Chenodiol

- First quarter 2025 total revenue of $111.6 million; 2025 guidance increased to $435 to $450 million - VISTAS study in PSC expected to complete enrollment in third quarter of 2025; topline data expected in second quarter of 2026 - LIVMARLI oral tablet formulation FDA approved - Conference call to provide business updates today, May 7 at 1:30 p.m. PT/4:30 p.m. ET FOSTER CITY, Calif.--(BUSINESS WIRE)-- Mirum Pharmaceuticals, Inc. (Nasdaq: MIRM) today reported financial results for the first quarter 2025 and provided a business update. “It’s been a strong start to the year with commercial growth and multiple milestones achieved across our pipeline,” said Chris Peetz, chief executive officer of Mirum. “We’re pleased with the FDA’s approval of LIMARLI’s tablet formulation, which provides more options for the ALGS and PFIC community in the U.S. in the form of a convenient single tablet dose. Our VISTAS study of volixibat in PSC is enrolling well and we expect to complete enrollment in the third quarter of this year. We’re excited to continue our strong execution across our commercial medicines and pipeline throughout the year.” Commercial: Raising full year revenue guidance to $435 to $450 million First quarter 2025 global net product sales of $111.6 million. First quarter 2025 LIVMARLI net product sales were $73.2 million representing 71% growth over first quarter 2024 net product sales. Bile Acid Medicines net product sales were $38.4 million representing 47% growth over first quarter 2024 net product sales. LIVMARLI oral tablet formulation approved. LIVMARLI approved in Japan for ALGS and PFIC. CTEXLI (chenodiol) approved in the US for cerebrotendinous xanthomatosis. Regulatory and Pipeline: Clinical milestones on track Volixibat VISTAS study in primary sclerosing cholangitis (PSC) expected to complete enrollment in third quarter of 2025; topline data expected in the second quarter of 2026. Oral presentation of 28-week interim data from volixibat in PBC (VANTAGE study) at EASL on Friday May 9th at 9:30am CEST. Volixibat VANTAGE study in primary biliary cholangitis (PBC) expected to complete enrollment in 2026. LIVMARLI EXPAND Phase 3 study for pruritus in rare cholestatic conditions expected to complete enrollment in 2026. Expect to initiate Phase 2 study for MRM-3379 in Fragile X Syndrome (FXS) in 2025. Corporate and Financial: Strong balance sheet and financial independence Total revenue for the quarter ended March 31, 2025, was $111.6 million compared to $69.2 million for the quarter ended March 31, 2024. Total operating expenses were $126.8 million for the quarter ended March 31, 2025 compared to $95.7 million for the quarter ended March 31, 2024. Total operating expenses for the quarter ended March 31, 2025 included $21.9 million of non-cash stock-based compensation, intangible amortization, and other non-cash expenses compared to $17.1 million for the quarter ended March 31, 2024. As of March 31, 2025, Mirum had unrestricted cash, cash equivalents and investments of $298.6 million compared to $292.8 million as of December 31, 2024. Business Update Conference Call Mirum will host a conference call today, May 7th at 1:30 p.m. PT/4:30 p.m. ET, to provide business updates. Join the call using the following details: Conference Call Details: U.S./Toll-Free: +1 833 470 1428 International: +1 404 975 4839 Passcode: 549600 You may also access the call via webcast by visiting the Events & Presentations section on Mirum’s website. A replay of this webcast will be available for 30 days. About LIVMARLI® (maralixibat) oral solution and LIVMARLI® (maralixibat) tablets LIVMARLI® (maralixibat) oral solution is an orally administered, ileal bile acid transporter (IBAT) inhibitor approved by the U.S. Food and Drug Administration for two pediatric cholestatic liver diseases. It is approved for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) in the U.S. three months of age and older and in Europe for patients two months of age and older. It is also approved in the U.S. for the treatment of cholestatic pruritus in patients with progressive familial intrahepatic cholestasis (PFIC) 12 months of age and older and in Europe for the treatment of PFIC in patients three months of age and older. For more information for U.S. residents, please visit LIVMARLI.com. LIVMARLI has received orphan designation for ALGS and PFIC. LIVMARLI is currently being evaluated in the Phase 3 EXPAND study in additional settings of cholestatic pruritus. To learn more about ongoing clinical trials with LIVMARLI, please visit Mirum’s clinical trials section on the company’s website. IMPORTANT SAFETY INFORMATION Limitation of Use: LIVMARLI is not for use in PFIC type 2 patients who have a severe defect in the bile salt export pump (BSEP) protein. LIVMARLI can cause side effects, including Liver injury. Changes in certain liver tests are common in patients with ALGS and PFIC but can worsen during treatment. These changes may be a sign of liver injury. In PFIC, this can be serious or may lead to liver transplant or death. Your healthcare provider should do blood tests and physical exams before starting and during treatment to check your liver function. Tell your healthcare provider right away if you get any signs or symptoms of liver problems, including nausea or vomiting, skin or the white part of the eye turns yellow, dark or brown urine, pain on the right side of the stomach (abdomen), bloating in your stomach area, loss of appetite