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 [3–5]. 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 CO2. 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 process of autophagy is also important for clearing intracellular pathogens and may be an important component in immune surveillance and innate and adaptive gut immunity [7]. The ability of topically delivered NAC to ameliorate colitis in colon segments diverted from luminal bacteria and nutrients draws attention to the role of oxidative stress in the perpetuation of this pathologic condition. NAC is a watersoluble amino acid with L-cysteine and one acetyl group. The hydrogen atom in the sulfhydryl (–SH) of sulfur-containing antioxidant molecules (thiols), including NAC and R. F. Harty (&) Altheus Therapeutics, Inc., 755 Research Parkway, Suite 435, Oklahoma City, OK 73104, USA e-mail: Richard.Harty@altheustherapeutics.com