Cathryn Nagler’s research while affiliated with University of Chicago and other places

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Publications (15)


The role of intestinal bacteria in promoting tolerance to food
  • Literature Review

September 2024

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6 Reads

Current Opinion in Immunology

Edward Ionescu

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Cathryn R Nagler

Inhibition of Immunological Suppression

November 2023

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3 Reads

The Journal of Immunology

This Pillars of Immunology article is a commentary on “Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation,” a pivotal article written by S. Read, V. Malmström, and F. Powrie, and published in the Journal of Experimental Medicine, in 2000. https://doi.org/10.1084/jem.192.2.295.


A new slow-releasing formulation of butyrate prolongs allograft survival

May 2023

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5 Reads

The Journal of Immunology

Martin N Sepulveda

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Luqiu Chen

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[...]

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Maria-Luisa Alegre

The microbiota consists of diverse microbes producing metabolites that can influence the immune system locally as well as systemically. These bioactive metabolites (postbiotics) have therapeutic potential and may prove useful to facilitate graft acceptance. Short-chain fatty acids (SCFA) promote intestinal homeostasis and have been linked to health and disease. The Hubbell-Nagler laboratories at the University of Chicago have developed a micelle-based platform that can deliver the SCFA butyrate systemically, with long-term retention and induction of tolerogenic responses. We hypothesized that the administration of this butyrate formulation will improve graft survival by suppressing the alloimmune response. Our preliminary data showed that only oral delivery of the butyrate formulation prolonged survival of a C57Bl/6 male to female minor-mismatched skin graft significantly, whereas sub-cutaneous and intra-peritoneal administration were ineffective. Improved graft survival was associated with diminished production of TNFα by splenic and skin-draining lymph node myeloid cells upon LPS stimulation, suggesting that butyrate modulates the myeloid compartment to reduce levels of pro-inflammatory cytokines. The postbiotic also enhanced survival of a BALB/c to C57Bl/6 major-mismatched skin graft, without the use of immunosuppressive drugs, and resulted in lower levels of donor-specific alloantibodies. Prolonging the administration of butyrate post-transplantation ameliorated graft survival even further, confirming the micelle-based platform has therapeutic potential. Current efforts focus on determining if the butyrate formulation drives myeloid cell polarization toward an anti-inflammatory phenotype. This project was supported by grant NIH/NIAID 2R01AI115716


A single species bacterial therapy reduces type 2 immune responses in the gut to prevent food allergy

May 2023

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9 Reads

The Journal of Immunology

The rising prevalence of food allergy is strongly correlated with dysbiosis of the gut microbiome. Rescuing this dysbiosis by reintroducing specific bacteria is a promising method to prevent or treat food allergy. We have shown that monocolonization with Anaerostipes caccae, a species representative of the healthy infant microbiota, protects against an allergic response to the milk protein b-lactoglobulin (BLG). Recently we developed a synbiotic bacterial therapy (A. caccaeplus prebiotic lactulose) which rescues the allergic phenotype of gnotobiotic mice colonized with the fecal bacteria of a dysbiotic, cow’s milk allergic (CMA) infant. Synbiotic treatment minimizes the anaphylactic response to intragastric BLG challenge and reduces circulating BLG-specific IgE and IgG1. To understand how a single bacterium regulates mucosal immunity during the onset of IgE-mediated allergy we first examined the alarmin response. CMA colonized mice express high transcript levels of both IL25and TLSPin ileal epithelial cells after sensitization with BLG plus cholera toxin. The synbiotic abrogated this alarmin response, potentially via increased mucus production. Synbiotic treatment also reduced the proportion and number of T follicular (Tf) helper cells in the ileal-draining lymph node (LN) and increased Tf-regulatory cells in the colon-draining LN, suggesting a role in T/B cell regulation. Ongoing experiments are examining how the synbiotic affects localization and expansion of IgE producing cells in mucosal tissues including Peyer’s patches and mesenteric LNs. These findings will help to uncover the mechanisms by which specific, protective bacteria prevent food allergy and inform the development of effective live biotherapeutics.


Commensal bacteria regulate host TGF-β and retinoic acid metabolism to promote intestinal homeostasis.

May 2023

The Journal of Immunology

TGF-β signaling and retinoic acid (RA) metabolism are essential to intestinal homeostasis, but the mechanisms by which the microbiota influence these host processes are not clear. We have previously reported a mouse model of cow’s milk allergy (CMA) in which germ-free mice were colonized with the fecal microbiota of healthy infants or infants with CMA. That study revealed that Tgfbr3was part of an ileal transcriptomic signature that distinguished healthy from CMA-colonized mice. Follow-up experiments using RT-qPCR confirmed that Tgfbr3expression was significantly higher in the ileum of healthy-colonized than CMA-colonized mice. Tgfbr3encodes a TGF-β co-receptor, and its expression is reported to be induced by RA; genes in the CMA transcriptomic signature encode enzymes with RA catabolic activity (Cyp2c29, Cyp2b10, Cyp3a59, and Akr1c19). The expression of RA-catabolic enzymes and concurrent downregulation of Tgfbr3led us to hypothesize that these distinct microbiotas differentially modulate host RA metabolism, and consequently influence TGF-β signaling through the induction of Tgfbr3. In support of this hypothesis, we found lower ileal expression of Aldh1a1in CMA-colonized mice, suggesting a lower capacity to produce RA. Furthermore, Tgfbr3expression correlated with the transcript levels of TGF-β pathway mediators, Smad3and Smad7, both of which are increased in the ileum of healthy-colonized mice. Ongoing experiments will use single cell RNA-sequencing to identify the cell populations responsible for the differential expression of Tgfbr3in the ileum and to characterize the microbial mechanisms responsible for modulating host RA metabolism. Supported by NIH R01 AI146099 Supported by NIH R01 AI146099


