Our research investigates the control of immune responses and how alterations in these responses contribute to the development of the chronic and debilitating inflammatory bowel disease, Crohn’s disease (CD).Crohn’s disease (CD) is complex with multiple risk factors combining to determine who will develop the disease. No single risk factor is enough to cause CD. What we don’t currently understand is how the combination of these factors multiply the risk of developing CD. Family history (genetics) is clearly linked to increased disease risk, but this is something that we cannot change. A different risk factor is diet and the global spread of eating a “Western diet” rich in fat, protein and processed foods parallels a recent, rapid, worldwide rise of CD development. Research in the McDonald lab is examining the effect of common dietary additives in a Western diet on the development of intestinal inflammation. Our data suggests that a widely used dietary additive changes both the composition and function of the normal intestinal microbiome and the antimicrobial defenses of the intestine. Similar to CD patients, these diet-induced changes don’t trigger disease by themselves, but when combined with other CD risk factors, results in intestinal inflammation. We are continuing this research using sophisticated molecular analyses in pre-clinical models that incorporate genetic risk factors, patient-derived cell systems, and in dietary studies with CD patients. As diet is a risk factor under our control, understanding how certain foods trigger disease could be a powerful and safe means to prevent its development in families with a history of CD or reduce disease flares in patients.
Another area of study is exploring the development of a new antimicrobial treatment for antibiotic-resistant bacteria wound infections. Antibiotic-resistant bacterial infections are a major problem in healthcare settings because our most powerful drugs to kill these bacteria are becoming ineffective. Therefore, there is an urgent need to develop new, safe and effective treatments. Our new antimicrobial enhances the innate immune response to bacteria mediated by the sensor protein, nucleotide-binding, oligomerization domain 2 (NOD2). Our studies show this antimicrobial agent increases the production and release of natural antibiotic factors from skin cells and increases the potency of bacterial killing by immune cells, rather than targeting bacteria directly. Induction of this multifaceted antimicrobial defense program will target a broad range of bacterial strains, avoid the development of resistant organisms, and could be combined with existing antimicrobial treatments to potentiate a therapeutic response.
In other words ...
Our research team investigates how we defend ourselves against bacterial infection. Alterations to these defenses are thought to be involved in the development of auto-inflammatory diseases, such as Crohn's disease. We are attempting to understand how risk factors for Crohn's disease, such as diet, family history, and the microbiome, change anti-microbial defenses in the gut and drive disease.
Some of the same anti-microbial defenses found in the gut also act in the skin. We are exploring whether drugs that increase these natural defenses of the skin can be used to prevent or treat infections with antibiotic-resistant bacteria.
- Kim Y., West G.A., Ray G., Kessler S.P., Petrey A.C., Fiocchi C., McDonald C., Longworth M.S., Nagy L.E., & de la Motte C.A. (2017) Layilin is critical for mediating hyaluronan 35 kDa-induced intestinal epithelial tight junction protein ZO-1 in vitro and in vivo. Matrix Biology, Epub 1 Oct 2017, in press, doi:10.1016/j.matbio.2017.09.003
- Schuster A.T.*, Homer C.R.*, Kemp J.R., Nickerson K.P., Deutschman E., Kim Y., West G., Sadler T., Stylianou E., Krokowski D., Hatzoglou M., de la Motte C.A., Rubin B., Fiocchi C., McDonald C.**, & Longworth M.S.** (2015) Chromosome-asociated protein D3 promotes bacterial clearance in human intestinal epithelial cells by repression of amino acid transporters. Gastroenterology, 148(7):1405-16.e3, Epub 2015 Feb 19, doi: 10.1053/j.gastro.2015.02.013. PCMID: 4446190. *co-first authors, **co-corresponding authors
- Nickerson K.P. & McDonald C. (2012) Crohn’s Disease-Associated Adherent-Invasive Escherichia coli Adhesion is Enhanced by Exposure to the Ubiquitous Dietary Polysaccharide Maltodextrin. PLoS One, 7(12): e52132. doi:10.1371/journal.pone.0052132. Epub 2012 Dec 12. PMCID: PMC3520894.
- Homer C.R., Richmond A.L., Rebert N.A., Achkar J.-P., & McDonald C. (2010)ATG16L1 and NOD2 interact in an autophagy-dependent, anti-bacterial pathway implicated in Crohn’s disease pathogenesis. Gastroenterology 139:1630-1641.e1-2. Epub 2010 Jul 14, PMCID: PMC2967588.
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