SPTLC1

双歧杆菌属（Bifidobacterium，也有中文直译为“比菲德氏菌”）是一种重要的肠道有益微生物，在医药和食品方面有着广泛的应用。对于经常便秘或者腹泻的人群来说，对双歧杆菌再熟悉不过。双歧杆菌相关的各类益生菌制剂，自然是各位宝妈宝爸的家中常备药品。以乳双歧杆菌和长双歧杆菌为代表的双歧杆菌在酸奶或者饮料中极为常见。早在1899年，法国巴斯德研究所的儿科医生Henry Tissier从母乳喂养的健康婴儿的粪便中分离出的一种厌氧的革兰氏阳性杆菌，当时命名为Bacillus bifidus。随后，Tissier就发现补充这种分叉状的杆菌能治疗肠道感染方面的疾病。在Tissier发现双歧杆菌以后，人们发现了更多的双歧杆菌属的成员，人们对双歧杆菌的生理功能进行了深入地发掘与研究。那么，除了改善肠道功能，双歧杆菌还有哪些其他的用途呢？双歧杆菌或可预防肝病患者的全身性感染由于代谢综合征和饮酒率的增加，慢性肝病越来越常见。慢性肝病的发展由肝细胞损失、炎症和纤维化引起，上述过程会导致关键肝功能的丧失，增加感染的风险。目前治疗肝衰竭并发症的干预措施，如针对全身感染的抗生素给药，或者针对肝性脑病的乳果糖治疗，都会影响肠道微生物组成和相关代谢物的产生。芝加哥大学Matthew A. Odenwald和Eric G. Pamer团队发现乳果糖和双歧杆菌可以作为合生元，降低严重肝病患者的感染率。相关成果以“Bifidobacteria metabolize lactulose to optimize gut metabolites and prevent systemic infection in patients with liver disease”为题目，2023年11月8日发表于Nature Microbiology杂志上。 DOI: 10.1038/s41564-023-01493-w芝加哥大学研究团队对262名急性或慢性肝病患者的847份粪便样本进行基因组测序和代谢组学分析。他们证实因肝病住院的患者微生物组多样性降低，生物活性代谢产物（包括短链脂肪酸和胆汁酸衍生物）缺乏，影响免疫防御和上皮屏障完整性。课题组发现，口服不可吸收的双糖乳果糖（disaccharide lactulose），可以增加患者肠道的双歧杆菌密度，降低感染率和死亡率。结合小鼠模型，研究团队还发现双歧杆菌可以代谢乳果糖，产生高浓度的乙酸盐，并酸化人类和小鼠的肠腔，这可以抑制耐药菌（如体外耐万古霉素的粪肠球菌）的生长。双歧杆菌或可防止饮食诱导的肥胖大量研究表明，瘦子和胖子的肠道微生物组有着显著的区别，肥胖与肠道微生物组以及许多环境因素的变化有关。作为对身材管理有着较严格要求的韩国，2022年韩国光州科学技术院（Gwangju Institute of Science and Technology, GIST）、韩国延世大学医学院（Yonsei University College of Medicine）和韩国首尔大学（Seoul National University）合作研究，报道了有两种双歧杆菌对控制韩国人口的代谢参数至关重要。相关成果以“Bifdobacterial carbohydrate/nucleoside metabolism enhances oxidative phosphorylation in white adipose tissue to protect against diet-induced obesity”为题目，于2022年11月4日发表在Microbiome杂志上。 DOI: 10.1186/s40168-022-01374-0基于对99名研究参与者（51例体重正常、48例肥胖）的肠道微生物进行分析，研究人员在内脏脂肪组织（VAT）、体重指数（BMI）、血液甘油三酯（TG）和脂肪肝增加的研究参与者中，发现长双歧杆菌（Bifdobacterium longum）和两歧双歧杆菌（Bifdobacterium bifdum）的丰度显著降低。细菌转录组学分析显示，长双歧杆菌和两歧双歧杆菌的碳水化合物/核苷代谢过程与预防饮食诱导的肥胖有关。口服商业化的长双歧杆菌（Bl_MG723）和两歧双歧杆菌（Bb_MG731）可增强胆汁酸信号传导，有助于增强脂肪组织中的氧化磷酸化，从而减少体重增加，改善肝脏脂肪变性和葡萄糖稳态。在无菌小鼠模型中，研究人员还发现长双歧杆菌和两歧双歧杆菌可以操纵肠道的固醇生物合成过程，以防止饮食诱导的肥胖。双歧杆菌或可改善皮肤衰老双歧杆菌在维持皮肤状态中发挥着重要作用，例如，二裂酵母发酵产物溶孢物在美容护肤品中风靡多时，其实则是经双歧杆菌培养、灭活及分解得到代谢产物、细胞质片段、细胞壁组分及多糖复合体。但双歧杆菌是如何作用于肤质的改善，其内部机制还不明确。中国农业大学任发政院士团队从肠道-皮肤轴的角度，进一步探讨了长双歧杆菌（B.longum 68S）在衰老的小鼠中改善皮肤屏障损伤的机制。相关成果以“Bifidobacterium longum 68S mediated gut-skin axis homeostasis improved skin barrier damage in aging mice”为题目，于2023年8月25日发表在Phytomedicine杂志上。 DOI: 10.1016/j.phymed.2023.155051通过对小鼠皮肤的转录组分析以及粪便的16S rRNA测序分析，研究团队发现衰老小鼠表现出皮肤屏障功能障碍和肠道微生态失调。此外，研究人员还发现衰老小鼠的经表皮失水量（trans epidermal water loss, TEWL）上调，而神经酰胺合成关键酶SPT1、神经酰胺和皮肤屏障相关蛋白水平（Loricrin、Keratin 10和Desmoglein 1）下调。将衰老小鼠的粪便移植给正常小鼠或者缺失SPT1的小鼠之后，可以重塑皮肤屏障损伤表型。补充长双歧杆菌68S可改善被移植小鼠的皮肤损伤。最后在细胞水平，研究团队探讨了相关的分子机制。他们发现长双歧杆菌68S可以介导SPT1产生神经酰胺，进而阻止神经酰胺合成受损诱导的内质网应激和凋亡反应，最终改善了体外皮肤屏障损伤。综上所述，这小小的双歧杆菌已经充分融入了我们的生活，是可辅助人体健康的重要益生菌之一。大家伙儿可以根据自身情况及需求，合理寻求双歧杆菌的帮助~参考文献：1. https://doi.org/10.1038/s41564-023-01493-w2. https://doi.org/10.1186/s40168-022-01374-03. https://doi.org/10.1016/j.phymed.2023.155051撰文 | 老汤圆编辑 | lcc部分文字来源于网络，本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！精彩推荐：1、为什么她/他看上去更年轻？研究显示最佳水合作用可能会延缓人类衰老过程2、不睡觉大脑“雪崩”！睡一觉大脑恢复最佳状态！Nature子刊：“需要睡觉”的根本原因找到了！3、不断卷土重来的新冠病毒变异株，注射疫苗还有用吗？最新 Science Immunology 研究给出解答4、维C抗癌新发现！Nature子刊 ：中国科学家揭示大剂量维C促进肿瘤血管正常化，激活免疫系统5、头发重生计划启动！研究发现：皮肤内的这项秘密武器或许能拯救你的发际线！

