Gastrointestinal organic acid production and metabolism

发生在腹泻和其他疾病中的代谢性酸中毒是疾病和死亡的重要原因，特别是在年幼动物和儿童中。代谢性酸中毒是一个值得关注的问题，因为当血液pH值下降到身体功能最佳的范围以下时，可能会导致包括死亡在内的各种问题。腹泻的另一个并发症是脱水，这会使血液中的酸中毒恶化。 腹泻时酸中毒的发生还不清楚。 我们最近发现，在消化不良的小牛中，血液中存在一种高水平的酸D-乳酸盐。 我们还表明，这种酸单独是造成酸中毒的一些症状的原因，特别是大脑紊乱，包括不适当的行为和混乱。这种酸只由肠道中的细菌产生。 在消化不良的小牛中，肠道损伤导致D-乳酸盐进入血液，引起有害的酸中毒。 我们相信类似的机制也发生在许多其他物种中，包括人类。 我们在这个赠款周期的目标是：A）确定在健康和患病条件下，小牛以外的物种中D-乳酸盐和D-乳酸酸中毒的存在，B）确定其他化合物是否有助于严重腹泻中存在的酸中毒，C）确定酸中毒以及D-乳酸盐对脑和肾功能的影响，D）确定D-乳酸盐是否抑制L-乳酸盐摄取进入脑细胞及其在脑中的代谢，和F）通过饲喂细菌治疗D-乳酸酸中毒不产生D-乳酸的益生菌或有助于减少D-乳酸产生的化合物（益生元）作为抗生素治疗的替代品。 这项研究将有助于我们进一步了解腹泻中的代谢性酸中毒，特别是D-乳酸酸中毒，这既是加拿大农业产业巨大经济损失的原因，也是困扰全球许多儿童的疾病。

The metabolic acidosis that occurs in diarrhea, as well as in other diseases, is a significant cause of illness and death, especially in young animals and children. Metabolic acidosis is a cause for concern because when blood pH decreases below the range at which the body functions best various problems including death can result. Another complication of diarrhea is dehydration which can make the acidosis in blood worse. The development of acidosis in diarrhea is not well understood. In diarrheic calves, we have recently shown that an acid, D-lactate, is present in the blood at high levels. We have also shown that this acid alone is responsible for some of the symptoms present in acidosis, especially brain disturbances including inappropriate behaviour and confusion. This acid is produced only by bacteria in the gut. In diarrheic calves, injury to the gut results in D-lactate passing into the blood causing the harmful acidosis. We believe a similar mechanism occurs in many other species, including humans. Our objectives for this grant cycle are: A) To determine the presence of D-lactate and D-lactic acidosis, in species other than the calf, in both healthy and diseased conditions, B) to determine whether additional compounds contribute to the acidosis present in severe diarrhea, C) to determine the effect of acidosis, as well as D-lactate, on brain and kidney function, D) to determine if D-lactate inhibits L-lactate uptake into brain cells and its metabolism in the brain, E) to valuate the current therapies used in reversing acidosis, and F) to treat D-lactic acidosis by feeding bacteria (probiotics) that do not produce D-lactate or compounds (prebiotics) which help in decreasing the production of D-lactate, as alternatives to antibiotic therapy. This research will help further our understanding of metabolic acidosis, especially D-lactic acidosis, in diarrhea, which is both a cause of great economic loss in the agricultural industry in Canada and a disease that afflicts many children worldwide.