Diet is a key health determinant. Its impact on diabetes and cardiovascular disease is well known. But does it matter for cancer outcome?
Recent discoveries suggest so. Omitting selected amino acids (components of protein) from the diet can slow tumor growth in mice. Fasting enhances the sensitivity of some tumors to chemotherapy. A ketogenic diet does too because the carbohydrate level is so low that eating fails to induce insulin. Insulin is the key hormonal indicator of the “fed” state and a factor in tumor growth.
Diet also impacts anticancer immune response. In ways not yet well understood, the bacteria in our intestine (the gut microbiome), which are impacted by the food that we eat, shape the activity of tumor-attacking T cells. A high-fiber diet promotes, via the microbiome, immunotherapy efficacy.
At the Ludwig Princeton Branch, we will explore the biochemical basis by which diet impacts cancer. We will build rational and quantitative understanding of diet’s influence on cancer’s growth, chemotherapy sensitivity, and immune response, and how these factors vary across tumor types and individuals. In so doing, we will lay the foundation for designer diets that robustly suppress cancer. In parallel, we will engage clinicians to prove the benefits of tailored diets for cancer patients.
Related Publications
Zeng X, Xing X, Gupta M, Keber FC, Lopez JG, Lee YJ, Roichman A, Wang L, Neinast MD, Donia MS, Wühr M, Jang C, Rabinowitz JD.Cell. 2022 Sep 1; 185(18):3441-3456.e19. doi: 10.1016/j.cell.2022.07.020. PMID: 36055202
Great progress has been made in understanding gut microbiomes' products and their effects on health and disease. Less attention, however, has been given to the inputs that gut bacteria consume. Here, we quantitatively examine inputs and outputs of the mouse gut microbiome, using isotope tracing. The main input to microbial carbohydrate fermentation is dietary fiber and to branched-chain fatty acids and aromatic metabolites is dietary protein. In addition, circulating host lactate, 3-hydroxybutyrate, and urea (but not glucose or amino acids) feed the gut microbiome. To determine the nutrient preferences across bacteria, we traced into genus-specific bacterial protein sequences. We found systematic differences in nutrient use: most genera in the phylum Firmicutes prefer dietary protein, Bacteroides dietary fiber, and Akkermansia circulating host lactate. Such preferences correlate with microbiome composition changes in response to dietary modifications. Thus, diet shapes the microbiome by promoting the growth of bacteria that preferentially use the ingested nutrients.
Xiao T, Khan A, Shen Y, Chen L, Rabinowitz JD.Nat Chem Biol. 2022 Aug 15. doi: 10.1038/s41589-022-01091-7. Online ahead of print. PMID: 35970997
Ethanol and lactate are typical waste products of glucose fermentation. In mammals, glucose is catabolized by glycolysis into circulating lactate, which is broadly used throughout the body as a carbohydrate fuel. Individual cells can both uptake and excrete lactate, uncoupling glycolysis from glucose oxidation. Here we show that similar uncoupling occurs in budding yeast batch cultures of Saccharomyces cerevisiae and Issatchenkia orientalis. Even in fermenting S. cerevisiae that is net releasing ethanol, media 13C-ethanol rapidly enters and is oxidized to acetaldehyde and acetyl-CoA. This is evident in exogenous ethanol being a major source of both cytosolic and mitochondrial acetyl units. 2H-tracing reveals that ethanol is also a major source of both NADH and NADPH high-energy electrons, and this role is augmented under oxidative stress conditions. Thus, uncoupling of glycolysis from the oxidation of glucose-derived carbon via rapidly reversible reactions is a conserved feature of eukaryotic metabolism.
Yang L, TeSlaa T, Ng S, Nofal M, Wang L, Lan T, Zeng X, Cowan A, McBride M, Lu W, Davidson S, Liang G, Oh TG, Downes M, Evans R, Von Hoff D, Guo JY, Han H, Rabinowitz JD. (2022) Med (NY), 3(2):119-136. PMID: 35425930
Background: Ketogenic diet is a potential means of augmenting cancer therapy. Here, we explore ketone body metabolism and its interplay with chemotherapy in pancreatic cancer.
Methods: Metabolism and therapeutic responses of murine pancreatic cancer were studied using KPC primary tumors and tumor chunk allografts. Mice on standard high-carbohydrate diet or ketogenic diet were treated with cytotoxic chemotherapy (nab-paclitaxel, gemcitabine, cisplatin). Metabolic activity was monitored with metabolomics and isotope tracing, including 2H- and 13C-tracers, liquid chromatography-mass spectrometry, and imaging mass spectrometry.
Findings: Ketone bodies are unidirectionally oxidized to make NADH. This stands in contrast to the carbohydrate-derived carboxylic acids lactate and pyruvate, which rapidly interconvert, buffering NADH/NAD. In murine pancreatic tumors, ketogenic diet decreases glucose's concentration and tricarboxylic acid cycle contribution, enhances 3-hydroxybutyrate's concentration and tricarboxylic acid contribution, and modestly elevates NADH, but does not impact tumor growth. In contrast, the combination of ketogenic diet and cytotoxic chemotherapy substantially raises tumor NADH and synergistically suppresses tumor growth, tripling the survival benefits of chemotherapy alone. Chemotherapy and ketogenic diet also synergize in immune-deficient mice, although long-term growth suppression was only observed in mice with an intact immune system.
Conclusions: Ketogenic diet sensitizes murine pancreatic cancer tumors to cytotoxic chemotherapy. Based on these data, we have initiated a randomized clinical trial of chemotherapy with standard versus ketogenic diet for patients with metastatic pancreatic cancer (NCT04631445).