IL-22-dependent responses and their role during Citrobacter rodentium infection Karine Melchior, Romana R. Gerner, Suzana Hossain, Sean-Paul Nuccio, Cristiano Gallina Moreira, et al. Infection and Immunity, 2024 The mouse pathogen Citrobacter rodentium is utilized as a model organism for studying infections caused by the human pathogens enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) and to elucidate mechanisms of mucosal immunity. In response to C. rodentium infection, innate lymphoid cells and T cells secrete interleukin (IL)-22, a cytokine that promotes mucosal barrier function. IL-22 plays a pivotal role in enabling mice to survive and recover from C. rodentium infection, although the exact mechanisms involved remain incompletely understood. Here, we investigated whether particular components of the host response downstream of IL-22 contribute to the cytokine’s protective effects during C. rodentium infection. In line with previous research, mice lacking the IL-22 gene ( Il22 −/− mice) were highly susceptible to C. rodentium infection. To elucidate the role of specific antimicrobial proteins modulated by IL-22, we infected the following knockout mice: S100A9 −/− (calprotectin), Lcn2 −/− (lipocalin-2), Reg3b −/− (Reg3β), Reg3g −/− (Reg3γ), and C3 −/− (C3). All knockout mice tested displayed a considerable level of resistance to C. rodentium infection, and none phenocopied the lethality observed in Il22 −/− mice. By investigating another arm of the IL-22 response, we observed that C. rodentium -infected Il22 −/ − mice exhibited an overall decrease in gene expression related to intestinal barrier integrity as well as significantly elevated colonic inflammation, gut permeability, and pathogen levels in the spleen. Taken together, these results indicate that host resistance to lethal C. rodentium infection may depend on multiple antimicrobial responses acting in concert, or that other IL-22-regulated processes, such as tissue repair and maintenance of epithelial integrity, play crucial roles in host defense to attaching and effacing pathogens.
lipocalin-2 expression identifies an intestinal regulatory neutrophil population during acute graft-versus-host disease Marie Czech, Sophia Schneider, Nina Peltokangas, Nadia El Khawanky, Sakhila Ghimire, et al. Science Translational Medicine, 2024 Acute graft-versus-host disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT), for which therapeutic options are limited. Strategies to promote intestinal tissue tolerance during aGVHD may improve patient outcomes. Using single-cell RNA sequencing, we identified a lipocalin-2 (LCN2)–expressing neutrophil population in mice with intestinal aGVHD. Transfer of LCN2-overexpressing neutrophils or treatment with recombinant LCN2 reduced aGVHD severity, whereas the lack of epithelial or hematopoietic LCN2 enhanced aGVHD severity and caused microbiome alterations. Mechanistically, LCN2 induced insulin-like growth factor 1 receptor (IGF-1R) signaling in macrophages through the LCN2 receptor SLC22A17, which increased interleukin-10 (IL-10) production and reduced major histocompatibility complex class II (MHCII) expression. Transfer of LCN2-pretreated macrophages reduced aGVHD severity but did not reduce graft-versus-leukemia effects. Furthermore, LCN2 expression correlated with IL-10 expression in intestinal biopsies in multiple cohorts of patients with aGVHD, and LCN2 induced IGF-1R signaling in human macrophages. Collectively, we identified a LCN2-expressing intestinal neutrophil population that reduced aGVHD severity by decreasing MHCII expression and increasing IL-10 production in macrophages. This work provides the foundation for administration of LCN2 as a therapeutic approach for aGVHD.
Commensal bacteria promote type I interferon signaling to maintain immune tolerance in mice Adriana Vasquez Ayala, Chia-Yun Hsu, Renee E. Oles, Kazuhiko Matsuo, Luke R. Loomis, et al. Journal of Experimental Medicine, 2024 Type I interferons (IFNs) exert a broad range of biological effects important in coordinating immune responses, which have classically been studied in the context of pathogen clearance. Yet, whether immunomodulatory bacteria operate through IFN pathways to support intestinal immune tolerance remains elusive. Here, we reveal that the commensal bacterium, Bacteroides fragilis, utilizes canonical antiviral pathways to modulate intestinal dendritic cells (DCs) and regulatory T cell (Treg) responses. Specifically, IFN signaling is required for commensal-induced tolerance as IFNAR1-deficient DCs display blunted IL-10 and IL-27 production in response to B. fragilis. We further establish that IFN-driven IL-27 in DCs is critical in shaping the ensuing Foxp3+ Treg via IL-27Rα signaling. Consistent with these findings, single-cell RNA sequencing of gut Tregs demonstrated that colonization with B. fragilis promotes a distinct IFN gene signature in Foxp3+ Tregs during intestinal inflammation. Altogether, our findings demonstrate a critical role of commensal-mediated immune tolerance via tonic type I IFN signaling.
