Fueling the fire: colonocyte metabolism and its effect on the colonic epithelia

Authors: MARTINEZ-RUIZ, MANUEL - Arkansas Children'S Nutrition Research Center (ACNC); ROBESON, MICHAEL - University Arkansas For Medical Sciences (UAMS); PICCOLO, BRIAN - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: Critical Reviews in Food Science and Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/9/2025
Publication Date: 5/23/2025
Citation: Martinez-Ruiz, M., Robeson, M.S., Piccolo, B.D. 2025. Fueling the fire: colonocyte metabolism and its effect on the colonic epithelia. Critical Reviews in Food Science and Nutrition. https://doi.org/10.1080/10408398.2025.2507701.
DOI: https://doi.org/10.1080/10408398.2025.2507701

Interpretive Summary: Our gut barrier defense system prevents many bad things from getting into our body, including things that our resident gut bacteria make that would cause us harm. Problems with our gut barrier defense system causes a leaky gut, which can happen when we have bad bacteria or with certain diseases in our gut. New research has described how our gut barrier defense systems and gut barrier health are maintained by the breakdown of small fats and sugars in the cells that make up our gut. The breakdown of small fats produced by beneficial bacteria causes a state of low oxygen in the cells of our gut an in the space where we pass the food that we consume. This low oxygen state helps keep beneficial bacteria in our gut; bacteria that help us breakdown the food we eat and prevent bad bacteria from growing in our gut. The low oxygen state also signals for the cells to produce more proteins that help bind neighboring cells closer together and produce a mucus that shields gut cells from directly being in contact with resident bacteria. These are all positive things that are derived from a low oxygen state that is driven by the cellular breakdown of small fats. However, there is more evidence that diseases cause the cell to switch from using small fats to breaking down a small sugar called glucose. The switch to breaking down glucose increases the level of oxygen in the cell, and higher oxygen levels in the gut is a necessary ingredient for harmful bacteria and is widely seen during disease. Most of the science that has a looked at this relationship has been focused on adults, with very little research focused on infants and kids. This review article will detail the type of fats and sugars that our cells breakdown for energy and how this breakdown is linked to health and disease. A significant focus of the review will detail this system in infants and during important developmental periods.

Technical Abstract: Colonic permeability is a major consequence of dysbiosis and diseases affecting the colon, further contributing to inflammation and extraintestinal diseases. Recent advances have shed light on the association between colonocyte energy utilization and the mechanisms that support epithelial function and homeostasis. One unifying theme is the induction of colonocyte hypoxia, driven by the aerobic oxidation of microbial-derived butyrate, as a critical factor promoting multiple cellular processes that support intestinal barrier function, mucus secretion, and the maintenance of synergistic luminal microbes. Particular attention will be focused on experimental evidence supporting beta-oxidation via activation of peroxisome proliferators-activated receptor-' (PPAR) and upregulation and activation of processes that promote barrier function by hypoxia-inducible factor (HIF) signaling. Growing evidence suggests that colonocyte energy utilization is tightly regulated and switches between beta-oxidation of butyrate and anaerobic glycolysis, the latter being associated with several disease states. As most of the primary literature associated with colonocyte energy utilization has focused on adult models, evidence supporting butyrate oxidation in the neonatal gut is lacking. Thus, this review details the current state of knowledge linking colonocyte substrate utilization to mechanisms supporting gut health, but also highlights the counterindications of colonic butyrate availability and utilization in developmental periods.