The differential influence of commensal and pathogenic flagella on intestinal barrier function.

May 2023

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19 Reads

The Journal of Immunology

It is well known that accumulated changes in microbiota composition over several decades have contributed to an increase in non-communicable chronic diseases. While much effort has been devoted toward achieving a consensus on the microbes, and their products, driving this increase, inconsistent results suggest more research is required to understand the disparity in observed outcomes. Previous work from our lab identified a consortium of commensal Clostridia that alone was sufficient to preserve intestinal barrier integrity and prevent sensitization to food allergens in mice by inducing IL-22. Further investigation determined that members of this consortium display flagella. When isolated, these commensal flagella (Fla-C) exhibited TLR5-dependent IL-22 induction at a magnitude comparable to flagellin from SalmonellaTyphimurium (Fla-ST). However, mice treated with Fla-C maintained intestinal barrier function significantly more effectively than Fla-ST or negative control PBS-treated mice as measured by a serum FITC-dextran permeability assay. This was accompanied by a striking difference in the expression of Reg3 antimicrobial peptides and IL-17; all of which were significantly increased by treatment with Fla-ST when compared to Fla-C. Sequencing of Clostridia consortium-derived flagellated isolates revealed flagellin genes with unique hypervariable regions when compared to fliC from S. Typhimurium. These results highlight the distinct impacts of commensal and pathogenic flagella and suggest an important role for flagellated commensal bacteria in the maintenance of intestinal epithelial barrier function. Supported by a grant from National Institutes of Health (RO1 AI06302)


Flagella and indole produced by commensal bacteria protect the intestinal barrier to prevent food allergy

May 2022

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13 Reads

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1 Citation

The Journal of Immunology

Lifestyle-induced changes to the diversity of the commensal microbiota have been causally linked to the increasing prevalence of food allergies and other non-communicable chronic diseases. We have shown that bacteria from the Clostridia class prevent an allergic response to food by eliciting an IL-22 dependent barrier protective response that limits allergen access to the systemic circulation. We have now examined the mechanisms by which commensal Clostridia induce this allergy-protective effect. We identified taxa in a consortium of Clostridia that possess flagella and produce indole, which are ligands for TLR5 and AhR, respectively. Lysates and flagella isolated from this consortium induced IL-22 in mouse intestinal explants. IL-22 was not induced in explants from mice in which TLR5 or MyD88 was knocked out globally or conditionally in CD11c+ cells. Treatment with the commensal flagellar isolate also reduced detection of intragastrically administered FITC dextran in the serum of antibiotic-treated mice. Similarly, indole exposure induced IL-22 in intestinal explants and reduced intestinal permeability to FITC dextran. Importantly, AhR signaling in RORγt+ cells was necessary for IL-22 induction by flagella. These results suggest that flagella and indole act synergistically to prevent an allergic response. Finally, we have isolated and characterized two Clostridial taxa which bear flagella and produce indole. We hypothesize that germ-free mice colonized with these two taxa will exhibit improved IL-22 dependent barrier function and be protected against an allergic response. Our work reveals novel features of Clostridia key to their allergy-protective capability which may be further exploited to develop therapeutics. Supported by NIH AI106302 and the Bunning Professorship Endowment Fund


Developing a synbiotic biotherapy to prevent allergic responses to food

May 2022

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4 Reads

The Journal of Immunology

Over the past generation, the prevalence of food allergies has risen dramatically, but the development of treatments has lagged. The commensal gut microbiome is critically involved in regulating allergic responses to food. Our laboratory has described a humanized model of cow’s milk allergy (CMA) in which germ-free mice are colonized with feces from healthy or CMA infants and sensitized to the cow’s milk allergen b-lactoglobulin (BLG). The healthy infant microbiota and specifically a single Clostridial species, Anaerostipes caccae, protect against the development of anaphylaxis, while the CMA microbiota does not induce this protection. We isolated a novel sub-strain of A. caccae (A. caccae_lahuc) from the feces of a healthy infant, sequenced its genome, and characterized its growth on various substrates in vitro. A. caccae_lahuc produces high concentrations of butyrate, a key immunoregulatory molecule in the gut which we hypothesize is critical to its protective impact. A. caccae_lahuc engrafts readily into the dysbiotic CMA microbiota, but co-delivery with lactulose is required for measurable butyrate production in vivo. Lactulose undergoes primary degradation by bacteria in the CMA feces which release small metabolites that A. caccae_lahuc can ferment into butyrate. Preliminary data show that this novel synbiotic biotherapy (A. caccae_lahuc + lactulose) prevents allergic responses to BLG in CMA-colonized mice as measured by serum mMCPT-1 and core body temperature upon challenge, and type 2 cytokine production in BLG-stimulated splenocytes. Further exploration into the mechanisms behind this therapeutic effect will contribute toward the larger goal of developing bacterial biotherapeutics against food allergies.


