Gut Microbial Metabolites Induce Changes in Circadian Oscillation of Clock Gene Expression in the Mouse Embryonic Fibroblasts.
- 作者列表："Ku K","Park I","Kim D","Kim J","Jang S","Choi M","Choe HK","Kim K
:Circadian rhythm is an endogenous oscillation of about 24-h period in many physiological processes and behaviors. This daily oscillation is maintained by the molecular clock machinery with transcriptional-translational feedback loops mediated by clock genes including Period2 (Per2) and Bmal1. Recently, it was revealed that gut microbiome exerts a significant impact on the circadian physiology and behavior of its host; however, the mechanism through which it regulates the molecular clock has remained elusive. 3-(4-hydroxyphenyl)propionic acid (4-OH-PPA) and 3-phenylpropionic acid (PPA) are major metabolites exclusively produced by Clostridium sporogenes and may function as unique chemical messengers communicating with its host. In the present study, we examined if two C. sporogenes-derived metabolites can modulate the oscillation of mammalian molecular clock. Interestingly, 4-OH-PPA and PPA increased the amplitude of both PER2 and Bmal1 oscillation in a dosedependent manner following their administration immediately after the nadir or the peak of their rhythm. The phase of PER2 oscillation responded differently depending on the mode of administration of the metabolites. In addition, using an organotypic slice culture ex vivo, treatment with 4-OH-PPA increased the amplitude and lengthened the period of PER2 oscillation in the suprachiasmatic nucleus and other tissues. In summary, two C. sporogenes-derived metabolites are involved in the regulation of circadian oscillation of Per2 and Bmal1 clock genes in the host's peripheral and central clock machineries.
: 昼夜节律是许多生理过程和行为中大约 24 h 周期的内源性振荡。这种每日振荡是由包括 Period2 (Per2) 和 bmal1 在内的时钟基因介导的转录-翻译反馈环的分子钟机器维持的。最近，人们发现肠道微生物组对其宿主的昼夜节律生理和行为产生重大影响; 然而，它调控分子钟的机制仍然难以捉摸。3-(4-羟基苯基) 丙酸 (4-OH-PPA) 和 3-苯基丙酸 (PPA) 是产孢梭菌产生的主要代谢产物，可能是与其宿主沟通的独特化学信使。在本研究中，我们检测了两个产孢菌衍生代谢物是否可以调节哺乳动物分子钟的振荡。有趣的是，4-OH-PPA 和 PPA 在最低点或节律峰值后立即给药，以剂量依赖性方式增加了 PER2 和 Bmal1 振荡的幅度。PER2 振荡的相位响应不同，取决于代谢物的给药方式。此外，使用离体器官型切片培养，4-OH-PPA 处理增加了视交叉上核和其他组织中 PER2 振荡的振幅并延长了周期。总之，两种产孢菌来源的代谢物参与了宿主外周和中心时钟机制中 Per2 和 Bmal1 时钟基因昼夜节律振荡的调控。
METHODS:OBJECTIVES:To evaluate the effect of esophageal stimulation on nutritional adequacy in critically ill patients at risk for enteral feeding intolerance. DESIGN:A multicenter randomized sham-controlled clinical trial. SETTING:Twelve ICUs in Canada. PATIENTS:We included mechanically ventilated ICU patients who were given moderate-to-high doses of opioids and expected to remain alive and ventilated for an additional 48 hours and who were receiving enteral nutrition or expected to start imminently. INTERVENTIONS:Patients were randomly assigned 1:1 to esophageal stimulation via an esophageal stimulating catheter (E-Motion Tube; E-Motion Medical, Tel Aviv, Israel) or sham treatment. All patients were fed via these catheters using a standardized feeding protocol. MEASUREMENTS AND MAIN RESULTS:The co-primary outcomes were proportion of caloric and protein prescription received enterally over the initial 7 days following randomization. Among 159 patients randomized, the modified intention-to-treat analysis included 155 patients: 73 patients in the active treatment group and 82 in the sham treatment group. Over the 7-day study period, the percent of prescribed caloric intake (± SE) received by the enteral route was 64% ± 2 in the active group and 65% ± 2 in sham patients for calories (difference, -1; 95% CI, -8 to 6; p = 0.74). For protein, it was 57% ± 3 in the active group and 60% ± 3 in the sham group (difference, -3; 95% CI, -10 to 3; p = 0.30). Compared to the sham group, there were more serious adverse events reported in the active treatment group (13 vs 6; p = 0.053). Clinically important arrhythmias were detected by Holter monitoring in 36 out of 70 (51%) in the active group versus 22 out of 76 (29%) in the sham group (p = 0.006). CONCLUSIONS:Esophageal stimulation via a special feeding catheter did not improve nutritional adequacy and was associated with increase risk of harm in critically ill patients.
