Research in our group focuses on understanding how homeostasis between the intestinal immune system and the gut microbiota is established and maintained, and how disruption of this relationship leads to the development and exacerbation of inflammatory bowel disease (IBD).
Our gut microbiota, the vast collection of harmless and beneficial microbes and viruses that inhabit our intestines, are key contributors to host health. IBD, encompassing Crohn's Disease (CD) and Ulcerative Colitis (UC), represent a set of severe inflammatory disorders of the gastrointestinal tract that result from inflammatory immune responses directed against members of the gut microbiota. A variety of immune cell types, from both the innate and adaptive immune compartments, have been implicated in the pathogenesis of IBD. Our work is aimed at further increasing our understanding of the dynamic interplay between intestinal CD4+ T cells and the gut microbiota during the development of intestinal inflammation, and how the gut microbiota can be targeted to treat IBD and restore host health.
Our group is currently focused on a number of questions related to the development and pathogenesis of IBD:
(1) What are the specific members of the microbiota that are responsible for the initiation and perpetuation of chronic inflammation in the intestine?
(2) How do gut microbes survive inflammatory environments to stably colonize the host?
(3) How do members of the gut microbiota regulate intestinal CD4+ T cell fate during steady state and disease?
(4) What pathways promote the resolution of bacterially-triggered intestinal inflammation and restoration of immune-microbiota homeostasis?
To address these questions our group employs a variety of cellular and molecular approaches allied to murine models of IBD in gnotobiotic and specific pathogen-free mice.
Our overarching goal is to identify host and microbial pathways that can be targeted to facilitate the development of new and improved therapeutic strategies for the treatment of IBD.
A postdoctoral position is currently available in our group to study niche establishment by gut microbes in the context of intestinal inflammation. Interested candidates should submit a cover letter (1 page maximum) outlining their research interests, as well as a CV and the contact information for 3 references to Dr. Philip Ahern at email@example.com
In other words ...
Our immune system is continuously on the alert so that it can identify and fight off potentially deadly infectious agents, such as pathogenic bacteria. However, our intestines are also loaded with bacteria and other microbes (collectively referred to as the gut microbiota) that, rather than posing a threat, are actually key contributors to host health and provide numerous benefits to the host. These include the breakdown of otherwise indigestible foods, priming of our immune system to deal with infectious agents and even directly helping resist attack by dangerous pathogens.
Our immune system is therefore faced with a major challenge whereby it has to discriminate between the harmless and helpful microbes that live in our intestines and those microbes that pose a significant health risk. This incredible discriminatory ability can be disrupted in certain individuals, resulting in the immune system attacking the gut microbiota, which in turn causes enormous damage to our own intestinal tissues. This aberrant response leads to the development of a chronic inflammatory disorder of our gastrointestinal tract known as inflammatory bowel disease (IBD) that significantly impedes the well-being of its sufferers.
Our research is focussed on gaining a better understanding of why the immune system may suddenly attack the gut microbiota, as well as developing strategies to reestablish the peaceful coexistence of our gut microbes with the intestinal immune system.
Cowardin CA, Ahern PP, Kung VL, Hibberd MC, Cheng J, Guruge JL, Sundaresan V, Head RD, Barile D, Mills DA, Barratt MJ, Huq S, Ahmed T, Gordon JI.
Mechanisms by which sialylated milk oligosaccharides impact bone biology in a gnotobiotic mouse model of infant undernutrition.
Proc. Natl. Acad. Sci., 2019 Jun 11;116(24):11988-11996
Cervantes-Barragan L, Chai JN, Tianero MD, Di Luccia B, Ahern PP, Merriman J, Cortez VS, Caparon MG, Donia MS, Gilfillan S, Cella M, Gordon JI, Hsieh CS, Colonna M.
Lactobacillus reuteri induces gut intraepithelial CD4+CD8αα+ T cells.
Science, 2017 Aug 25; 357(6353): 806-810
Griffin NW, Ahern PP, Cheng J, Heath AC, Ilkayeva O, Newgard CB, Fontana L, Gordon JI.
Prior Dietary Practices and Connections to a Human Gut Microbial Metacommunity Alter Responses to Diet Interventions.
Cell Host Microbe., 2017 Jan 11;21(1):84-96
Semenkovich NP, Planer JD, Ahern PP, Griffin NW, Lin CY, Gordon JI.