Early intervention and prevention of allergic diseases
  • Preprint
  • File available

June 2021

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62 Reads

Food Allergy (FA) is now one of the most common chronic diseases of childhood often lasting throughout life and leading to significant worldwide healthcare burden. The precise mechanisms responsible for the development of this inflammatory condition are largely unknown; however, a multifactorial aetiology involving both environmental and genetic contributions is well accepted. A precise understanding of the pathogenesis of FA is an essential first step to developing comprehensive prevention strategies that could mitigate this epidemic. As it is frequently preceded by atopic dermatitis and can be prevented by early antigen introduction, the development of FA is likely facilitated by the improper initial presentation of antigen to the developing immune system. Primary oral exposure of antigens allowing for presentation via a well-developed mucosal immune system, rather than through a disrupted skin epidermal barrier, is essential to prevent FA. In this review, we present the data supporting the necessity of 1) an intact epidermal barrier to prevent epicutaneous antigen presentation, 2) the presence of specific commensal bacteria to maintain an intact mucosal immune system and 3) maternal/infant diet diversity, including vitamins and minerals, and appropriately timed allergenic food introduction to prevent FA.

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Early intervention and prevention of allergic diseases

May 2021

·

9 Reads

Food Allergy (FA) is now one of the most common chronic diseases of childhood often lasting throughout life and leading to significant worldwide healthcare burden. The precise mechanisms responsible for the development of this inflammatory condition are largely unknown; however, a multifactorial aetiology involving both environmental and genetic contributions is well accepted. A precise understanding of the pathogenesis of FA is an essential first step to developing comprehensive prevention strategies that could mitigate this epidemic. As it is frequently preceded by atopic dermatitis and can be prevented by early antigen introduction, the development of FA is likely facilitated by the improper initial presentation of antigen to the developing immune system. Primary oral exposure of antigens allowing for presentation via a well-developed mucosal immune system, rather than through a disrupted skin epidermal barrier, is essential to prevent FA. In this review, we present the data supporting the necessity of 1) an intact epidermal barrier to prevent epicutaneous antigen presentation, 2) the presence of specific commensal bacteria to maintain an intact mucosal immune system and 3) maternal/infant diet diversity, including vitamins and minerals, and appropriately timed allergenic food introduction to prevent FA.


Citations (3)


... Moreover, the abundance of stool Anaerostipes was not correlated with AST and ALT levels (p < 0.05) in primary biliary cholangitis (PBC) patients [34]. It is of more interest that the relative abundance of the Anaerostipes species has reportedly decreased in infants and children suffering from food or respiratory allergies and eczema [35][36][37][38][39]. Although a gut microbiota analysis was not performed in our recent clinical study on allergic symptoms [14], it is expected that similar changes may also have occurred in the subjects, suggesting that an increase in Anaerostipes contributed to the improvement in hepatic parameters and allergic status. ...

Reference:

Plant-Derived Lactobacillus paracasei IJH-SONE68 Improves the Gut Microbiota Associated with Hepatic Disorders: A Randomized, Double-Blind, and Placebo-Controlled Clinical Trial
Developing synbiotic bacterial therapeutics to treat food allergy
  • Citing Article
  • May 2021

The Journal of Immunology

... Moreover, the abundance of stool Anaerostipes was not correlated with AST and ALT levels (p < 0.05) in primary biliary cholangitis (PBC) patients [34]. It is of more interest that the relative abundance of the Anaerostipes species has reportedly decreased in infants and children suffering from food or respiratory allergies and eczema [35][36][37][38][39]. Although a gut microbiota analysis was not performed in our recent clinical study on allergic symptoms [14], it is expected that similar changes may also have occurred in the subjects, suggesting that an increase in Anaerostipes contributed to the improvement in hepatic parameters and allergic status. ...

Optimizing bacteriotherapy to prevent or treat food allergy
  • Citing Article
  • May 2020

The Journal of Immunology

... Yapılan çalışmalar düşük lifli diyetle beslenmenin kısa sayılabilecek bir zaman diliminde bile mikrobiata da takson kaybına neden olabileceğini göstermiştir. Clostridia sınıfı bakterilerde olduğu gibi lifi sindiren ve bütirat üreten bakteriler toleransı indükleyen IL-22 artışına neden olabilmektedirler.2 Bağırsak mikrobiata değişimleri ile besin alerjileri arasındaki ilişki çeşitli epidemiyolojik çalışmalarla doğrulanmıştır. ...

Drugging the microbiome