RESUMEN
Chronic ethanol consumption is a risk factor for colorectal cancer, and ethanol-induced reactive oxygen species have been suggested to play important roles in the pathogenesis of ethanol-related colorectal cancer (ER-CRC). In this study, the effects of 10-week chronic administration of ethanol on the colonic levels of oxidative stress and advance glycation end product (AGE) levels, as well as fecal microbiota structures, were examined in a mouse model. Chronic oral administration of ethanol in mice (1.0 mL of 1.5% or 5.0% ethanol (v/v) per day per mouse, up to 10 weeks) resulted in the elevation of colonic levels of oxidative stress markers (such as 8-hydroxy-2'-deoxyguanosine and 4-hydroxynonenal) compared to control mice, and this was consistently accompanied by elevated levels of inflammation-associated cytokines and immune cells (Th17 and macrophages) and a decreased level of regulatory T (Treg) cells to produce colonic lesions. It also resulted in an alteration of mouse fecal microbiota structures, reminiscent of the alterations observed in human inflammatory bowel disease, and this appeared to be consistent with the proposed sustained generation of oxidative stress in the colonic environment during chronic ethanol consumption. Moreover, the first experimental evidence that chronic ethanol administration results in elevated levels of advanced glycation end products (AGEs) and their receptors (RAGE) in the colonic tissues in mice is also shown, implying enhanced RAGE-mediated signaling with chronic ethanol administration. The RAGE-mediated signaling pathway has thus far been implicated as a link between the accumulation of AGEs and the development of many types of chronic colitis and cancers. Thus, enhancement of this pathway likely exacerbates the ethanol-induced inflammatory states of colonic tissues and might at least partly contribute to the pathogenesis of ER-CRC.
Asunto(s)
Biomarcadores/metabolismo , Colon/metabolismo , Neoplasias Colorrectales/patología , Etanol/administración & dosificación , Heces/microbiología , Microbiota , Estrés Oxidativo , Administración Oral , Animales , Bacterias , Peso Corporal , Quimiocinas/genética , Quimiocinas/metabolismo , Colon/patología , Microbioma Gastrointestinal , Inflamación/inmunología , Inflamación/patología , Masculino , Ratones Endogámicos C57BL , Membrana Mucosa/patología , Filogenia , Análisis de Componente Principal , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Ethanol is oxidized by alcohol dehydrogenase to acetaldehyde, a recognized carcinogen for the esophagus. However, no previous study has measured the acetaldehyde levels in the esophageal tissue. L-cysteine has been shown to reduce the acetaldehyde levels in the saliva; however, it is unknown whether L-cysteine intake affects the acetaldehyde concentration in the esophageal tissue. The aim of this study was to measure the acetaldehyde concentration in the esophageal tissue after ethanol drinking and evaluate the effect of L-cysteine intake on the acetaldehyde levels in the esophagus. We enrolled 10 male subjects with active acetaldehyde dehydrogenase-2*1/*1 (ALDH2*1/*1) genotype and 10 male subjects with the inactive acetaldehyde dehydrogenase-2*1/*2 (ALDH2*1/*2) genotype, the mean ages of whom were 25.6 and 27.9 years, respectively. In this prospective, single-blind, placebo-controlled study using L-cysteine and placebo lozenges (first and second examination), saliva and blood were collected before and after ethanol drinking. Esophageal tissue was obtained by endoscopic biopsy at 60 minutes after drinking, and the acetaldehyde and ethanol concentrations were measured. The acetaldehyde concentration of the saliva was significantly lower in those taking L-cysteine than in those taking the placebo. Acetaldehyde in the esophageal tissue was detected only in those taking L-cysteine lozenges. There were no correlations between the acetaldehyde concentrations in the esophageal tissue and saliva or blood. In conclusion, we detected acetaldehyde in the human esophageal tissue after ethanol drinking. Unexpectedly, intake of L-cysteine lozenges appears to contribute to detection of acetaldehyde in the esophageal tissue.
