Gabe M. Barrón

All Publications

• Tuft cells mediate commensal remodeling of the small intestinal antimicrobial landscape. Proceedings of the National Academy of Sciences of the United States of America Fung, C., Fraser, L. M., Barrón, G. M., Gologorsky, M. B., Atkinson, S. N., Gerrick, E. R., Hayward, M., Ziegelbauer, J., Li, J. A., Nico, K. F., Tyner, M. D., DeSchepper, L. B., Pan, A., Salzman, N. H., Howitt, M. R. 2023; 120 (23): e2216908120

  Abstract

  Succinate produced by the commensal protist Tritrichomonas musculis (T. mu) stimulates chemosensory tuft cells, resulting in intestinal type 2 immunity. Tuft cells express the succinate receptor SUCNR1, yet this receptor does not mediate antihelminth immunity nor alter protist colonization. Here, we report that microbial-derived succinate increases Paneth cell numbers and profoundly alters the antimicrobial peptide (AMP) landscape in the small intestine. Succinate was sufficient to drive this epithelial remodeling, but not in mice lacking tuft cell chemosensory components required to detect this metabolite. Tuft cells respond to succinate by stimulating type 2 immunity, leading to interleukin-13-mediated epithelial and AMP expression changes. Moreover, type 2 immunity decreases the total number of mucosa-associated bacteria and alters the small intestinal microbiota composition. Finally, tuft cells can detect short-term bacterial dysbiosis that leads to a spike in luminal succinate levels and modulate AMP production in response. These findings demonstrate that a single metabolite produced by commensals can markedly shift the intestinal AMP profile and suggest that tuft cells utilize SUCNR1 and succinate sensing to modulate bacterial homeostasis.

  View details for DOI 10.1073/pnas.2216908120

  View details for PubMedID 37253002

• Gut microbiota modulates bleomycin-induced acute lung injury response in mice. Respiratory research Yoon, Y. M., Hrusch, C. L., Fei, N., Barrón, G. M., Mills, K. A., Hollinger, M. K., Velez, T. E., Leone, V. A., Chang, E. B., Sperling, A. I. 2022; 23 (1): 337

  Abstract

  Airway instillation of bleomycin (BLM) in mice is a widely used, yet challenging, model for acute lung injury (ALI) with high variability in treatment scheme and animal outcomes among investigators. Whether the gut microbiota plays any role in the outcome of BLM-induced lung injury is currently unknown.Intratracheal instillation of BLM into C57BL/6 mice was performed. Fecal microbiomes were analyzed by 16s rRNA amplicon and metagenomic sequencing. Germ-free mice conventionalization and fecal microbiota transfer between SPF mice were performed to determine dominant commensal species that are associated with more severe BLM response. Further, lungs and gut draining lymph nodes of the mice were analyzed by flow cytometry to define immunophenotypes associated with the BLM-sensitive microbiome.Mice from two SPF barrier facilities at the University of Chicago exhibited significantly different mortality and weight loss during BLM-induced lung injury. Conventionalizing germ-free mice with SPF microbiota from two different housing facilities recapitulated the respective donors' response to BLM. Fecal microbiota transfer from the facility where the mice had worse mortality into the mice in the facility with more survival rendered recipient mice more susceptible to BLM-induced weight loss in a dominant negative manner. BLM-sensitive phenotype was associated with the presence of Helicobacter and Desulfovibrio in the gut, decreased Th17-neutrophil axis during steady state, and augmented lung neutrophil accumulation during the acute phase of the injury response.The composition of gut microbiota has significant impact on BLM-induced wasting and death suggesting a role of the lung-gut axis in lung injury.

  View details for DOI 10.1186/s12931-022-02264-7

  View details for PubMedID 36496380

  View details for PubMedCentralID PMC9741526

• Gut microbiota modulate susceptibility to bleomycin-induced lung injury Yoon, Y., Barron, G. M., Hrusch, C. L., Fei, N., Leone, V. A., Sperling, A. I. AMER ASSOC IMMUNOLOGISTS. 2021

  View details for Web of Science ID 000713665801316

• P311 Promotes Lung Fibrosis via Stimulation of Transforming Growth Factor-β1, -β2, and -β3 Translation. American journal of respiratory cell and molecular biology Duan, F. F., Barron, G., Meliton, A., Mutlu, G. M., Dulin, N. O., Schuger, L. 2019; 60 (2): 221-231

  Abstract

  Interstitial lung fibrosis, a frequently idiopathic and fatal disease, has been linked to the increased expression of profibrotic transforming growth factor (TGF)-βs. P311 is an RNA-binding protein that stimulates TGF-β1, -β2, and -β3 translation in several cell types through its interaction with the eukaryotic translation initiation factor 3b. We report that P311 is switched on in the lungs of patients with idiopathic pulmonary fibrosis (IPF) and in the mouse model of bleomycin (BLM)-induced pulmonary fibrosis. To assess the in vivo role of P311 in lung fibrosis, BLM was instilled into the lungs of P311-knockout mice, in which fibrotic changes were significantly decreased in tandem with a reduction in TGF-β1, -β2, and -β3 concentration/activity compared with BLM-treated wild-type mice. Complementing these findings, forced P311 expression increased TGF-β concentration/activity in mouse and human lung fibroblasts, thereby leading to an activated phenotype with increased collagen production, as seen in IPF. Consistent with a specific effect of P311 on TGF-β translation, TGF-β1-, -β2-, and -β3-neutralizing antibodies downregulated P311-induced collagen production by lung fibroblasts. Furthermore, treatment of BLM-exposed P311 knockouts with recombinant TGF-β1, -β2, and -β3 induced pulmonary fibrosis to a degree similar to that found in BLM-treated wild-type mice. These studies demonstrate the essential function of P311 in TGF-β-mediated lung fibrosis. Targeting P311 could prove efficacious in ameliorating the severity of IPF while circumventing the development of autoimmune complications and toxicities associated with the use of global TGF-β inhibitors.

  View details for DOI 10.1165/rcmb.2018-0028OC

  View details for PubMedID 30230348

  View details for PubMedCentralID PMC6376409