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Item Correction: γδ T cell IFNγ production is directly subverted by Yersinia pseudotuberculosis outer protein YopJ in mice and humans(Public Library of Science, 2022-05-25) Chu, Timothy H.; Khairallah, Camille; Shieh, Jason; Cho, Rhea; Qiu, Zhijuan; Zhang, Yue; Eskiocak, Onur; Thanassi, David G.; Kaplan, Mark H.; Beyaz, Semir; Yang, Vincent W.; Bliska, James B.; Sheridan, Brian S.; Microbiology and Immunology, School of MedicineThis corrects the article "γδ T cell IFNγ production is directly subverted by Yersinia pseudotuberculosis outer protein YopJ in mice and humans" in volume 17, e1010103.Item Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db/db Mice(American Diabetes Association, 2018-09) Beli, Eleni; Yan, Yuanqing; Moldovan, Leni; Vieira, Cristiano P.; Gao, Ruli; Duan, Yaqian; Prasad, Ram; Bhatwadekar, Ashay; White, Fletcher A.; Townsend, Steven D.; Chan, Luisa; Ryan, Caitlin N.; Morton, Daniel; Moldovan, Emil G.; Chu, Fang-I; Oudit, Gavin Y.; Derendorf, Hartmut; Adorini, Luciano; Wang, Xiaoxin X.; Evans-Molina, Carmella; Mirmira, Raghavendra G.; Boulton, Michael E.; Yoder, Mervin C.; Li, Qiuhong; Levi, Moshe; Busik, Julia V.; Grant, Maria B.; Pediatrics, School of MedicineIntermittent fasting (IF) protects against the development of metabolic diseases and cancer, but whether it can prevent diabetic microvascular complications is not known. In db/db mice, we examined the impact of long-term IF on diabetic retinopathy (DR). Despite no change in glycated hemoglobin, db/db mice on the IF regimen displayed significantly longer survival and a reduction in DR end points, including acellular capillaries and leukocyte infiltration. We hypothesized that IF-mediated changes in the gut microbiota would produce beneficial metabolites and prevent the development of DR. Microbiome analysis revealed increased levels of Firmicutes and decreased Bacteroidetes and Verrucomicrobia. Compared with db/db mice on ad libitum feeding, changes in the microbiome of the db/db mice on IF were associated with increases in gut mucin, goblet cell number, villi length, and reductions in plasma peptidoglycan. Consistent with the known modulatory effects of Firmicutes on bile acid (BA) metabolism, measurement of BAs demonstrated a significant increase of tauroursodeoxycholate (TUDCA), a neuroprotective BA, in db/db on IF but not in db/db on AL feeding. TGR5, the TUDCA receptor, was found in the retinal primary ganglion cells. Expression of TGR5 did not change with IF or diabetes. However, IF reduced retinal TNF-α mRNA, which is a downstream target of TGR5 activation. Pharmacological activation of TGR5 using INT-767 prevented DR in a second diabetic mouse model. These findings support the concept that IF prevents DR by restructuring the microbiota toward species producing TUDCA and subsequent retinal protection by TGR5 activation.Item Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response(Springer Nature, 2019-01-03) Haberman, Yael; Karns, Rebekah; Dexheimer, Phillip J.; Schirmer, Melanie; Somekh, Judith; Jurickova, Ingrid; Braun, Tzipi; Novak, Elizabeth; Bauman, Laura; Collins, Margaret H.; Mo, Angela; Rosen, Michael J.; Bonkowski, Erin; Gotman, Nathan; Marquis, Alison; Nistel, Mason; Rufo, Paul A.; Baker, Susan S.; Sauer, Cary G.; Markowitz, James; Pfefferkorn, Marian D.; Rosh, Joel R.; Boyle, Brendan M.; Mack, David R.; Baldassano, Robert N.; Shah, Sapana; Leleiko, Neal S.; Heyman, Melvin B.; Grifiths, Anne M.; Patel, Ashish S.; Noe, Joshua D.; Aronow, Bruce J.; Kugathasan, Subra; Walters, Thomas D.; Gibson, Greg; Thomas, Sonia Davis; Mollen, Kevin; Shen-Orr, Shai; Huttenhower, Curtis; Xavier, Ramnik J.; Hyams, Jeffrey S.; Denson, Lee A.; Pediatrics, School of MedicineMolecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α4β7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.Item γδ T cell IFNγ production is directly subverted by Yersinia pseudotuberculosis outer protein YopJ in mice and humans(Public Library of Science, 2021-12-06) Chu, Timothy H.; Khairallah, Camille; Shieh, Jason; Cho, Rhea; Qiu, Zhijuan; Zhang, Yue; Eskiocak, Onur; Thanassi, David G.; Kaplan, Mark H.; Beyaz, Semir; Yang, Vincent W.; Bliska, James B.; Sheridan, Brian S.; Microbiology and Immunology, School of MedicineYersinia pseudotuberculosis is a foodborne pathogen that subverts immune function by translocation of Yersinia outer protein (Yop) effectors into host cells. As adaptive γδ T cells protect the intestinal mucosa from pathogen invasion, we assessed whether Y. pseudotuberculosis subverts these cells in mice and humans. Tracking Yop translocation revealed that the preferential delivery of Yop effectors directly into murine Vγ4 and human Vδ2+ T cells inhibited anti-microbial IFNγ production. Subversion was mediated by the adhesin YadA, injectisome component YopB, and translocated YopJ effector. A broad anti-pathogen gene signature and STAT4 phosphorylation levels were inhibited by translocated YopJ. Thus, Y. pseudotuberculosis attachment and translocation of YopJ directly into adaptive γδ T cells is a major mechanism of immune subversion in mice and humans. This study uncovered a conserved Y. pseudotuberculosis pathway that subverts adaptive γδ T cell function to promote pathogenicity.