19 Mar Protective Bacteria May Reverse Inflammation In Some Forms of IBD
MedicalResearch.com Interview with:
Justin E. Wilson, Ph.D On behalf of the authors
Research Assistant Professor – Laboratory of Jenny Ting
Department of Genetics
Lineberger Comprehensive Cancer Center
The University of North Carolina at Chapel Hill
Chapel Hill, NC 27599
MedicalResearch.com: Could you provide me with some background on this project? Why did you decide to do this research project? What prior work led up to this latest paper?
Response: Previous work from our lab and others discovered two major points about NLRP12:
a) NLRP12 suppresses inflammation in response to bacterial components
b) NLRP12 provides protection against the inflammatory bowel disease colitis and colitis-associated colon cancer (i.e., Nlrp12-defcient mice have greater colon inflammation and inflammation-driven colon cancer).
Therefore, we wanted to know if Nlrp12 was regulating inflammation in the colon by responding to the trillions of intestinal microbes collective referred to as the microbiome. Mounting evidence also indicates that the immune system both responds to and influences the composition of the intestinal microbiome during intestinal health and disease, and we hypothesized that NLRP12 could be one of the important immune components during this process. Moreover, we were also interested in this topic because targeting the microbiome to treat inflammatory disorders and other diseases is an attractive method that has many advantages over immune suppression.
MedicalResearch.com: Can you explain the methodology used in your paper? Why did you decide to adopt this approach?
Response: We used many techniques in this manuscript to identify this new role for NLRP12:
a) We analyzed data publically available gene expression studies on human colitis patients and twin studies and found that NLRP12 expression is reduced in colitis. This approach allowed us to determine the translational relevance of NLRP12 expression during human colitis without having to perform clinical studies.
b) We used the DSS model of experimental colitis throughout the paper because this is a commonly used and reproducible mouse model of colitis. We and others have also previously shown that Nlrp12-deficient mice have a more severe response to this model compared to wild-type mice;
c) We developed germ-free mice in sterile isolators in the UNC gnotobiotic facility to test the impact of the microbiota on NLRP12 function because this is the only way to develop animals in a sterile environment;
d) We characterized the intestinal microbiota under different conditions by isolating total DNA from mouse fecal samples and performing next-generation Illumina-based sequencing using bacteria-specific primers. This is the most unbiased and comprehensive way to measure and compare the total composition of the intestinal microbiome;
e) In order to assess the impact of the microbiota derived from wild-type vs. Nlrp12-deficient mice, we performed co-housing studies and fecal translation studies. In cohousing studies, the wild-type and Nlrp12-defieicent animals are housed in the same cages, and the animals consume each others fecal material, which causes transfer the microbiota between animals. We also took a direct approach to this by directly feeding germ-free animals fecal material (fecal transplant) or beneficially probiotic Lachnospiraceae strains.
f) NLRP12 is expressed by different cell type, but predominantly by immune macrophages, dendritic cells and neutrophils. To better understand what cell type expressing NLRP12 was responsible for regulating the microbiome, we generated bone marrow chimeric mice to develop mice with NLRP12 expression only in the bone marrow-derived cells and mice lacking NLRP12 in all cells except bone marrow. This experiment found that bone marrow-derived immune cells expressing NLRP12 shapes the microbiome. We further identified specific populations of colonic macrophages and dendritic cells in the Nlrp12-deficient mice that display increased inflammatory cytokine expression.
g) To understand how NLRP12 shapes the microbiome composition, we targeting the excessive inflammation in Nlrp12-deficient mice by treatment with neutralizing antibodies against TNF and IL-6 receptor. This made the microbiome in Nlrp12-deficient mice look more like that in wild-type mice, indicating the excessive inflammation resulting from Nlrp12 deficiency caused alterations in the microbiome composition (dysbiosis). Importantly, these antibodies are either being used in clinical settings for treating human colitis or are undergoing clinical trials for similar treatments.
MedicalResearch.com: What were the most significant findings? How do they relate to what was already known about this subject?
a) Human colitis patients have reduced NLRP12 expression, which is consistent with our animal studies where loss of NLRP12 leads to more experimental colitis.
b) Nlrp12-deficient mice require the microbiota for the exacerbated colitis.
c) Nlrp12-deficiency results in an altered microbiome composition (dysbiosis), which is characterized by loss of protective Lachnospiraceae strains and increased inflammation-associated Erysipelotrichaceae strains.
d) Both Nlrp12 gene deficiency and the resulting dysbiotic microbiota contribute to distinct inflammatory signaling pathways. The combination of these two factor results in fulminant colitis observed in Nlrp12-deficient mice.
e) Exacerbated colitis and dysbiosis in Nlrp12-deficient mice can be reversed by treating these animals with anti-TNF/IL6R antibodies or feeding with protective Lachnospiraceae strains.
Overall, these findings show that NLRP12 not only regulates inflammation on the molecular level to prevent colitis, but also maintains a healthy microbiome through its anti-inflammatory role, which in itself also contributes to colitis pathogenesis.
MedicalResearch.com: How do you plan to take this work forward? What are the implications for future research?
Response: We still have many questions and future directions for this work. One major question is how NLRP12-regulated inflammation impacts the different bacterial species that promote or prevent colitis. In addition, we want to better understand how our identified protective and inflammation-associated bacteria contribute to intestinal health and colitis susceptibility by identifying and characterizing the factors produced by these bacteria during disease conditions. We very much like to know if the bacteria we identified has any role in reversing gut inflammation in humans.
Liang Chen, Justin E Wilson, Mark J Koenigsknecht, Wei-Chun Chou, Stephanie A Montgomery, Agnieszka D Truax, W June Brickey, Christopher D Packey, Nitsan Maharshak, Glenn K Matsushima, Scott E Plevy, Vincent B Young, R Balfour Sartor, Jenny P-Y Ting. . Nature Immunology, 2017; DOI: 10.1038/ni.3690
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Last Updated on March 19, 2017 by Marie Benz MD FAAD