Impact of the gut microbiota on enhancer accessibility in gut intraepithelial lymphocytes.
Proc. Natl. Acad. Sci., 2016 Dec 20;113(51):14805-14810.
Wagner VE, Dey N, Guruge J, Hsiao A, Ahern PP, Semenkovich NP, Blanton LV, Cheng J, Griffin N, Stappenbeck TS, Ilkayeva O, Newgard CB, Petri W, Haque R, Ahmed T, Gordon JI.
Effects of a gut pathobiont in a gnotobiotic mouse model of childhood undernutrition.
Sci. Transl. Med., 2016 Nov 23;8(366):366ra164.
Krausgruber T, Schiering C, Adelmann K, Harrison OJ, Chomka A, Pearson C, Ahern PP, Shale M, Oukka M, Powrie F.
T-bet is a key modulator of IL-23-driven pathogenic CD4(+) T cell responses in the intestine.
Nat. Commun., 2016 May 19;7:11627
Rakoff-Nahoum S, Kong Y, Kleinstein SH, Subramanian S, Ahern PP, Gordon JI, Medzhitov R.
Analysis of gene-environment interactions in postnatal development of the mammalian intestine.
Proc. Natl. Acad. Sci., 2015 Feb 17;112(7):1929-36
Faith JJ*, Ahern PP*, Ridaura VK, Cheng J, Gordon JI.
Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice.
Sci Transl Med., 2014 Jan 22;6(220):220ra11
*, equal contribution
Rey FE, Gonzalez MD, Cheng J, Wu M, Ahern PP, Gordon JI.
Metabolic niche of a prominent sulfate-reducing human gut bacterium.
Proc. Natl. Acad. Sci., 2013 Aug 13; 110(33):13582-7
Yockey LJ, Demehri S, Turkoz M, Turkoz A, Ahern PP, Jassim O, Manivasagam, Kearney JF, Gordon JI, Kopan R.
The absence of a microbiota enhances TSLP expression in mice with defective skin barrier but does not affect the severity of their allergic inflammation.
J Invest Dermatol., 2013 Epub May 22; 133(12):2714-21
Ahern PP*, Schiering C*, Buonocore S, McGeachy MJ, Cua DJ, Maloy KJ, Powrie F.
Interleukin-23 drives intestinal inflammation through direct activity on T cells.
Immunity, 2010 Aug 27;33(2):279-88
*, equal contribution
Buonocore S, Ahern PP, Uhlig HH, Ivanov II, Littman DR, Maloy KJ and Powrie F.
Innate lymphoid cells drive interleukin-23 dependent innate intestinal pathology.
Nature, 2010 Apr 29;464(7293):1371-5
Izcue A, Hue S, Buonocore S, Arancibia-Cárcamo CV, Ahern PP, Iwakura Y, Maloy KJ and Powrie F.
Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis.
Immunity, 2008 Apr;28(4):559-70
Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS, Powrie F and Maloy KJ.
Interleukin-23 drives innate and T cell-mediated intestinal inflammation.
J Exp Med., 2006 Oct 30;203(11):2473-83
Ahern PP, Maloy KJ.
Understanding immune-microbiota interactions in the intestine.
Immunology. 2020 Jan;159(1):4-14.
Ahmed T, Auble D, Berkley JA, Black R, Ahern PP, Hossain M, Hsieh A, Ireen S, Arabi M, Gordon JI.
An evolving perspective about the origins of childhood undernutrition and nutritional interventions that includes the gut microbiome.
Ann N Y Acad Sci., 2014 Aug 12, doi: 10.1111/nyas.12487
Ahern PP*, Faith JJ*, Gordon JI.
Mining the human gut microbiota for effector strains that shape the immune system.
Immunity, 2014 Jun 19;40(6):815-23
*, equal contribution
Kau AL*, Ahern PP*, Griffin NW, Goodman AL, Gordon JI.
Human nutrition, the gut microbiome and the immune system.
Nature, 2011 Jun 15; 474(7351):327-36
*, equal contribution
Ahern PP, Izcue A, Maloy KJ and Powrie F.
The interleukin-23 axis in Intestinal Inflammation.
Immunological Reviews, 2008, Dec;226;147-59
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