Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi, USA.
Department of Biological Sciences, College of Arts and Sciences, Mississippi State University, Mississippi State, Mississippi, USA.
mSphere. 2024 Mar 26;9(3):e0077423. doi: 10.1128/msphere.00774-23. Epub 2024 Mar 1.
Diabetic foot ulcers (DFUs) are the most common complications of diabetes resulting from hyperglycemia leading to ischemic hypoxic tissue and nerve damage. is the most frequently isolated bacteria from DFUs and causes severe necrotic infections leading to amputations with a poor 5-year survival rate. However, very little is known about the mechanisms by which dominantly colonizes and causes severe disease in DFUs. Herein, we utilized a pressure wound model in diabetic TALLYHO/JngJ mice to reproduce ischemic hypoxic tissue damage seen in DFUs and demonstrated that anaerobic fermentative growth of significantly increased the virulence and the severity of disease by activating two-component regulatory systems leading to expression of virulence factors. Our studies showed that supplementation of nitrate as a terminal electron acceptor promotes anaerobic respiration and suppresses the expression of virulence factors through inactivation of two-component regulatory systems, suggesting potential therapeutic benefits by promoting anaerobic nitrate respiration. Our studies revealed that dietary supplementation of L-arginine (L-Arg) significantly attenuated the severity of disease caused by in the pressure wound model by providing nitrate. Collectively, these findings highlight the importance of anaerobic fermentative growth in pathogenesis and the potential of dietary L-Arg supplementation as a therapeutic to prevent severe infection in DFUs.IMPORTANCE is the most common cause of infection in DFUs, often resulting in lower-extremity amputation with a distressingly poor 5-year survival rate. Treatment for infections has largely remained unchanged for decades and involves tissue debridement with antibiotic therapy. With high levels of conservative treatment failure, recurrence of ulcers, and antibiotic resistance, a new approach is necessary to prevent lower-extremity amputations. Nutritional aspects of DFU treatment have largely been overlooked as there has been contradictory clinical trial evidence, but very few and modelings of nutritional treatment studies have been performed. Here we demonstrate that dietary supplementation of L-Arg in a diabetic mouse model significantly reduced duration and severity of disease caused by . These findings suggest that L-Arg supplementation could be useful as a potential preventive measure against severe infections in DFUs.
糖尿病足溃疡（DFU）是糖尿病最常见的并发症，是由高血糖导致的缺血缺氧组织和神经损伤引起的。 是从 DFU 中最常分离出来的细菌，它会导致严重的坏死性感染，导致截肢，5 年生存率很差。然而，人们对 主要定植并导致 DFU 发生严重疾病的机制知之甚少。在此，我们利用糖尿病 TALLYHO/JngJ 小鼠的压力性伤口模型复制了 DFU 中所见的缺血缺氧组织损伤，并证明 的厌氧发酵生长通过激活双组分调节系统显著增加了毒力和疾病的严重程度，导致毒力因子的表达。我们的研究表明，作为末端电子受体的硝酸盐的补充促进了厌氧呼吸，并通过抑制双组分调节系统来抑制 毒力因子的表达，这表明通过促进厌氧硝酸盐呼吸可能具有潜在的治疗益处。我们的研究表明，膳食补充 L-精氨酸（L-Arg）通过提供硝酸盐，可显著减轻压力性伤口模型中 引起的疾病严重程度。总的来说，这些发现强调了厌氧发酵生长在 发病机制中的重要性，以及膳食 L-Arg 补充作为预防 DFU 中严重 感染的治疗方法的潜力。
重要的是， 是 DFU 中最常见的感染原因，常导致下肢截肢，5 年生存率极差。几十年来， 感染的治疗方法基本没有改变，包括组织清创术和抗生素治疗。由于保守治疗失败率高、溃疡复发和抗生素耐药性，需要采取新的方法来预防下肢截肢。DFU 治疗的营养方面在很大程度上被忽视了，因为有矛盾的临床试验证据，但很少有关于营养治疗研究的 和 模型。在这里，我们证明在糖尿病小鼠模型中，膳食补充 L-Arg 可显著减少 引起的疾病持续时间和严重程度。这些发现表明，L-Arg 补充可能是预防 DFU 中严重 感染的有用措施。