Asunto(s)
Acetaldehído/metabolismo , Cisteína/administración & dosificación , Esófago/metabolismo , Etanol/administración & dosificación , Adulto , Alcohol Deshidrogenasa , Consumo de Bebidas Alcohólicas , Aldehído Deshidrogenasa/genética , Aldehído Deshidrogenasa Mitocondrial/genética , Neoplasias Esofágicas/prevención & control , Genotipo , Voluntarios Sanos , Humanos , Masculino , Estudios Prospectivos , Saliva , Método Simple Ciego , Adulto JovenRESUMEN
Chronic consumption of excess ethanol increases the risk of colorectal cancer. The pathogenesis of ethanol-related colorectal cancer (ER-CRC) is thought to be partly mediated by gut microbes. Specifically, bacteria in the colon and rectum convert ethanol to acetaldehyde (AcH), which is carcinogenic. However, the effects of chronic ethanol consumption on the human gut microbiome are poorly understood, and the role of gut microbes in the proposed AcH-mediated pathogenesis of ER-CRC remains to be elaborated. Here we analyse and compare the gut microbiota structures of non-alcoholics and alcoholics. The gut microbiotas of alcoholics were diminished in dominant obligate anaerobes (e.g., Bacteroides and Ruminococcus) and enriched in Streptococcus and other minor species. This alteration might be exacerbated by habitual smoking. These observations could at least partly be explained by the susceptibility of obligate anaerobes to reactive oxygen species, which are increased by chronic exposure of the gut mucosa to ethanol. The AcH productivity from ethanol was much lower in the faeces of alcoholic patients than in faeces of non-alcoholic subjects. The faecal phenotype of the alcoholics could be rationalised based on their gut microbiota structures and the ability of gut bacteria to accumulate AcH from ethanol.
Asunto(s)
Alcoholismo/microbiología , Bacteroides/aislamiento & purificación , Neoplasias Colorrectales/patología , Etanol/metabolismo , Microbioma Gastrointestinal , Ruminococcus/aislamiento & purificación , Streptococcus/aislamiento & purificación , Acetaldehído/química , Acetaldehído/metabolismo , Adolescente , Adulto , Anciano , Alcohol Deshidrogenasa/genética , Alcoholismo/patología , Aldehído Deshidrogenasa Mitocondrial/genética , Bacteroides/genética , Análisis por Conglomerados , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/microbiología , Heces/química , Heces/microbiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo Genético , Análisis de Componente Principal , ARN Ribosómico 16S/química , ARN Ribosómico 16S/genética , Ruminococcus/genética , Análisis de Secuencia de ADN , Streptococcus/genética , Adulto JovenRESUMEN
AIMS: The importance of ethanol oxidation by intestinal aerobes and facultative anaerobes under aerobic conditions in the pathogenesis of ethanol-related colorectal cancer has been proposed. However, the role of obligate anaerobes therein remains to be established, and it is still unclear which bacterial species, if any, are most important in the production and/or elimination of carcinogenic acetaldehyde under such conditions. This study was undertaken to address these issues. METHODS: More than 500 bacterial strains were isolated from the faeces of Japanese alcoholics and phylogenetically characterized, and their aerobic ethanol metabolism was studied in vitro to examine their ability to accumulate acetaldehyde beyond the minimum mutagenic concentration (MMC, 50 µM). RESULTS: Bacterial strains that were considered to potentially accumulate acetaldehyde beyond the MMC under aerobic conditions in the colon and rectum were identified and referred to as 'potential acetaldehyde accumulators' (PAAs). Ruminococcus, an obligate anaerobe, was identified as a genus that includes a large number of PAAs. Other obligate anaerobes were also found to include PAAs. The accumulation of acetaldehyde by PAAs colonizing the colorectal mucosal surface could be described, at least in part, as the response of PAAs to oxidative stress. CONCLUSION: Ethanol oxidation by intestinal obligate anaerobes under aerobic conditions in the colon and rectum could also play an important role in the pathogenesis of ethanol-related colorectal cancer.
Asunto(s)
Acetaldehído/metabolismo , Bacterias Anaerobias/metabolismo , Colon/microbiología , Etanol/metabolismo , Recto/microbiología , Heces/microbiología , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Masculino , Persona de Mediana Edad , Oxidación-Reducción , Filogenia , Especies Reactivas de Oxígeno/metabolismo , Ruminococcus/metabolismoRESUMEN
A facultatively anaerobic, Gram-stain-positive, rod-shaped bacterium, designated strain KB0549T, was isolated from sesame oil cake. Cells were motile, round-ended rods, and produced central or terminal spores. The cell wall peptidoglycan contained meso-diaminopimelic acid as the diamino acid. The major fatty acids were anteiso-C15:0 and anteiso-C17:0. The DNA G+C content of strain KB0549T was 51.9 mol%. On the basis of 16S rRNA gene sequence phylogeny, strain KB0549T was affiliated with the genus Paenibacillus in the phylum Firmicutes and was most closely related to Paenibacillus cookii with 97.4% sequence similarity. Strain KB0549T was physiologically differentiated from P. cookii by the high content of anteiso-C17:0, inability to grow at 50 °C, spore position, and negative Voges-Proskauer reaction. Based on these unique physiological and phylogenetic characteristics, it is proposed that the isolate represents a novel species, Paenibacillus relictisesami sp. nov.; the type strain is KB0549T (=JCM 18068T=DSM 25385T).