Biology subjects

Kao, J. Y.

Publications and source records attributed to Kao, J. Y..

6 recordsLinked to original sources

bioRxiv2025

Immune phenotype-guided identification of disease-associated pathobionts in Crohn's disease

Aberrant immune activation within the gut mucosa and gut dysbiosis have been implicated in the pathogenesis of Crohns disease (CD). However, the specific immune responses triggered by dysbiotic microbiota, as well as the bacteria responsible for this activation, remain incompletely understood. Here, using the human microbiota-associated (HMA) mouse system, we demonstrated that colonization with dysbiotic gut microbiota from CD patients specifically induces the accumulation of mononuclear phagocytes, which may drive an interleukin-1 (IL-1)-driven inflammatory signature. Moreover, we identified pathobiont strains with a potent IL-1{beta}-inducing capacity, termed IL-1{beta}-inducing pathobionts (IBIP). Isolated IBIP strains exhibit genetic and functional similarities to adherent-invasive Escherichia coli but harbor unique virulence-associated genes. Colonization with the IBIP E. coli strain exacerbated experimental colitis in an IL-1 signal-dependent manner. Notably, the colonization of IBIP E. coli can be detected by measuring the levels of specific immunoglobulin A (IgA) in their stool samples. Moreover, the level of IBIP-reactive IgA in stool may serve as a predictive biomarker for treatment response to anti-TNF therapies in treatment-naive pediatric CD patients. Altogether, IBIP colonization could help identify CD patients with inflammatory dysbiosis who are likely to be refractory to anti-TNF therapies.

immunology↗

bioRxiv2024

Inflammation induced Th17 cells synergize with the inflammation-trained microbiota to mediate host-resiliency against intestinal injury

Background and AimsInflammation can generate pathogenic Th17 cells and cause a inflammatory dysbiosis. In the context of Inflammatory Bowel Disease (IBD) these inflammatory Th17 cells and dysbiotic microbiota may perpetuate injury to intestinal epithelial cells (IECs). However, many models of IBD like T-cell transfer colitis and IL-10-/- mice rely on the absence of regulatory pathways, so it is difficult to tell if inflammationcan also induce protective Th17 cells. MethodsWe subjected C57BL6, RAG1-/- or JH-/- mice to systemic or gastrointestinal (GI) Citrobacter rodentium (Cr). Mice were then subject to 2.5% dextran sodium sulfate to cause epithelial injury. Fecal microbiota transfer was performed by bedding transfer and co-housing. Flow cytometry, qPCR, 16s sequencing and histology were used to assess parameters. ResultsTransient inflammation with GI but not systemic Cr was protective from subsequent intestinal injury. This was replicated with sequential DSS collectively indicating that transient inflammation provides tissue-specific protection. Inflammatory Th17 cells that have a tissue resident memory signature expanded in the intestine. Experiments with reconstituted RAG1-/-, JH-/- mice and cell trafficking inhibitors showed that inflammation induced Th17 cells were required for protection. Fecal microbiota transfer showed that the inflammation-trained microbiota was necessary for protection, likely by maintaining protective Th17 cells in situ. ConclusionInflammation can generate protective Th17 cells which synergize with the inflammation-trained microbiota to provide host resiliency against subsequent injury, indicating that inflammation induced Th17 tissue resident memory T cells are heterogenous and contain protective subsets.

immunology↗

bioRxiv2023

IL-15 promotes inflammatory Th17 cells in the intestine

Ulcerative Colitis (UC) is a chronic gastrointestinal condition with high morbidity. While modern medical therapies have revolutionized the care of UC, 10-25% of patients fail medications and still progress to surgery. Thus, developing new treatments is a core problem in UC. T-cells, especially Th17 cells, are strongly linked with UC and are major targets of medications in UC. Tissue-resident memory T-cells (TRM) are a distinct class of T-cells that are highly enriched in the intestine, closely aligned with the microbiota, and are implicated in the pathogenesis of UC. Unlike circulating T-cells, TRM are difficult to target because they do not recirculate. Thus, we focused on cytokines like IL-15 which act as a tissue danger signal and regulate T-cells in situ. We found that the IL15 axis is upregulated in UC and predicts treatment response. IL-15 was redundant for Th17 differentiation but could activate terminally differentiated Th17 cells to promote intestinal inflammation. Finally, in CD4+ TRM from patients with UC, IL-15 upregulated RORC, the master transcription factor for Th17 cells, via a Janus Kinase (JAK)1 pathway. Thus, IL-15 promotes terminally differentiated inflammatory Th17 cells in the intestine raising the possibility that IL-15 may be a target for UC treatments.

immunology↗

bioRxiv2022

Mucolytic bacteria license pathobionts to acquire host-derived nutrients during dietary nutrient restriction