or bleeding or bruising more easily than normal. Stomach and intestinal (gastrointestinal) problems. LIVMARLI can cause stomach and intestinal problems, including diarrhea and stomach pain. Your healthcare provider may advise you to monitor for new or worsening stomach problems including stomach pain, diarrhea, blood in your stool or vomiting. Tell your healthcare provider right away if you have any of these symptoms more often or more severely than normal for you. A condition called Fat Soluble Vitamin (FSV) Deficiency caused by low levels of certain vitamins (vitamin A, D, E, and K) stored in body fat is common in patients with Alagille syndrome and PFIC but may worsen during treatment. Your healthcare provider should do blood tests before starting and during treatment and may monitor for bone fractures and bleeding which have been reported as common side effects. US Prescribing Information EU SmPC Canadian Product Monograph About Volixibat Volixibat is an oral, minimally absorbed agent designed to selectively inhibit the ileal bile acid transporter (IBAT). Volixibat may offer a novel approach in the treatment of adult cholestatic diseases by blocking the recycling of bile acids, through inhibition of IBAT, thereby reducing bile acids systemically and in the liver. Volixibat is currently being evaluated in Phase 2b studies for primary sclerosing cholangitis (PSC) (VISTAS study), and primary biliary cholangitis (PBC) (VANTAGE study). In June, Mirum announced positive interim results from the Phase 2b VANTAGE study showing statistically significant improvement in pruritus as well as meaningful reductions in serum bile acids and improvements in fatigue for patients treated with volixibat. No new safety signals were observed, and the most common adverse event was diarrhea with all cases mild to moderate. Volixibat has been granted breakthrough therapy designation for the treatment of PBC. About CHOLBAM® (cholic acid) capsules The FDA approved CHOLBAM (cholic acid) capsules in March 2015, the first FDA-approved treatment for pediatric and adult patients with bile acid synthesis disorders due to single enzyme defects, and for adjunctive treatment of patients with peroxisome biogenesis disorder-Zellweger spectrum disorder. The effectiveness of CHOLBAM has been demonstrated in clinical trials for bile acid synthesis disorders and the adjunctive treatment of peroxisomal disorders. An estimated 200 to 300 patients are current candidates for therapy. CHOLBAM® (cholic acid) Indication CHOLBAM is a bile acid indicated for Treatment of bile acid synthesis disorders due to single enzyme defects. Adjunctive treatment of peroxisomal disorders, including Zellweger spectrum disorders, in patients who exhibit manifestations of liver disease, steatorrhea, or complications from decreased fat-soluble vitamin absorption. LIMITATIONS OF USE The safety and effectiveness of CHOLBAM on extrahepatic manifestations of bile acid synthesis disorders due to single enzyme defects or peroxisomal disorders, including Zellweger spectrum disorders, have not been established. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS – Exacerbation of liver impairment Monitor liver function and discontinue CHOLBAM in patients who develop worsening of liver function while on treatment. Concurrent elevations of serum gamma glutamyltransferase (GGT) and alanine aminotransferase (ALT) may indicate CHOLBAM overdose. Discontinue treatment with CHOLBAM at any time if there are clinical or laboratory indicators of worsening liver function or cholestasis. ADVERSE REACTIONS The most common adverse reactions (≥1%) are diarrhea, reflux esophagitis, malaise, jaundice, skin lesion, nausea, abdominal pain, intestinal polyp, urinary tract infection, and peripheral neuropathy. Please see full Prescribing Information for additional Important Safety Information. About CTEXLI™ (chenodiol) tablets CTEXLI™ (chenodiol) tablets is FDA-approved for the treatment of adults with cerebrotendinous xanthomatosis (CTX). Chenodiol is another name for chenodeoxycholic acid (CDCA). CDCA is a naturally occurring bile acid that was originally approved for the treatment of people with radiolucent stones in the gallbladder. CTEXLI was evaluated as part of the Phase 3 RESTORE study, the first and only clinical trial for CTX. CTX is a rare progressive disease that can affect the brain, spinal cord, tendons, eyes and arteries. IMPORTANT SAFETY INFORMATION CTEXLI can cause side effects, including: Liver Injury: You will need to undergo laboratory testing before starting and while taking CTEXLI to check your liver function. Changes in certain liver tests may occur during treatment and may be a sign of liver injury. This can be serious. Stop taking CTEXLI immediately and tell your healthcare provider right away if you get any signs or symptoms of liver problems, including, stomach (abdomen) pain, bruising, dark-colored urine, feeling tired (fatigue), bleeding, yellowing of the skin and eyes, nausea, and itching. Most Common Side Effects: Diarrhea, headache, stomach pain, constipation, high blood pressure, muscular weakness, and upper respiratory tract infection. Tell your healthcare provider about all the medications that you take, as CTEXLI may interact with other medicines. US Prescribing Information About Mirum Pharmaceuticals Mirum Pharmaceuticals, Inc. is a biopharmaceutical company dedicated to transforming the treatment of rare diseases affecting children and adults. Mirum