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Celecoxib Alters the Intestinal Microbiota and Metabolome in Association with Reducing Polyp Burden David C

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Celecoxib Alters the Intestinal Microbiota and Metabolome in Association with Reducing Polyp Burden David C Published OnlineFirst July 18, 2016; DOI: 10.1158/1940-6207.CAPR-16-0095 Research Article Cancer Prevention Research Celecoxib Alters the Intestinal Microbiota and Metabolome in Association with Reducing Polyp Burden David C. Montrose1, Xi Kathy Zhou2, Erin M. McNally1, Erika Sue1, Rhonda K. Yantiss3, Steven S. Gross4, Nitai D. Leve2, Edward D. Karoly5, Chen S. Suen6, Lilan Ling7, Robert Benezra8, Eric G. Pamer7,9,10, and Andrew J. Dannenberg1 Abstract Treatment with celecoxib, a selective COX-2 inhibitor, reduces well as increased Coriobacteriaceae. Metabolomic analysis dem- formation of premalignant adenomatous polyps in the gastroin- onstrated that celecoxib caused a strong reduction in many fecal testinal tracts of humans and mice. In addition to its chemo- metabolites linked to carcinogenesis, including glucose, amino preventive activity, celecoxib can exhibit antimicrobial activity. acids, nucleotides, and lipids. Ingenuity Pathway Analysis sug- Differing bacterial profiles have been found in feces from colon gested that these changes in metabolites may contribute to cancer patients compared with those of normal subjects. More- reduced cell proliferation. To this end, we showed that celecoxib over, preclinical studies suggest that bacteria can modulate intes- reduced cell proliferation in the base of normal appearing ileal þ tinal tumorigenesis by secreting specific metabolites. In the cur- and colonic crypts of APCMin/ mice. Consistent with this finding, rent study, we determined whether celecoxib treatment altered lineage tracing indicated that celecoxib treatment reduced the rate the luminal microbiota and metabolome in association with at which Lgr5-positive stem cells gave rise to differentiated cell reducing intestinal polyp burden in mice. Administration of types in the crypts. Taken together, these results demonstrate that celecoxib for 10 weeks markedly reduced intestinal polyp burden celecoxib alters the luminal microbiota and metabolome along þ in APCMin/ mice. Treatment with celecoxib also altered select with reducing epithelial cell proliferation in mice. We hypothesize þ luminal bacterial populations in both APCMin/ and wild-type that these actions contribute to its chemopreventive activity. mice, including decreased Lactobacillaceae and Bifidobacteriaceae as Cancer Prev Res; 9(9); 721–31. Ó2016 AACR. Introduction sible for tumor initiation or growth or simply represent an epiphenomenon resulting from tumor presence is not clear. This The mammalian intestinal tract harbors 1014 microorgan- question has been addressed, in part, through the use of mouse isms, which may play a role in modulating cancer development in models suggesting that microbes may modulate tumorigenesis. the gastrointestinal (GI) tract (1). Data suggest that individuals For example, inoculation of specific bacterial species can enhance with colorectal cancer have a distinct bacterial profile compared þ intestinal and colonic tumor development in APCMin/ and with healthy controls (2, 3). Whether these differences are respon- À À Il10 / mice (4–6). Furthermore, lowering bacterial abundance can reduce tumor incidence in both colitis-associated and spon- taneous tumor models (7, 8). Bacteria are believed to influence 1Department of Medicine, Weill Cornell Medical College, New York, New York. 2Department of Healthcare Policy and Research, Weill intestinal tumorigenesis through multiple mechanisms, includ- Cornell Medical College, New York, New York. 3Department of Pathol- ing the release of key metabolites such as bile acids, short chain ogy and Laboratory Medicine,Weill Cornell Medical College, New York, fatty acids, and polyamines (9–13). We previously reported 4 New York. Department of Pharmacology, Weill Cornell Medical Col- alterations in fecal metabolites in association with colorectal lege, New York, New York. 5Metabolon, Inc., Durham, North Carolina. 6Division of Cancer Prevention, National Cancer Institute, Rockville, tumor growth in mice, many of which were likely to be microbe Maryland. 