Influences of low carbohydrate-high fat diets and prehabilitation on cancer immunity and host response to surgical insults

• Project/Area Number: 18H03174
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: The University of Tokyo
• Principal Investigator: Fukatsu Kazuhiko 東京大学, 医学部附属病院, 教授 (70323590)
• Co-Investigator(Kenkyū-buntansha): 村越 智 東京大学, 医学部附属病院, 講師 (10647407) ; 齋藤 祐平 東京大学, 医学部附属病院, 講師 (90422295) ; 室屋 充明 東京大学, 医学部附属病院, 講師 (90431866) ; 安原 洋 東京大学, 医学部附属病院, 教授 (50251252)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥11,440,000 (Direct Cost: ¥8,800,000、Indirect Cost: ¥2,640,000); Fiscal Year 2020: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 低糖質高脂肪食 / 腸管虚血再灌流 / がん性腹膜炎 / がん免疫 / オートファジー / 炎症反応 / 大豆油 / 魚油 / プレハビリテーション / ホエイたんぱく / ω３系脂肪酸 / 制御性T細胞 / 生体反応 / 臓器障害 / メディエーター

Outline of Final Research Achievements

We investigated whether low carbohydrate high fat diets(LCHFDs) modulate host response to surgical insults and cancer immunity in a murine carcinomatous peritonitis model. LCHFD decreased inflammatory response after gut ischemia reperfusion and improved outcome, while LCHFD reduced cancer immunity and worsened survival. However, we found that types of fats affected the cancer immunity, i.e. soy bean oil exacerbated the detrimental effects, but fish oil rather improved the immunity.
With regard to the prehabilitation effects on host response to surgical insult, modulation of autophagy, apoptosis and heat shock protein was observed, thereby reducing organ injury and improving outcome.

Academic Significance and Societal Importance of the Research Achievements

ある病態に対して有効な栄養療法が紹介されると、すべての病態に同様に有効であると考えられがちである。しかし、耐糖能異常や進行がん患者の治療に有効と注目されている低糖質高脂肪食も、病態によっては有効（外科侵襲時）であったり、むしろ悪影響（がん性腹膜炎時）を及ぼす場合があることが、明らかになった。今後は新規栄養療法の導入は、病態ごとに基礎研究により効果を精査する必要があることが再認識された。
手術後の筋肉量と筋力の維持により回復を促進すると期待されてきたプレハビリテーションには、侵襲後の炎症反応調節作用もあることが判明し、運動の重要性が示された。