METHODS:RATIONALE:The long-term effects of delivering approximately 100% of recommended calorie intake via the enteral route during critical illness compared to a lesser amount of calories are unknown. OBJECTIVES:Our hypotheses were that achieving approximately 100% of recommended calorie intake during critical illness would increase quality of life scores, return to work and key life activities and reduce death and disability six months later. METHODS:We conducted a multicenter, blinded, parallel group, randomized clinical trial, with 3957 mechanically ventilated critically ill adults allocated to energy-dense (1.5 kcal/ml) or routine (1.0 kcal/ml) enteral nutrition. MEASUREMENTS AND MAIN RESULTS:Participants assigned energy-dense nutrition received more calories (% recommended energy intake, mean (SD) (energy-dense: 103% (28) vs. usual: 69% (18)). Mortality at day-180 was similar (560/1895 (29.6%) vs. 539/1920 (28.1%); relative risk 1.05 (95%CI, 0.95 to 1.16)). At a median [IQR] of 185 [182, 193] days after randomization, 2492 survivors were surveyed and reported similar quality of life (EuroQol five dimensions five-level quality of life questionnaire visual analogue scale, median [IQR]: 75 [60-85]; group difference: 0 (95%CI, 0 to 0)). Similar numbers of participants returned to work with no difference in hours worked or effectiveness at work (n=818). There was no observed difference in disability (n=1208) or participation in key life activities (n=705). CONCLUSIONS:The delivery of approximately 100% compared to 70% of recommended calorie intake during critical illness does not improve quality of life, or functional outcomes, or increase the number of survivors six months later. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT02306746.
METHODS:BACKGROUND:Provision of enteral nutrition with jejunal feeding in upper gastrointestinal obstruction is highly recommended. Access to jejunum can be obtained surgically, percutaneously, or endoscopically. Our institution routinely and preferentially utilizes a silicone nasojejunal tube that is inserted past the obstruction endoscopically. We use a custom dual channel tube that allows feeding at the distal tip and another channel 40 cm from the tip that enables decompression proximally. This is a report of our experience with this custom nasojejunal tube. METHODS:This is a prospective observational study of 201 patients who underwent endoscopic nasojejunal wire-guided feeding tube insertions for obstruction of either the esophagus or the stomach including both benign and malignant pathologies between January 2015 to June 2018 in Hospital Sungai Buloh and Hospital Sultanah Aminah, Malaysia. The indications for tube insertion, insertion technique, and tube-related problems were described. RESULTS:The nasojejunal tube was used to establish enteral feeding in patients with obstructing tumors of the distal esophagus in 65 patients (32.3%) and gastric outlet obstruction in 72 patients (35.8%). There were 54 patients (26.9%) who required reinsertion. The most common reason for reinsertion was unintentional dislodgement, where 32 patients (15.9%) followed by tube blockage 20 patients (10.0%). Using our method of advancement under direct vision, we had only 2 cases of malposition due to severely deformed anatomy. We had no incidence of aspiration in this group of patients and overall, the patients tolerated the tube well. CONCLUSIONS:The novel nasojejunal feeding tube with gastric decompression function is a safe and effective method of delivery of enteral nutrition in patients with upper gastrointestinal obstruction. These tubes if inserted properly are well tolerated with almost no risk of malposition and are tolerated well even for prolonged periods of time until definitive surgery could be performed.