NEW YORK--( BUSINESS WIRE )-- RTW Charitable Foundation (“RTWCF”) announced today that it has awarded $900,000 in research grants to support six research studies. These studies aim to drive transformational progress in genetic therapies and align with RTWCF’s mission to power community initiatives and scientific research to improve the health of underserved communities. Grant Recipients The following studies and researchers each received $150,000 research grants from RTWCF: “ Establishing gene replacement therapy for NEDAMSS, an ultra-rare neurological disorder caused by mutations in the IRF2BPL gene” (Kathrin Meyer, Nationwide Children’s Hospital, Columbus, OH). “ Optimizing AAV-SPL gene therapy for sphingosine phosphate lyase insufficiency syndrome” (Julie Saba, University of California, San Francisco, San Francisco, CA). “Gene therapy for SURF1-related Leigh Syndrome” (Steven Gray, The University of Texas Southwestern, Dallas, TX). “ Safety and toxicity assessment of AAV-based gene therapy for creatine transporter deficiency” (Jagdeep Walia, Queen’s University, Kingston, Ontario, Canada). “Advanced therapeutics for SELENON-related myopathy” (Alan Beggs, Boston Children’s Hospital, Boston, MA). “ Preclinical studies of ASO therapy for SPTLC1-related hereditary sensory neuropathy” (Haiyan Zhou, University College London, London, UK). “ Despite considerable advancements in gene and cell therapies that deliver more targeted and effective treatments for rare diseases, a significant amount of additional research is still required to move these advances out of the lab and safely to patients,” said Juan Carlos López, PhD, Managing Director, Research Grants, RTW Charitable Foundation. “ RTW Charitable Foundation is proud to provide financial and scientific support to these six incredible researchers and their respective studies. We believe that each of these studies will help expedite the development of gene therapies for rare and ultrarare diseases, and greatly improve the lives of individuals with unmet medical needs.” Grant Recipient Commentary Julie Saba, MD, PhD, commented : “ I am honored and grateful to receive this award from RTWCF, which will support studies to optimize gene therapy for sphingosine phosphate lyase insufficiency syndrome. This newly recognized inborn error of metabolism leads to kidney failure in most of the affected