Lactobacillus rhamnosus: A Novel Probiotic Therapy for treating Alcohol Use Disorder

鼠李糖乳杆菌：一种治疗酒精使用障碍的新型益生菌疗法

• 批准号: 10620258
• 负责人: Vatsalya Vatsalya
• 金额: $ 14.08万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-10 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620258
• 关键词: Abstinence; Adverse effects; Adverse event; Albumins; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Alcohols; Animal Model; Animals; Award; Behavior Therapy; Behavioral; Bilirubin; Biochemical Markers; Biochemistry; Biological Assay; Biological Markers; Blood; Brain; Chronic; Circulation; Clinical; Clinical Research; Complex; Data; Diagnosis; Dietary Fiber; Disease; Disulfiram; Dopamine; Double-Blind Method; Endotoxemia; Enrollment; Equipment and supply inventories; FDA approved; Faculty; Fermentation; Frequencies; Functional disorder; Goals; Grant; Health; Healthcare; Heavy Drinking; Hepatitis; Human; Inflammation; Inflammatory; Inflammatory Response; Intervention; Intestinal permeability; Knowledge; Lactobacillus casei rhamnosus; Lipopolysaccharides; Liver; Liver diseases; Measures; Mediating; Medical; Mentors; Mentorship; Methodology; Naltrexone; National Institute on Alcohol Abuse and Alcoholism; Neurotransmitters; Outcome; Pathway interactions; Patient Outcomes Assessments; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pilot Projects; Placebos; Positioning Attribute; Probiotics; Prognostic Marker; Property; Psychological reinforcement; Public Health; Publications; Quality of life; Randomized; Regulation; Relapse; Reporting; Research; Research Personnel; Research Project Grants; Resources; Rewards; Role; Serotonin; Severities; Structure; Symptoms; Testing; Therapeutic; Training; Tryptophan; United States; Universities; Volatile Fatty Acids; Withdrawal; Woman; Work; Writing; alcohol use disorder; bench to bedside; candidate marker; chronic alcohol ingestion; comorbidity; craving; design; drinking; effective therapy; efficacy testing; efficacy validation; eligible participant; experience; gamma-Aminobutyric Acid; gut microbiome; gut microbiota; gut-brain axis; improved; liver development; liver inflammation; liver injury; men; metabolomics; microbiome alteration; neurobehavioral; neuroinflammation; new therapeutic target; novel; organ injury; preventable death; probiotic therapy; programs; response; restoration; skills; success; symptomatic improvement; tenure track; therapeutic target; treatment adherence; treatment comparison; treatment trial

This application is a proposal for a mentored clinical research award (K23) that will enable Dr. Vatsalya Vatsalya to continue to develop his skills in clinical research; specifically, identifying new therapeutic targets for the treatment of patients with alcohol use disorder (AUD) and concomitant moderate alcohol associated hepatitis (AH). AUD represents one of the leading causes of preventable deaths in the United States and efforts are in progress to identify new interventions. Emerging animal and human research suggest that Lactobacillus rhamnosus GG (LGG), a probiotic, is involved in the restoration of a normal gut microbiome, attenuating gut dysfunction and lowering endotoxemia and inflammation. Dr. Vatsalya’s overall goal is to complete mentored research and transition to independent research. He also plans to successfully obtain a tenure-track faculty position that will allow him to fully establish his own independent research program. Dr. Vatsalya’s training goals are to: (1) broaden his conceptual knowledge in researching the neuropharmacological mechanisms in AUD; (2) enhance his experience with human studies in the field of AUD and alcohol associated liver disease (ALD); (3) improve his methodological skills in order to conduct effective large-scale trials; and (4) improve his grant- and publication-writing skills. These training goals will be achieved through: (a) the resources available at the University of Louisville; (b) the high quality of mentorship provided by his mentor and the mentor committee; (c) focused training and clinical experiences; and (d) the proposed research project. During the award period, Dr. Vatsalya’s goals are to: (1) complete the K23 research and develop preliminary data to conduct a larger bedside-to-bench study using the results and skills obtained during the K23 grant; and (2) apply for an NIAAA investigator-initiated (R01) grant based on the preliminary outcomes. Alcohol consumption is associated with altered microbiome and gut dysfunction, increased gut permeability, systemic endotoxemia (gut-derived bacterial products in the circulation), and proinflammatory activity. The gut dysfunction observed with heavy drinking has also been associated with the development of liver injury and inflammation observed in ALD. The research component of Dr. Vatsalya’s application will investigate if LGG can restore normal gut function, reduce gut permeability and proinflammatory activity, thereby improving the symptomology of concomitant AUD and ALD. The proposed research project extends Dr. Vatsalya’s previous work on the pharmacological treatment of AUD and on the role of LGG in mediating the gut-brain axis that could be expanded to identifying new interventional-mechanistic targets in AUD.

