Energy, Oxidative Stress, and Inflammation in the Colon

Abstract

The manuscript by Martinez et al. [1] describes the effects of topically applied N-acetylcysteine (NAC) on colonic histology and oxidative DNA damage in a rodent model of diversion colitis. The antioxidant NAC significantly improved histological inflammation scores in the diverted colon segments after 2 and 4 weeks of treatment. Furthermore, oxidative DNA damage in colonocytes was significantly reduced in segments without and with fecal stream exposure. These observations broaden our understanding of the role of oxidative stress in diversion colitis, and provide an opportunity to examine other interrelated factors involved in inflammation of the colon.Energy metabolism in colonocytes is dependent on the luminal availability of short-chain fatty acids (SCFA), for example butyrate, propionate, and acetate [2]. Obligate anaerobic bacteria within the gut microbiome ferment and break down dietary complex carbohydrates and proteins to produce SCFA. Whereas glucose is a principal energy source for enterocytes in the small intestine, colonocytes are dependent on SCFAs to maintain energy homeostasis. Experimental and clinical studies support the concept that luminal deficiency of SCFAs, for example butyrate, exacerbate diversion colitis [3][4][5]. Clinical trials utilizing SCFA enemas to treat diversion colitis have been limited and inconclusive. Thus, because SCFA enemas are not used routinely to treat diversion colitis, surgical restoration of bowel continuity is definitive [5].Butyrate regulation of energy metabolism in colonocytes has been studied in germfree (GF) mice [6]. Similar to humans, mouse colonocytes utilize bacterially-produced butyrate as their primary energy source. In conventionally raised mice, butyrate is required for normal colonocyte ATP concentration. When gut flora is normal, microbiomegenerated butyrate is transported into colonocytes, entering the mitochondria, after which butyrate undergoes b-oxidation to acetyl-CoA, which then enters the tricarboxylic acid (TCA) cycle, reducing NAD? to NADH. Upon entering the electron transport chain, NADH generates ATP and CO 2 . In the GF state, or likely in colonic diversion, colonocytes increase glucose uptake which increases the rate of glycolysis and lactate production at the expense of oxidative metabolism. Consequently, colonocyte ATP concentration is reduced because of inadequate butyrate availability. Nutrient-deficient and energy-deficient colonocytes will experience alterations in their redox state and decreased cellular oxidative phosphorylation with resultant increase in oxidative stress. In an effort to maintain energy homeostasis and cellular integrity, colonocytes in GF mice degrade cellular proteins and damaged organelles to generate amino acids for energy consumption in a process termed autophagy [6]. Addition of butyrate to GF colonocytes partially restores mitochondrial respiration and prevents autophagy. If these rescue efforts, for example autophagy, are not successful then cell death or apoptosis occurs. Recent research indicates that ...

The long-term consequences of antibiotic therapy: Role of colonic short-chain fatty acids (SCFA) system and intestinal barrier integrity

“…Thus, antibiotics can lead to long-term oxidative disturbance in the colonic mucosa of rats. Similarly, nutrient-deficient and energy-deficient colonocytes of germ-free mice experienced alterations in their redox state because of inadequate butyrate availability and decreased cellular oxidative phosphorylation with a resultant increase in oxidative stress [50, 67]. Increasing oxygenation of the mucosal surface promotes the outgrowth of aerotolerant taxa such as mouse pathogen Citrobacter rodentium [68].…”

Integrated In Vitro and In Silico Modeling Delineates the Molecular Effects of a Synbiotic Regimen on Colorectal-Cancer-Derived Cells

“…Experimental and clinical studies indicate that colonocyte homeostasis requires gut microbial fermentation of dietary fiber. Oxidative stress and inflammation in the colon can thereby be caused by dysbiotic luminal fermentation and/or deficiencies in SCFAs (Harty, 2013;Singh et al, 2018). In addition to deficiencies in SCFAs, specific components present in the HF regimen (e.g., pectins), which in the absence of LGG are not prone to microbial fermentation, are most likely responsible for the pro-inflammatory effects observed in the human cells (Singh et al, 2018).…”

Effects of anti-TNF-α in experimental diversion colitis

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