children, causing more than half of them to die in their first years of life. While kidney transplantation can be lifesaving, it is invasive, costly, unavailable to many, and does not address the many other serious consequences of the disorder. Gene therapy offers a potentially lifesaving alternative treatment. The studies undertaken with RTWCF funding should improve our gene therapy potency, allowing us to advance to toxicology studies and clinical trials. I appreciate RTWCF’s dedication to advancing research in ultrarare diseases, which are overwhelmingly underfunded. Every child deserves personalized therapy!” Alan Beggs, PhD, commented: “ Our group has studied a neuromuscular condition called Multiminicore Disease or Rigid Spine Muscular Dystrophy for many years to understand how mutations of a gene called SELENON lead to weakness. We are now on the cusp of translating our laboratory experiments into a treatment that can be tested in patients. I’m thrilled that support from the RTWCF is helping us to work towards developing a next-generation gene therapy candidate designed for eventual testing in a clinical trial.” Haiyan Zhou, MD, PhD, commented: “ We are extremely grateful for the generous award from RTWCF. This grant serves as a vital catalyst in advancing our groundbreaking work on a novel nucleic acid therapy designed for an ultrarare neurodegenerative condition, currently devoid of effective treatment options. The crucial support from RTWCF will propel the preclinical development and hasten the clinical translation of this experimental therapy. Moreover, this award will play a pivotal role in elevating the impact of our translational genetic therapy program at the Great Ormond Street Institute of Child Health and NIHR GOSH Biomedical Research Centre. It also contributes to the growth of the UK platform for nucleic acid therapy in rare diseases.” To date, RTWCF has awarded over 20 research grants, totaling over $3 million in funding. In addition to delivering financial resources, RTWCF also provides grant recipients with hands-on scientific support, helping them improve or further develop their research and research tools and identify new therapeutic targets. About RTW Charitable Foundation Founded in 2018 as the charitable foundation arm of RTW Investments, LP, RTW Charitable Foundation works to power community initiatives and scientific research to improve the health of underserved communities. The Foundation is able to provide capital, manpower, and logistical support to help scientists push such projects forward. In addition, the Foundation aims to assist in advocacy, disease awareness and directly support organizations and communities in New York City. To learn more, visit www.rtwcf.org .