Siderophore Immunization Restricted Colonization of Adherent-Invasive Escherichia coli and Ameliorated Experimental Colitis Romana R. Gerner, Suzana Hossain, Artur Sargun, Kareem Siada, Grant J. Norton, et al. Mbio, 2022 Adherent-invasive Escherichia coli (AIEC) is abnormally prevalent in patients with ileal Crohn’s disease and exacerbates intestinal inflammation, but treatment strategies that selectively target AIEC are unavailable. Iron is an essential micronutrient for most living organisms, and bacterial pathogens have evolved sophisticated strategies to capture iron from the host environment.
Siderophore-mediated zinc acquisition enhances enterobacterial colonization of the inflamed gut Judith Behnsen, Hui Zhi, Allegra T. Aron, Vivekanandan Subramanian, William Santus, et al. Nature Communications, 2021 Zinc is an essential cofactor for bacterial metabolism, and many Enterobacteriaceae express the zinc transporters ZnuABC and ZupT to acquire this metal in the host. However, the probiotic bacterium Escherichia coli Nissle 1917 (or “Nissle”) exhibits appreciable growth in zinc-limited media even when these transporters are deleted. Here, we show that Nissle utilizes the siderophore yersiniabactin as a zincophore, enabling Nissle to grow in zinc-limited media, to tolerate calprotectin-mediated zinc sequestration, and to thrive in the inflamed gut. We also show that yersiniabactin’s affinity for iron or zinc changes in a pH-dependent manner, with increased relative zinc binding as the pH increases. Thus, our results indicate that siderophore metal affinity can be influenced by the local environment and reveal a mechanism of zinc acquisition available to commensal and pathogenic Enterobacteriaceae.
Immunomodulatory metabolites define long-term gut microbiome recovery after allogeneic HCT and associate with improved survival and reduced relapse related mortality A Schwarz, T Eismann, T Zheng, S Holzinger, A Denk, S Goeldel, ... medRxiv, 2026.03. 26.26349381 , 2026 2026
Escherichia coli shapes intestinal B-cell responses and influences susceptibility to Inflammatory Bowel Disease S Adlkirchner, V Becker, V Betz, K Muhlschlegel, M Hubersberger, ... JOURNAL OF CROHNS & COLITIS 20 , 2026 2026
DOP144 Escherichia coli shapes intestinal B-cell responses and influences susceptibility to Inflammatory Bowel Disease S Adlkirchner, V Becker, V Betz, K Mühlschlegel, M Hubersberger, ... Journal of Crohn’s and Colitis 20 (Supplement_1), jjaf231. 181 , 2026 2026
The role of microbial metabolites in fecal microbiota transplantation in patients with acute gvhd of the gut A Schwarz, S Holzinger, P Herhaus, M Verbeek, K Neuhaus, K Kleigrewe, ... Blood 146 (Supplement 1), 4236-4236 , 2025 2025
Commensal Escherichia coli colonization triggers Peyer’s patch development RR Gerner, GT Walker, SM Klaus, K Melchior, S Hossain, K Siada, ... bioRxiv, 2025.10. 06.680803 , 2025 2025
Uniting against enteric invaders: IgA meets its microbial ally S Adlkirchner, RR Gerner Cell Host & Microbe 33 (6), 932-934 , 2025 2025
Multidimensional differences of right-and left-sided colorectal cancer and their impact on targeted therapies MA Hamid, LM Pammer, S Oberparleiter, M Günther, A Amann, ... NPJ precision oncology 9, 116 , 2025 2025 Citations: 17
Multidimensional differences of right-and left-sided colorectal cancer and their impact on targeted therapies M Abdel Hamid, LM Pammer, S Oberparleiter, M Günther, A Amann, ... npj Precision Oncology 9 (1), 116 , 2025 2025 Citations: 20
