Program Official

Principal Investigator

Lisa
Tussing-Humphreys
Awardee Organization

University Of Illinois At Chicago
United States

Fiscal Year
2023
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Mediating Role of Gut Microbiota in the Regulation of Colorectal Cancer Risk in the Context of Time-restricted Eating and Calorie Restriction

The goal of this Diversity Supplement is to extend the significance and innovation of the Parent grant by examining the effect of time-restricted eating (TRE) and daily calorie restriction (CR) on the gut microbiota (GM) and host-microbial interactions relevant to the prevention of colorectal cancer (CRC), the third most incident cancer in the United States. The Diversity Supplement will also provide essential training in cancer prevention to a promising Hispanic woman and Early-Stage Career Investigator, Dr. Beatriz Peñalver Bernabé. Obesity is a major modifiable lifestyle risk factor for CRC. TRE is emerging as an alternative approach to managing weight that involves simply watching the clock and eating for 4-10 hours daily, thus restricting the body’s exposure to nutrients for extended periods of time. TRE demonstrates excellent adherence as it is simple and omits burdensome calorie counting, a hallmark of traditional daily CR. The GM can produce beneficial metabolites, such anti-inflammatory butyrate, or improve gut integrity by promoting mucus production, but a dysregulated GM can lead to increase colonic levels of pro-inflammatory and cancer-promoting metabolites. Existing studies on the effects of TRE on the GM are limited in scope and methodology due to small samples sizes, short duration, use of low-resolution methods that fail to examine changes in microbial metabolic function, and lack of a robust assessment of host-microbial interactions in response to TRE. Further, the differential effects of TRE versus CR on the GM and the relevance to colonic carcinogenesis remains unknown. We hypothesize that both TRE and CR will promote a GM environment less permissive of colonic carcinogenesis and that TRE will be superior due to differences in nutrient exposures, a downstream effect of the shortened eating window. Further, we surmise that systems-level approaches, such as network analysis, can identify the key communications between the host and microbial metabolic and colon genetic networks that play mechanistic roles in CRC risk and prevention. Levering the infrastructure of the Parent grant, the proposed Diversity Supplement will use high-resolution methods, such as metagenomics and metabolomics, to characterize GM composition and metabolic function and host systemic metabolism. Statistical and network approaches will be employed to integrate these multiomics data and colonic transcriptional profiles to determine the effect of TRE and CR on GM and host-microbial interactions. We aim to examine the microbial-regulated metabolite signatures and host-microbial interactions in response to TRE and daily CR while promoting and enhancing diversity among cancer prevention researchers. The Diversity Supplement will provide needed insight into the modulation of the GM and host-microbial interactions in response to TRE and CR and its relevance to the prevention of colorectal carcinogenesis.

Publications

  • Ezpeleta M, Cienfuegos S, Lin S, Pavlou V, Gabel K, Tussing-Humphreys L, Varady KA. Time-restricted eating: Watching the clock to treat obesity. Cell metabolism. 2024 Feb 6;36(2):301-314. Epub 2024 Jan 3. PMID: 38176412
  • Jebeile H, Lister NB, Libesman S, Hunter KE, McMaster CM, Johnson BJ, Baur LA, Paxton SJ, Garnett SP, Ahern AL, Wilfley DE, Maguire S, Sainsbury A, Steinbeck K, Askie L, Braet C, Hill AJ, Nicholls D, Jones RA, Dammery G, Grunseit AM, Cooper K, Kyle TK, Heeren FA, Quigley F, Barnes RD, Bean MK, Beaulieu K, Bonham M, Boutelle KN, Branco BHM, Calugi S, Cardel MI, Carpenter K, Cheng HL, Dalle Grave R, Danielsen YS, Demarzo M, Dordevic A, Eichen DM, Goldschmidt AB, Hilbert A, Houben K, Lofrano do Prado M, Martin CK, McTiernan A, Mensinger JL, Pacanowski C, do Prado WL, Ramalho SM, Raynor HA, Rieger E, Robinson E, Salvo V, Sherwood NE, Simpson SA, Skjakodegard HF, Smith E, Partridge S, Tanofsky-Kraff M, Taylor RW, Van Eyck A, Varady KA, Vidmar AP, Whitelock V, Yanovski J, Seidler AL, Eating Disorders In weight-related Therapy (EDIT) Collaboration. Eating disorders in weight-related therapy (EDIT): Protocol for a systematic review with individual participant data meta-analysis of eating disorder risk in behavioural weight management. PloS one. 2023 Jul 10;18(7):e0282401. doi: 10.1371/journal.pone.0282401. eCollection 2023. PMID: 37428754
  • Gabel K, Cares K, Varady K, Gadi V, Tussing-Humphreys L. Current Evidence and Directions for Intermittent Fasting During Cancer Chemotherapy. Advances in nutrition (Bethesda, Md.). 2022 Mar;13(2):667-680. Epub 2023 Feb 10. PMID: 34788373
  • Gupta DK, Lewis CE, Varady KA, Su YR, Madhur MS, Lackland DT, Reis JP, Wang TJ, Lloyd-Jones DM, Allen NB. Effect of Dietary Sodium on Blood Pressure: A Crossover Trial. JAMA. 2023 Dec 19;330(23):2258-2266. PMID: 37950918
  • Kalam F, Akasheh RT, Cienfuegos S, Ankireddy A, Gabel K, Ezpeleta M, Lin S, Tamatam CM, Reddy SP, Spring B, Khan SA, Varady KA. Effect of time-restricted eating on sex hormone levels in premenopausal and postmenopausal females. Obesity (Silver Spring, Md.). 2023 Feb;31 Suppl 1(Suppl 1):57-62. Epub 2022 Oct 6. PMID: 36203273
  • Lima Oliveira M, Biggers A, Oddo VM, Naylor KB, Chen Z, Hamm A, Pezley L, Peñalver Bernabé B, Gabel K, Sharp LK, Tussing-Humphreys LM. Design of a Remote Time-Restricted Eating and Mindfulness Intervention to Reduce Risk Factors Associated with Early-Onset Colorectal Cancer Development among Young Adults. Nutrients. 2024 Feb 10;16. (4). PMID: 38398828
  • Gabel K, Fitzgibbon ML, Yazici C, Gann P, Sverdlov M, Guzman G, Chen Z, McLeod A, Hamm A, Varady KA, Tussing-Humphreys L. The basis and design for time-restricted eating compared with daily calorie restriction for weight loss and colorectal cancer risk reduction trial (TRE-CRC trial). Obesity (Silver Spring, Md.). 2022 Dec;30(12):2376-2385. Epub 2022 Nov 1. PMID: 36319597

Clinical Trials

Study Name Clinical Trial ID
Time-restricted Eating Versus Daily Continuous Calorie Restriction on Body Weight and Colorectal Cancer Risk Markers NCT05114798