该研究构建了新型蛋白，并以此作为鼻腔内病毒陷阱，旨在高效捕获及中和多种新冠病毒变体，以限制病毒感染与传播。团队将此种新型蛋白制成鼻腔喷雾，並以叙利亚仓鼠非接触性病毒传播模型证明了其能有效减少仓鼠呼吸道 世界各地处于后疫情时期，公共场所中很多人都不再配戴口罩。但新冠病毒仍继续传播，对易感人群，如儿童、老年人和免疫力低下的群众构成一定的健康风险。 近日，香港大学医学院生物医学学院黄建东教授、中国科学院深圳先进技术研究院张宝中副研究员及香港大学医学院微生物系研究助理教授赵旵军博士等在 Advanced Functional Materials 期刊发表了题为：Engineered Intranasal Virus Trap Provides Effective Protection Against SARS-CoV-2 Infection in Hamsters的研究论文。 该研究构建了新型蛋白，并以此作为鼻腔内病毒陷阱，旨在高效捕获及中和多种新冠病毒变体，以限制病毒感染与传播。团队将此种新型蛋白制成鼻腔喷雾，並以叙利亚仓鼠非接触性病毒传播模型证明了其能有效减少仓鼠呼吸道病毒复制和细胞损伤，降低并控制新冠病毒感染与传播。该研究亦验证了鼻腔可作为病毒防控的有效靶点。 新型蛋白Fn-LCB1包含两个组成部分：其Fn域能与纤连蛋白（fibronectin）结合，而LCB1区域则与新冠病毒刺突蛋白受体结合域（RBD）有极高亲和力。该研究的设计理念在於將能够中和新冠病毒的蛋白喷入鼻腔，以形成一个防护膜。当病毒被吸入鼻腔后，因LCB1比 ACE2 受体具有更高的病毒亲和力，病毒会在感染细胞前被新型蛋白抓住，从而失去活性。减少细胞感染则能减少病毒复制，一来减低感染者呼吸道细胞损伤，二来减少病毒脱落与传播。 基于Fn -LCB1抗新冠病毒的EIVT设计图 首先，为确认病毒的捕捉效率，研究团队用Fn-LCB1在体外证明能以飞摩尔至皮摩尔的浓度中和多种新冠假病毒的变体，并能以极低浓度中和新冠真病毒。Fn-LCB1也具有极高稳定性，在长时间存放于室温亦可维持其蛋白结构并中和病毒。 Fn-LCB1于体外对不同变体的新冠真/假病毒的中和能力 最后，该研究将新型蛋白Fn-LCB1滴至叙利亚仓鼠鼻腔中，並进行了非接触式病毒传染模型。实验结果显示显示，此新型蛋白可以保护与感染鼠密切接触的仓鼠。吸入的病毒可被此新型蛋白捕获，并停留在细胞外基质，从而失去活性。此新型蛋白滴鼻组的仓鼠鼻腔与肺部都存有较少的活病毒以及病毒RNA。其鼻腔上皮细胞以及肺组织亦受到较少伤害，也有较少的炎症反应。因此证明该新型蛋白可以在呼吸道形成一个有效的保护膜，可以在病毒感染宿主之前于上呼吸道捕获病毒，令其失去活性，减少病毒复制、脱落与传染，以控制病毒在人群中的传播。 EIVT能有效阻断新冠病毒非接触的传播。 香港大学医学院生物医学学院黄建东教授，中国科学院深圳先进技术研究院张宝中副研究员及港大医学院微生物系研究助理教授赵旵军博士为该文章的通讯作者。香港大学李嘉诚医学院生物医学学院博士生欧阳依汶， 微生物系研究助理张楚媛为论文共同第一作者。