Clonal Hematopoiesis and Immune Cell Phenotypes as Predictive Biomarkers of CAR-T Therapy Outcomes in Multiple Myeloma A Purcarea, S Baumann, S Stein, J Ferstl, F Bassermann, RR Gerner, ... 2025
Loss of Microbiota-Derived Metabolites Is Associated with Mucosal-Barrier-Injury Bloodstream Infection in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation S Göldel, T Zheng, T Eismann, M Tiefgraber, M Urban, A Schwarz, ... Blood 144 (Supplement 1), 4904-4904 , 2024 2024
CCL28 modulates neutrophil responses during infection with mucosal pathogens GT Walker, A Perez-Lopez, S Silva, MH Lee, E Bjånes, N Dillon, ... Elife 13, e78206 , 2024 2024 Citations: 7
IL-22-dependent responses and their role during Citrobacter rodentium infection K Melchior, RR Gerner, S Hossain, SP Nuccio, CG Moreira, M Raffatellu Infection and immunity 92 (5), e00099-24 , 2024 2024 Citations: 19
Lipocalin-2 expression identifies an intestinal regulatory neutrophil population during acute graft-versus-host disease M Czech, S Schneider, N Peltokangas, N El Khawanky, S Ghimire, ... Science translational medicine 16 (735), eadi1501 , 2024 2024 Citations: 31
Commensal bacteria promote type I interferon signaling to maintain immune tolerance in mice A Vasquez Ayala, CY Hsu, RE Oles, K Matsuo, LR Loomis, E Buzun, ... Journal of Experimental Medicine 221 (1), e20230063 , 2023 2023 Citations: 52
Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of T H 17 cell immunity CH Lin, CJ Wu, S Cho, R Patkar, WJ Huth, LL Lin, MC Chen, E Israelsson, ... Nature immunology 24 (12), 2108-2120 , 2023 2023 Citations: 44
Murine Models of Salmonella Infection GT Walker, RR Gerner, SP Nuccio, M Raffatellu Current protocols 3 (7), e824 , 2023 2023 Citations: 40
Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of Th17 immunity CH Lin, CJ Wu, S Cho, R Patkar, LL Lin, MC Chen, E Israelsson, J Betts, ... bioRxiv , 2023 2023 Citations: 3
Siderophore Immunization Restricted Colonization of Adherent-Invasive Escherichia RR Gerner, S Hossain, A Sargun mBio, 13 (5) , 2022 2022
Siderophore immunization restricted colonization of adherent-invasive Escherichia coli and ameliorated experimental colitis RR Gerner, S Hossain, A Sargun, K Siada, GJ Norton, T Zheng, ... MBio 13 (5), e02184-22 , 2022 2022 Citations: 27
Multi-omics analyses of the ulcerative colitis gut microbiome link Bacteroides vulgatus proteases with disease severity RH Mills, PS Dulai, Y Vázquez-Baeza, C Sauceda, N Daniel, RR Gerner, ... Nature microbiology 7 (2), 262-276 , 2022 2022 Citations: 389
MOST CITED SCHOLAR PUBLICATIONS
The intestinal microbiota in colorectal cancer H Tilg, TE Adolph, RR Gerner, AR Moschen Cancer cell 33 (6), 954-964 , 2018 2018 Citations: 910
Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease C Grander, TE Adolph, V Wieser, P Lowe, L Wrzosek, B Gyongyosi, ... Gut 67 (5), 891-901 , 2018 2018 Citations: 702
Lipocalin-2: a master mediator of intestinal and metabolic inflammation AR Moschen, TE Adolph, RR Gerner, V Wieser, H Tilg Trends in Endocrinology & Metabolism 28 (5), 388-397 , 2017 2017 Citations: 418
Lipocalin 2 protects from inflammation and tumorigenesis associated with gut microbiota alterations AR Moschen, RR Gerner, J Wang, V Klepsch, TE Adolph, SJ Reider, ... Cell host & microbe 19 (4), 455-469 , 2016 2016 Citations: 391