Pathobionts employ unique metabolic adaptation mechanisms to maximize their growth in disease conditions. Adherent-invasive Escherichia coli (AIEC), a pathobiont enriched in the gut mucosa of patients with inflammatory bowel disease (IBD), utilizes diet-derived L-serine to adapt to the inflamed gut. Therefore, the restriction of dietary L-serine starves AIEC and limits its fitness advantage. Here, we find that AIEC can overcome this nutrient limitation by switching the nutrient source from the diet to the host cells in the presence of mucolytic bacteria. During diet-derived L-serine restriction, the mucolytic symbiont Akkermansia muciniphila promotes the encroachment of AIEC to the epithelial niche by degrading the mucus layer. In the epithelial niche, AIEC acquires L-serine from the colonic epithelium and thus proliferates. Our work suggests that the indirect metabolic network between pathobionts and commensal symbionts enables pathobionts to overcome nutritional restriction and thrive in the gut.

microbiology↗

bioRxiv2017

Chemotaxis allows bacteria to overcome host-generated reactive oxygen species that constrain gland colonization

The epithelial layer of the gastrointestinal tract contains invaginations, called glands or crypts, which are colonized by symbiotic and pathogenic microorganisms and may function as designated niches for certain species. Factors that control gland colonization are poorly understood, but bacterial chemotaxis aids occupation of these sites. We report here that a Helicobacter pylori cytoplasmic chemoreceptor, TlpD, is required for gland colonization in the stomach. tlpD mutants demonstrate gland colonization defects characterized by a reduction in the percent of glands colonized, but not in number of bacteria per gland. Consistent with TlpDs reported role in reactive oxygen species (ROS) avoidance, tlpD mutants showed hallmarks of exposure to large amounts of ROS. To assess the role of host-generated ROS in TlpD-dependent gland colonization, we utilized mice that lack either the ability to generate epithelial hydrogen peroxide or immune cell superoxide. tlpD gland colonization defects were rescued to wild-type H. pylori levels in both of these mutants. These results suggest that multiple types of innate immune generated ROS production limit gland colonization and that bacteria have evolved specific mechanisms to migrate through this gauntlet to establish in the glands.\n\nClassification: Biological sciences; microbiology\n\nSignificance statementMicrobial colonization of the gastrointestinal tract occurs at distinct sites within the tissue including glandular structures found in the stomach and intestine. Multiple lines of evidence suggest that glands supply niches that promote chronic microbial colonization, a process that is critical for symbiotic and pathogenic bacteria to maintain themselves. In this report, we show that host-produced reactive oxygen species (ROS) constrain gland colonization by the gastric pathogen Helicobacter pylori. A bacterial cytoplasmic chemoreceptor, TlpD, allows H. pylori to avoid ROS and enhances H. pyloris ability to colonize a broad swath of glands. We propose that hosts limit gland access and spread by producing ROS, and bacteria counter with chemotactic responses that allow navigation through this gauntlet.

microbiology↗

bioRxiv2017

Inter-individual Recovery Of The Microbiota And Metabolome Over Time Following Fecal Microbiota Transplantation In Patients With Recurrent Clostridium difficile Infection

A significant proportion of individuals develop recurrent Clostridium difficile infection (CDI) following initial disease. Fecal microbiota transplantation (FMT), a highly effective treatment method for recurrent CDI, has been demonstrated to induce microbiota recovery, a critical component of disease recovery. However, identification of the specific microbes and their functions that directly impact recovery from CDI remains difficult. We assessed for associations among microbial community members and metabolites in patients with recurrent CDI following treatment with FMT over time to identify groups of bacteria with potential restorative functions. Using 16S rRNA gene-based sequencing, we observed marked similarity of the microbiota between recipients following FMT (n = 6, sampling up to 6 months post-FMT) and their respective donors. Increased levels of the secondary bile acid deoxycholic acid and the short chain fatty acids (SCFAs) butyrate, acetate, and propionate were observed post-FMT. To take into account longitudinal sampling and intra-individual differences, we applied a generalized estimating equation approach to model metabolite concentrations with the presence of specific members of the microbiota. Microbial metabolites that were increased following FMT associated with members classified within the Lachnospiraceae, Ruminococcaceae, and unclassified Clostridiales families. In contrast, members of these taxa were inversely associated with primary bile acids. The longitudinal aspect of this study allowed us to characterize individualized patterns of recovery, revealing variability between and within patients following FMT.\n\nIMPORTANCEClostridium difficile infection (CDI) is an urgent and serious healthcare-associated problem. In recent years, fecal microbiota transplantation (FMT) has been successfully used to treat recurrent CDI, a frequent outcome of disease. While it is apparent that FMT promotes recovery of the microbiota, it is unclear how microbes and their functions promote recovery from disease. This study aimed to identify associations among microbes and metabolites following FMT and to identify critical microbial functions following FMT treatment for recurrent CDI. Overall, recovery of the metabolome was highly dynamic and individualized in all patients, who were all successfully treated. Our results suggest that microbial changes following FMT may be highly specific to the donor-recipient relationship. Further understanding of the host-microbe environments necessary to enable successful transplantation of microbes during FMT could aid development of specific microbial therapeutics for recurrent CDI and other gastrointestinal diseases.

microbiology↗