本申请是指导临床研究奖 (K23) 的提案，该奖项将使 Vatsalya 博士能够 Vatsalya 继续发展临床研究技能；特别是确定新的治疗靶点 治疗患有酒精使用障碍（AUD）和伴随中度酒精相关的患者 肝炎 (AH) 是美国和美国可预防死亡的主要原因之一。 正在寻找新的干预措施，新兴的动物和人类研究表明。 鼠李糖乳杆菌 GG (LGG) 是一种益生菌，参与正常肠道微生物组的恢复， Vatsalya 博士的总体目标是减轻肠道功能障碍并降低内毒素血症和炎症。 他还计划成功获得导师研究并过渡到独立研究。 终身教授职位将使他能够完全建立自己的独立研究计划。 Vatsalya 的培训目标是：(1) 拓宽研究领域的概念知识。 (2) 增强AUD领域的人体研究经验 和相关的酒精性肝病（ALD）；（3）提高他的方法技能，以便有效地进行 大规模试验；以及（4）提高他的资助和出版物写作技能。 通过：(a) 路易斯维尔大学提供的资源；(b) 提供的高质量指导； 由他的导师和导师委员会负责；(c) 重点培训和临床经验；以及 (d) 拟议的 在获奖期间，Vatsalya博士的目标是：（1）完成K23研究并 开发初步数据，利用获得的结果和技能进行更大规模的临床研究 在 K23 资助期间；以及 (2) 根据初步申请申请 NIAAA 研究者发起的 (R01) 资助 饮酒与微生物群和肠道功能障碍、肠道菌群增加有关。 渗透性、全身性内毒素血症（循环中肠道衍生的细菌产物）和促炎性 大量饮酒引起的肠道功能障碍也与疾病的发生有关。 Vatsalya 博士的应用程序的研究部分将观察到 ALD 中的肝损伤和炎症。 研究LGG是否可以恢复正常的肠道功能，降低肠道通透性和促炎活性， 改善 AUD 和 ALD 的症状，从而扩展了拟议的研究项目。 Vatsalya 博士之前关于 AUD 的药物治疗以及 LGG 在介导 AUD 中的作用的研究 肠-脑轴可以扩展到确定 AUD 中新的介入机制目标。

项目成果

Association of Hypomagnesemia and Liver Injury, Role of Gut-Barrier Dysfunction and Inflammation: Efficacy of Abstinence, and 2-Week Medical Management in Alcohol Use Disorder Patients.

低镁血症和肝损伤的关联、肠道屏障功能障碍和炎症的作用：戒酒的功效以及酒精使用障碍患者的两周医疗管理。

• 发表时间: 2022-09-26
• 影响因子: 5.6
• 作者: Winrich, Evan J;Gala, Khushboo S;Rajhans, Abhas;Rios;Royer, Amor J;Zamani, Zarlakhta;Parthasarathy, Ranganathan;Marsano;Barve, Ashutosh J;Schwandt, Melanie L;Vatsalya, Vatsalya
• 通讯作者: Vatsalya, Vatsalya

Illustration of Gut-Thyroid Axis in Alcohol Use Disorder: Interplay of Gut Dysfunction, Pro-Inflammatory Responses, and Thyroid Function.

酒精使用障碍中肠道-甲状腺轴的图示：肠道功能障碍、促炎症反应和甲状腺功能的相互作用。

• 发表时间: 2022-10-01
• 影响因子: 6
• 作者: Sagaram, Manasa;Royer, Amor J;Hu, Huirong;Rajhans, Abhas;Parthasarathy, Ranganathan;Krishnasamy, Sathya Sridevi;Mokshagundam, Sri Prakash;Kong, Maiying;Schwandt, Melanie L;Parajuli, Dipendra;Cave, Matthew C;Vatsalya, Vatsalya
• 通讯作者: Vatsalya, Vatsalya

Keratin 18-M65: A biomarker for early-stage alcohol-associated liver disease.

角蛋白 18-M65：早期酒精相关肝病的生物标志物。

• 发表时间: 2023-07
• 作者: McClain, Craig J;Kirpich, Irina;Song, Ming;Vatsalya, Vatsalya
• 通讯作者: Vatsalya, Vatsalya

Elevated stearoyl-CoA desaturase 1 activity is associated with alcohol-associated liver disease.

硬脂酰辅酶 A 去饱和酶 1 活性升高与酒精相关性肝病有关。

• 发表时间: 2022-08
• 作者: Klepp, T D;Sloan, M E;Soundararajan, Soundarya;Ramsden, C E;Cinar, R;Schwandt, M L;Diazgranados, N;Vatsalya, V;Ramchandani, V A
• 通讯作者: Ramchandani, V A

Diagnostic Prospectives with Tau Protein and Imaging Techniques to Detect Development of Chronic Traumatic Encephalopathy.

Tau 蛋白和成像技术检测慢性创伤性脑病发展的诊断前景。

• 发表时间: 2023-04
• 作者: Naskar, Amit;Jayanty, Danielle;Head, Kimberly;Khanna, Gulshan L;Vatsalya, Vatsalya;Banerjee, Arpan
• 通讯作者: Banerjee, Arpan