Chronic disruption of rhythms (CDR) impacts sleep and can result in circadian misalignment of physiological systems, which in turn is associated with increased disease risk. Exposure to repeated or severe stressors also disturbs sleep and diurnal rhythms. Prebiotic nutrients produce favorable changes in gut microbial ecology, the gut metabolome, and reduce several negative impacts of acute severe stressor exposure, including disturbed sleep, core body temperature rhythmicity, and gut microbial dysbiosis. This study tested the hypothesis whether prebiotics can also reduce the negative impacts of CDR by facilitating light/dark realignment of sleep/wake, core body temperature, and locomotor activity; and whether prebiotic-induced changes in bacteria and bile acid profiles are associated with these effects. Male, Sprague Dawley rats were fed diets enriched in prebiotic substrates or calorically matched control chow. After 5 weeks on diet, rats were exposed to CDR (12h light/dark reversal, weekly for 8 weeks) or remained on undisturbed normal light/dark cycles (NLD). Sleep EEG, core body temperature, and locomotor activity were recorded via biotelemetry in freely moving rats. Fecal samples were collected on experimental days -33, 0 (day of onset of CDR), and 42. Taxonomic identification and relative abundances of gut microbes were measured in fecal samples using 16S rRNA gene sequencing and shotgun metagenomics. Fecal primary, bacterially-modified secondary, and conjugated bile acids were measured using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Prebiotic diet produced rapid and stable increases in the relative abundances of Parabacteroides distasonis and Ruminiclostridium 5. Shotgun metagenomics analyses confirmed reliable increases in relative abundances of Parabacteroides distasonis and Clostridium leptum, a member of the Ruminiclostridium genus. Prebiotic diet also modified fecal bile acid profiles; and based on correlational and step-wise regression analyses, Parabacteroides distasonis and Ruminiclostridium 5 were positively associated with each other and negatively associated with secondary and conjugated bile acids. Prebiotic diet, but not CDR, impacted beta diversity. Measures of alpha diversity evenness were decreased by CDR and prebiotic diet prevented that effect. Rats exposed to CDR while eating prebiotic, compared to control diet, more quickly realigned NREM sleep and core body temperature (ClockLab) diurnal rhythms to the altered light/dark cycle. Finally, both cholic acid and Ruminiclostridium 5 prior to CDR were associated with time to realign CBT rhythms to the new light/dark cycle after CDR; whereas both Ruminiclostridium 5 and taurocholic acid prior to CDR were associated with NREM sleep recovery after CDR. These results suggest that ingestion of prebiotic substrates is an effective strategy to increase the relative abundance of health promoting microbes, alter the fecal bile acid profile, and facilitate the recovery and realignment of sleep and diurnal rhythms after circadian disruption.

中文翻译：

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益生菌饮食可调节益生菌和胆汁酸，并在慢性节律紊乱后促进昼夜时钟/睡眠重排

慢性节律（CDR）会影响睡眠，并可能导致生理系统的昼夜节律失调，进而导致疾病风险增加。暴露于反复或严重的压力下也会干扰睡眠和昼夜节律。益生元营养素可在肠道微生物生态学，肠道代谢组中产生有利的变化，并减少急性严重应激源暴露的若干负面影响，包括睡眠不安，核心体温节律和肠道微生物失调。这项研究检验了以下假设：益生元是否也可以通过促进睡眠/觉醒的明暗调整，核心体温和运动能力来减少CDR的负面影响。以及益生元诱导的细菌和胆汁酸谱变化是否与这些作用有关。男性，给Sprague Dawley大鼠喂食富含益生元底物或热量匹配的对照食物的饮食。饮食5周后，将大鼠暴露于CDR（12h光照/黑暗逆转，每周8周）或保持正常的光照/黑暗循环（NLD）。通过生物遥测法记录自由运动大鼠的睡眠脑电图，核心体温和运动能力。在实验的第33天，第0天（CDR发作的天）和第42天收集粪便样品。使用16S rRNA基因测序和shot弹枪宏基因组学方法，对粪便样品中的肠道菌群进行分类学鉴定和相对丰度。使用液相色谱-串联质谱法（LC-MS / MS）测量粪便中的伯酸，细菌修饰的仲酸和缀合的胆汁酸。益生元饮食使副细菌副杆菌和Ruminiclostridium 5的相对丰度迅速而稳定地增加。Shotgun宏基因组学分析证实了副细菌副杆菌和Clostridium leptum（Ruminiclostridium属的成员）的相对丰度有可靠的增加。益生元饮食还可以改变粪便中的胆汁酸。并且基于相关和逐步回归分析，副细菌副杆菌和Ruminiclostridium 5彼此正相关，而与仲胆汁酸和共轭胆汁酸负相关。益生元饮食，而不是CDR，影响了β多样性。CDR降低了α多样性均匀性的量度，而益生元饮食则阻止了这种效果。与对照饮食相比，在食用益生元时暴露于CDR的大鼠，更快地将NREM睡眠和核心体温（ClockLab）的昼夜节律重新调整为改变的明暗周期。最后，CDR之前的胆酸和Ruminiclostridium 5都与时间相关，以使CBT节奏重新适应CDR之后的新的明/暗周期。而CDR之前的Ruminiclostridium 5和牛磺胆酸都与CDR之后的NREM睡眠恢复有关。这些结果表明，摄入益生元底物是一种有效的策略，可以增加人体健康促进微生物的相对丰度，改变粪便胆汁酸谱并促进昼夜节律后睡眠和昼夜节律的恢复和调整。CDR之前的胆酸和Ruminiclostridium 5都与将CDR后CBT节奏重新调整为新的明/暗周期的时间相关。而CDR之前的Ruminiclostridium 5和牛磺胆酸都与CDR之后的NREM睡眠恢复有关。这些结果表明，摄入益生元底物是一种有效的策略，可以增加人体健康促进微生物的相对丰度，改变粪便胆汁酸谱并促进昼夜节律后睡眠和昼夜节律的恢复和调整。CDR之前的胆酸和Ruminiclostridium 5都与将CDR后的CBT节奏重新调整为新的明/暗周期的时间相关。而CDR之前的Ruminiclostridium 5和牛磺胆酸都与CDR之后的NREM睡眠恢复有关。这些结果表明，摄入益生元底物是一种有效的策略，可以增加人体健康促进微生物的相对丰度，改变粪便胆汁酸谱并促进昼夜节律后睡眠和昼夜节律的恢复和调整。