Multi-omics analyses of the ulcerative colitis gut microbiome link Bacteroides vulgatus proteases with disease severity RH Mills, PS Dulai, Y Vázquez-Baeza, C Sauceda, N Daniel, RR Gerner, ... Nature microbiology 7 (2), 262-276 , 2022 2022 Citations: 389
Dietary lipids fuel GPX4-restricted enteritis resembling Crohn’s disease L Mayr, F Grabherr, J Schwärzler, I Reitmeier, F Sommer, T Gehmacher, ... Nature communications 11 (1), 1775 , 2020 2020 Citations: 306
NAD metabolism fuels human and mouse intestinal inflammation RR Gerner, V Klepsch, S Macheiner, K Arnhard, TE Adolph, C Grander, ... Gut 67 (10), 1813-1823 , 2018 2018 Citations: 212
Pre-B cell colony enhancing factor/NAMPT/visfatin in inflammation and obesity-related disorders A R Moschen, R R Gerner, H Tilg Current pharmaceutical design 16 (17), 1913-1920 , 2010 2010 Citations: 165
Adult human and mouse ovaries lack DDX4-expressing functional oogonial stem cells H Zhang, S Panula, S Petropoulos, D Edsgärd, K Busayavalasa, L Liu, ... Nature medicine 21 (10), 1116-1118 , 2015 2015 Citations: 154
Adipose tissue and liver expression of SIRT1, 3, and 6 increase after extensive weight loss in morbid obesity AR Moschen, V Wieser, RR Gerner, A Bichler, B Enrich, P Moser, ... Journal of hepatology 59 (6), 1315-1322 , 2013 2013 Citations: 118
Lipocalin 2 drives neutrophilic inflammation in alcoholic liver disease V Wieser, P Tymoszuk, TE Adolph, C Grander, F Grabherr, B Enrich, ... Journal of Hepatology 64 (4), 872-880 , 2016 2016 Citations: 111
Metabolic inflammation: role of cytokines in the crosstalk between adipose tissue and liver RR Gerner, V Wieser, AR Moschen, H Tilg Canadian journal of physiology and pharmacology 91 (11), 867-872 , 2013 2013 Citations: 102
Pre-B cell colony enhancing factor/NAMPT/visfatin and its role in inflammation-related bone disease AR Moschen, S Geiger, R Gerner, H Tilg Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 690 (1 … , 2010 2010 Citations: 101
Siderophore-mediated zinc acquisition enhances enterobacterial colonization of the inflamed gut J Behnsen, H Zhi, AT Aron, V Subramanian, W Santus, MH Lee, ... Nature Communications 12 (1), 7016 , 2021 2021 Citations: 92
Lipocalin‐2 ensures host defense against Salmonella Typhimurium by controlling macrophage iron homeostasis and immune response M Nairz, A Schroll, D Haschka, S Dichtl, T Sonnweber, I Theurl, M Theurl, ... European journal of immunology 45 (11), 3073-3086 , 2015 2015 Citations: 77
Multi-omics analyses of the ulcerative colitis gut microbiome link Bacteroides vulgatus proteases with disease severity. Nat Microbiol 7: 262–276 RH Mills, PS Dulai, Y Vázquez-Baeza, C Sauceda, N Daniel, RR Gerner, ... 2022 Citations: 55
Liver complications in inflammatory bowel diseases V Wieser, R Gerner, AR Moschen, H Tilg Digestive diseases 31 (2), 233-238 , 2013 2013 Citations: 54
Iron at the host-microbe interface RR Gerner, SP Nuccio, M Raffatellu Molecular Aspects of Medicine 75, 100895 , 2020 2020 Citations: 53
Commensal bacteria promote type I interferon signaling to maintain immune tolerance in mice A Vasquez Ayala, CY Hsu, RE Oles, K Matsuo, LR Loomis, E Buzun, ... Journal of Experimental Medicine 221 (1), e20230063 , 2023 2023 Citations: 52
Nuclear orphan receptor NR2F6 as a safeguard against experimental murine colitis V Klepsch, RR Gerner, S Klepsch, WJ Olson, H Tilg, AR Moschen, G Baier, ... Gut 67 (8), 1434-1444 , 2018 2018 Citations: 48