any bowel preparation procedure. The biopsies and home-collected stool were subjected to 16S rRNA gene sequencing and Random Forest classification models were built using taxa abundance and location to identify microbiota specific to each site. The right mucosa and lumen had the most similar community structures of the five sites we considered from each subject. The distal mucosa had higher relative abundance of Finegoldia, Murdochiella, Peptoniphilus, Porphyromonas and Anaerococcus. The proximal mucosa had more of the genera Enterobacteriaceae, Bacteroides and Pseudomonas. The classification model performed well when classifying mucosal samples into proximal or distal sides (AUC = 0.808). Separating proximal and distal luminal samples proved more challenging (AUC = 0.599) and specific microbiota that differentiated the two were hard to identify. By sampling the unprepped colon, we identified distinct bacterial populations native to the proximal and distal sides. Further investigation of these bacteria may elucidate if and how these groups contribute to different disease processes on their respective sides of the colon.

microbiology↗