Research Products

• [Journal Article] Influence of a Low‐Carbohydrate High‐Fat Diet on Peritoneal Inflammation, Cancer‐Associated Lymphocytes, and Survival in a Murine Carcinomatous Peritonitis Model (2020)
  • Author(s): Watkins Ayako、Fukatsu Kazuhiko、Higashizono Kazuya、Watanabe Tomoki、Noguchi Midori、Tominaga Eiji、Murakoshi Satoshi、Yasuhara Hiroshi
  • Journal Title: Journal of Parenteral and Enteral Nutrition Volume: － Issue: 6 Pages: 1293-1301
  • DOI: 10.1002/jpen.2007
  • Peer Reviewed
• [Journal Article] 外科領域での期待と現況 (2020)
  • Author(s): 高橋一哉，深柄和彦
  • Journal Title: 脂質・脂肪酸関連物質の使いこなし方-素材開発・機能創生・応用技術-ω-3系脂肪酸 Volume: - Pages: 83-89
• [Journal Article] 手術侵襲と臓器不全 (2020)
  • Author(s): 高橋一哉，深柄和彦
  • Journal Title: 外科と代謝・栄養 Volume: 55 Pages: 17-21
• [Journal Article] Appropriate treadmill exercise improves survival after gut ischemia reperfusion in mice (2019)
  • Author(s): 109.Higashizono K, Fukatsu K, Watkins A, Watanabe T, Noguchi M, Murakoshi S, Yasuhara H, Seto Y.
  • Journal Title: Clinical Nutrition Experimental Volume: 25 Pages: 36-41
  • Peer Reviewed / Open Access
• [Presentation] Influences of a whey-enriched diet on gut ischemia reperfusion injury in a murine prehabilitation model (2021)
  • Author(s): Kazuya Takahashi, Kazuhiko Fukatsu, Satoshi Murakoshi, Haruka Takayama, Ayako Watkins, Midori Noguchi, Nana Matsumoto, Yasuyuki Seto
  • Organizer: ASPEN 2021 Nutrition Science & Practice Conference
  • Int'l Joint Research
• [Presentation] Beta-hydroxy-beta-methylbutyrate (HMB) moderately reverses atrophy of gut associated lymphoid tissue (GALT) induced by lack of enteral nutrition in mice (2021)
  • Author(s): Haruka Takayam, Kazuhiko Fukatsu, Kazuya Takahashi, Midori Noguchi, Ayako Watkins, Nana Matsumoto, Satoshi Murakoshi
  • Organizer: ASPEN 2021 Nutrition Science & Practice Conference
  • Int'l Joint Research
• [Presentation] プレハビリテーションによる腸管虚血再灌流傷害軽減のホエイタンパクによる修飾～マウストレッドミル走モデルを用いた基礎的研究～ (2020)
  • Author(s): 高橋一哉，深柄和彦，高山はるか，ワトキンス彩子，野口緑，村越智，瀬戸泰之
  • Organizer: 日本外科代謝栄養学会第５７回学術集会
• [Presentation] Whey protein diminishes the beneficial effects of preoperative treadmill exercise on gut ischemia reperfusion (2020)
  • Author(s): Kazuya Takahashi, Kazuhiko Fukatsu, Satoshi Murakoshi, Haruka Takayama, Ayako Watkins, Midori Noguchi, Nana Matsumoto, Yasuyuki Seto
  • Organizer: 42nd ESPEN Congress on Clinical Nutrition and Metabolism
  • Int'l Joint Research
• [Presentation] 発酵乳が腸管免疫におよぼす影響：マウスモデルによる基礎的検討 (2020)
  • Author(s): 高山はるか、深柄和彦1、野口緑、髙橋一哉、Watkins彩子、村越智
  • Organizer: 日本外科代謝栄養学会第５７回学術集会
• [Presentation] Influences of a fermented milk on gut associated lymphoid tissue in mice (2020)
  • Author(s): Haruka Takayama, Kazuhiko Fukatsu, Kazuya Takahashi, Midori Noguchi, Ayako Watkins, Nana Matsumoto, Satoshi Murakoshi
  • Organizer: 42nd ESPEN Congress on Clinical Nutrition and Metabolism
  • Int'l Joint Research
• [Presentation] Combination of whey protein-enriched diet and treadmill exercise diminishes beneficial effect of preoperative exercise on survival after gut ischemia reperfusion (2020)
  • Author(s): Kazuya Takahashi, Kazuhiko Fukatsu, Haruka Takayama, Ayako Watkins, Midori Noguchi, Satoshi Murakoshi, Yasuyuki Seto
  • Organizer: ASPEN 2020 Nutrition Science & Practice Conference
  • Int'l Joint Research
• [Presentation] Influences of different types of high fat diets on peritoneal cytokines in a murine carcinomatous peritonitis model (2019)
  • Author(s): Watkins A, Fukatsu K, Murakoshi S,H Higashizono K, Noguchi M, Yasuhara H
  • Organizer: ASPEN
  • Int'l Joint Research
• [Presentation] Treadmill running modulates regulatory T cell, macrophage and activated neutrophil numbers in the spleen and blood after gut ischemia reperfusion in mice: A possible mechanism underlying improved survival (2019)
  • Author(s): HIがしぞのK, Fukatsu K, Watkins A, Watanabe T, Noguchi M, Tominaga E, Ri M, Murakosi S, Yasuhara H, Seto Y
  • Organizer: ASPEN
  • Int'l Joint Research
• [Presentation] Does enteral feeding improve outcome of mice with carcinomatous peritonitis? (2019)
  • Author(s): Noguchi M, Fukatsu K, Watkins A, Murakoshi S, Watanabe T, Higashizono K, Takahashi K, Takayama H, Yasuhara H
  • Organizer: ESPEN
  • Int'l Joint Research
• [Presentation] Influences of different types of high fat diets on anti-cancer immunity in a murine carcinomatous peritonitis model (2018)
  • Author(s): Watkins A, Fukatsu K, Murakoshi S, Watanabe T, Higashizono K, Noguchi M, Yasuhara H
  • Organizer: ESPEN
  • Int'l Joint Research
• [Presentation] Both soy bean oil based- and fish oil based-high fat diets reduce plasma and gut pro-inflammatory cytokine levels in a murine gut ischemia reperfusion model (2018)
  • Author(s): Watanabe T, Fukatsu K, Murakoshi S, Higashizono K, Watkins A, Noguchi M, Ueno C, Yasuhara H
  • Organizer: ESPEN
  • Int'l Joint Research