Gastrointestinal organic acid production and metabolism

腹泻会导致严重的疾病和死亡，特别是对幼小的动物和儿童。腹泻的两个并发症是脱水和代谢性酸中毒。代谢性酸中毒会在血液pH值降到身体最佳功能范围以下时引发问题，并可能导致包括死亡在内的各种问题。腹泻中酸中毒的发展还不是很清楚。我们最近发现一种酸，D-乳酸，存在于血液中，含量很高，是导致腹泻小牛酸中毒的原因。这种酸只由肠道中的细菌产生。在腹泻的小牛身上，肠道的损伤会导致D-乳酸进入血液，导致有害的酸中毒。我们相信许多其他物种也存在类似的机制，包括人类。我们这次拨款周期的目标是：1)确定在健康和患病的情况下，小牛以外的物种中是否存在D-乳酸和D-乳酸酸中毒，2)确定其他化合物是否导致严重腹泻中的酸中毒，3)确定酸中毒对大脑和肾脏功能的影响。4)评估目前用于逆转酸中毒的治疗方法，以及5)通过喂养不产生D-乳酸的细菌(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方案来治疗D-乳酸酸中毒。这项研究将有助于加深我们对腹泻代谢性酸中毒，特别是D-乳酸酸中毒的了解，这既是加拿大农业的巨大经济损失，也是一种困扰世界各地许多儿童的疾病。

Diarrhea causes significant illness and death, especially in young animals and children. Two complications of diarrhea are dehydration and metabolic acidosis. Metabolic acidosis causes problems when blood pH decreases below the range at which the body functions best, and various problems including death can result. The development of acidosis in diarrhea is not well understood.  We have recently shown that an acid, D-lactate, is present in the blood at high levels and contributes to acidosis in diarrheic calves. 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: 1) To determine the presence of D-lactate and D-lactic acidosis, in species other than the calf, in both healthy and diseased conditions, 2) to determine whether additional compounds contribute to the acidosis present in severe diarrhea, 3) to determine the effect of acidosis on brain and kidney function, 4) to evaluate the current therapies used in reversing acidosis, and 5) 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.