7Lucille Castori Center for Microbes, Inflammation and derived (14). Cancer, Memorial Sloan Kettering Cancer Center, New York, New York. Celecoxib is a selective COX-2 inhibitor that has been used 8Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York. 9Immunology Program, Memorial as a chemopreventive agent in at-risk populations to reduce the Sloan Kettering Cancer Center, New York, New York. 10Infectious recurrence and burden of premalignant colorectal adenomas. Diseases Service, Department of Medicine, Memorial Sloan Kettering For example, celecoxib administration reduced polyp number Cancer Center, New York, New York. in Familial Adenomatous Polyposis patients as well as recur- Note: Supplementary data for this article are available at Cancer Prevention rence of sporadic colorectal adenomas (15, 16). Importantly, Research Online (http://cancerprevres.aacrjournals.org/). the efficacy of celecoxib as a chemopreventive agent in humans þ Corresponding Author: Andrew J. Dannenberg, Weill Cornell Medical College, was predicted by studies in APCMin/ mice, in which celecoxib 1300 York Avenue, Room F-206, New York, NY 10021. Phone: 212-746-4403; was effective in both preventing the development of polyps Fax: 212-746-4885; E-mail: [email protected] and inducing their regression (17). The chemopreventive effi- doi: 10.1158/1940-6207.CAPR-16-0095 cacy of celecoxib is believed to be a consequence of COX-2 Ó2016 American Association for Cancer Research. inhibition in both humans and mice, although data from www.aacrjournals.org 721 Downloaded from cancerpreventionresearch.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst July 18, 2016; DOI: 10.1158/1940-6207.CAPR-16-0095 Montrose et al. several studies suggest that celecoxib, and similar agents, exert dNTPs, 1.5 mmol/L MgCl2, 2.5 U Platinum Taq DNA polymerase, effects through bacteria. For example, nonsteroidal anti-inflam- 2.5 mL of 10X PCR buffer, and 0.5 mmol/L of each primer designed matory drug (NSAID)-induced enteropathy can be mediated to amplify the V4-V5: 563F (5'-nnnnnnnn-NNNNNNNNNNNN- through interactions with the intestinal microbiota (18, 19). AYTGGGYDTAAAGNG-3') and 926R (50-nnnnnnnn-NNNNN- One study demonstrated that individuals who take NSAIDs NNNNNNN-CCGTCAATTYHTTTRAGT-30). A unique 12-base have a different bacterial profile compared with those who do Golay barcode (Ns) precedes the primers for sample identification not take NSAIDs (20). Celecoxib also has direct antimicrobial (23), and 1 to 8 additional nucleotides were placed in front of the activity, although it is not clear whether its chemopreventive barcode to offset the sequencing of the primers. Cycling condi- action is related to its effects on microbiota or the metabolites tions were 94C for 3 minutes, followed by 27 cycles of 94C for they produce (21, 22). 50 seconds, 51C for 30 seconds, and 72C for 1 minute. 72C for In this study, we tested whether celecoxib could alter the fecal 5 minutes is used for the final elongation step. Replicate PCRs microbiota and metabolome in association with reducing intes- were pooled, and amplicons were purified using the Qiaquick tinal tumor burden. We found that celecoxib treatment marked- PCR Purification Kit (Qiagen). PCR products were quantified þ ly reduced intestinal polyp burden in APCMin/ mice. Drug and pooled at equimolar amounts before Illumina barcodes administration altered bacterial populations in both ileal con- and adaptors were ligated on using the Illumina TruSeq Sample tent and feces. Subsequent metabolomic analysis demonstrated Preparation protocol. The completed library was sequenced on that celecoxib reduced a large number of pro-proliferative an Illumina Miseq platform. metabolites in the GI tract, and administration of this agent Sequence data were compiled and processed using MOTHUR resulted in reduced proliferation of normal intestinal crypt stem (24). Paired-end read files were converted to standard FASTQ cells. Taken together, these results suggest that celecoxib may format before being merged. Sequences were grouped into oper- exert its chemopreventive effects, in part, through effects on the ational taxonomic units (OTU) using the farthest neighbor algo- luminal microbiota and metabolome. rithm. Sequences with distance-based similarities of 97% or greater were assigned to the same OTU. OTU-based microbial diversity was estimated by calculating the Shannon and Inverse Materials and Methods Simpson diversity indices (25). Phylogenetic classification was Mouse treatments and sample collection performed for each sequence, using the Bayesian classifier algo- þ Male APCMin/ and wild-type (WT) mice from the same colony rithm described by Wang and colleagues with a bootstrap cutoff were obtained from The Jackson Laboratory at 4 weeks of age and of 60% (26). A phylogenetic tree was inferred using Clearcut (27), placed on AIN-93G purified diet (Research Diets). In order to on the 16S rRNA sequence alignment generated by MOTHUR. equilibrate the microbiota across mice by microbial exchange, 2 Unweighted or weighted UniFrac analysis was carried out using mice of each genotype were housed together until 6 weeks of age. the resulting tree. Principal coordinate analysis (PCoA) was At 6 weeks of age, feces was collected from individual mice and performed on the resulting matrix of distances between each pair snap frozen in liquid nitrogen and stored at À80 C until meta- of samples. bolomic
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