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京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22039号 / 医博第4524号 / 新制||医||1038(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 濵﨑 洋子, 教授 武藤 学, 教授 妹尾 浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22120号 / 医博第4533号 / 新制||医||1039(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 妹尾 浩, 教授 竹内 理, 教授 濵﨑 洋子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22307号 / 医博第4548号 / 新制||医||1040(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 松田 道行, 教授 髙折 晃史 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22343号 / 医博第4584号 / 新制||医||1042(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 妹尾 浩, 教授 佐藤 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22374号 / 医博第4615号 / 新制||医||1043(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 松田 道行, 教授 小西 靖彦 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22740号 / 医博第4658号 / 新制||医||1046(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 羽賀 博典, 教授 髙折 晃史, 教授 伊藤 貴浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23422号 / 医博第4767号 / 新制||医||1053(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 河本 宏, 教授 濵﨑 洋子, 教授 上野 英樹 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

<p>    </p> <p>In the United States, colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer mortality in men and women. Recent epidemiological evidence has shown that there’s been a steady increase in young onset CRC, underlying a continued need to understand mechanisms that may be contributing to its development. One risk factor that continues to persist and rise is obesity. Obesity is a multifaceted disease characterized by various metabolic and physiologic changes that influence tumorigenesis. Another component that is altered in obesity and has been shown to contribute to CRC is the gut microbiota. Obesity associated gut microbiota is different relative to a lean counterpart and has been linked poor colonic health, which can increase risk for CRC. Researchers have shown that intestinal tumorigenesis is worse in diet induced obesity but given other related conditions like chronic inflammation, the role of the gut microbiota in obesity associated CRC risk has not been adequately isolated. To address this gap and to further explore the role of diet in this relationship given its importance in driving obesity and impacting gut microbiota composition, we performed two studies. First, we assessed the role of obesity and/or two different obesogenic diets on gut microbiota composition and intestinal permeability. We hypothesized that diet and obesity would affect gut microbial community composition and that obese mice would have higher intestinal permeability relative to lean mice regardless of diet. Our results indicated that both diet and obesity were significant predictors and had varying effects on species richness and community structure of the gut microbiota and significantly enriched multiple bacterial taxa. Second, to isolate the role of obesity- and/or diet- influenced gut microbiota on CRC development, fecal microbial transplantation was performed by transferring the intestinal content from mice in the first study into recipient mice before chemical induction of CRC. We hypothesized that the gut microbiota from obese mice on obesogenic diets would promote CRC independent from the development of obesity. Our results indicated that gut microbiota shaped by the obesogenic diets was associated with worse colonic tumor measurements, while the differences in gut microbiota due to obesity or leanness did not affect CRC outcomes. Overall, we have demonstrated that diet and obesity have significant effects on gut microbial communities, but only dietary-induced gut microbial changes promote CRC. These results highlight the importance of understanding dietary effects on gut microbiota in CRC development which improves our ability to determine better strategies of prevention and treatment. </p>

PROBLEM: Colorectal cancer (CRC) is a top three leading cause of death among western countries. Epidemiological evidence shows a positive correlation between western diet, which consists of high-fat, meat and processed foods. Positive correlations indicate that diets high in fruits and vegetables could greatly decrease risk of CRC. Specifically the ubiquitous spice, turmeric, and its main active constituent have been broadly researched to determine its efficacy in the treatment and prevention of CRC. RESULTS: Curcumin proves to be effective in the treatment and prevention of CRC. It acts as a chemosensitizer for chemotherapeutics which increases their effectiveness especially against chemoresistant CRC cell lines. In many in vitro studies curcumin has inhibited critical pathways involved in CRC progression such as Wnt/β-catenin and sonic hedgehog pathway. Curcumin can also act as a ligand for VDR, which is significant because high vitamin D intake is associated with a decreased risk of CRC. In vivo, curcumin has minimized tumor growth in animal models. In clinical trials curcumin proves to be a naturally derived, non-toxic agent. CONCLUSION: Curcumin and turmeric should be further studied for its use against CRC, specifically its use in nanotechnology and NDDS as either a stand-alone nutraceutical or a chemosensitizer. Additionally, it would likely be advantageous to prescribe turmeric in the diet in combination with black pepper, heat, and oil (which increases its bioavailability) in patients at high risk of developing CRC.