has three approved medications: LIVMARLI® (maralixibat) oral solution and LIVMARLI® (maralixibat) tablets, CHOLBAM® (cholic acid) capsules, and CTEXLI™ (chenodiol) tablets. LIVMARLI, an IBAT inhibitor, is approved for the treatment of two rare liver diseases affecting children and adults. It is approved for the treatment of cholestatic pruritus in patients with Alagille syndrome in the U.S. (three months and older), in Europe (two months and older), and in other regions globally. It is also approved in the U.S. in cholestatic pruritus in PFIC patients 12 months of age and older; in Europe, it is approved for patients with PFIC three months of age and older. Mirum has initiated the Phase 3 EXPAND study, a label expansion opportunity for LIVMARLI in additional settings of cholestatic pruritus. CHOLBAM is FDA-approved for the treatment of bile acid synthesis disorders due to single enzyme deficiencies and adjunctive treatment of peroxisomal disorders in patients who show signs or symptoms of liver disease. CTEXLI is FDA-approved for the treatment of cerebrotendinous xanthomatosis (CTX) in adults. Mirum's late-stage pipeline includes two investigational treatments for several rare diseases. Volixibat, an IBAT inhibitor, is being evaluated in two potentially registrational studies including the Phase 2 VISTAS study for primary sclerosing cholangitis (PSC) and Phase 2b VANTAGE study for primary biliary cholangitis. Volixibat has been granted Breakthrough Therapy Designation for the treatment of cholestatic pruritus in patients with PBC. Mirum is also planning for a Phase 2 study evaluating MRM-3379, a PDE4D inhibitor for the treatment of Fragile X syndrome, a rare genetic neurocognitive disorder. To learn more about Mirum, visit mirumpharma.com and follow Mirum on Facebook, LinkedIn, Instagram and Twitter (X). Forward-Looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include statements regarding, among other things, significant increase or continued commercial results for our approved medicines, including continued financial growth, the potential achievement of our yearly financial guidance, continued strong execution across our approved medicines and pipeline, the results, enrollment, conduct and progress of our ongoing and planned studies for our product candidates, the timing and results of interim analyses of our ongoing studies and the regulatory approval path for our product candidates in any indication or any specific territory. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as “expected,” “will,” “could,” “would,” “guidance,” “potential,” “continue” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Mirum’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks and uncertainties associated with Mirum’s business in general, the impact of geopolitical and macroeconomic events, and the other risks described in Mirum’s Annual Report for the year ended December 31, 2024, filed with the Securities and Exchange Commission on February 26, 2025, and subsequent filings with the Securities and Exchange Commission, which are available at www.sec.gov. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on management’s assumptions and estimates as of such date. Mirum undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law. Mirum Pharmaceuticals, Inc. Condensed Consolidated Statement of Operations Data (in thousands, except share and per share amounts) (Unaudited) Three Months Ended March 31, 2025 2024 Revenue: Product sales, net $ 111,585 $ 68,917 License and other revenue — 305 Total revenue 111,585 69,222 Operating expenses: Cost of sales (1) 23,018 17,830 Research and development 46,044 32,222 Selling, general and administrative 57,706 45,638 Total operating expenses (2) 126,768 95,690 Loss from operations (15,183 ) (26,468 ) Other income (expense): Interest income 3,023 3,633 Interest expense (3,596 ) (3,577 ) Other income, net 2,108 1,757 Net loss before provision for income taxes (13,648 ) (24,655 ) Provision for income taxes 1,029 624 Net loss (14,677 ) (25,279 ) Net loss per share, basic and diluted $ (0.30 ) $ (0.54 ) Weighted-average shares of common stock outstanding, basic and diluted 48,889,058 46,927,550 (1) Amounts include intangible amortization expense as follows: Intangible amortization $ 5,893 $ 5,402 (2) Amounts include stock-based compensation expense as follows: Cost of sales $ 331 $ — Research and development 5,229 3,861 Selling, general and administrative 10,243 7,589 Total stock-based compensation $ 15,803 $ 11,450 Mirum Pharmaceuticals, Inc. Condensed Consolidated Balance Sheet Data (in thousands) (Unaudited) March 31, December 31, 2025 2024 Assets Current assets: Cash and cash equivalents $ 211,822 $ 222,503 Short-term investments 65,852 57,812 Accounts receivable 95,852 78,286 Inventory 22,418 22,403 Prepaid expenses and other current assets 14,874 11,784 Total current assets 410,818 392,788 Restricted cash 425 425 Long-term investments 20,912 12,526 Intangible assets, net 243,845 249,819 Other noncurrent assets 14,245 15,196 Total assets $ 690,245 $ 670,754 Liabilities and Stockholders’ Equity Current liabilities: Accounts payable $ 11,639 $ 14,618 Accrued expenses and other current liabilities 115,938 111,933 Total current liabilities 127,577 126,551 Operating lease liabilities, noncurrent 7,003 7,972 Convertible notes payable, net, noncurrent 308,509 308,082 Other liabilities 13,900 2,509 Total liabilities 456,989 445,114 Commitments and contingencies Stockholders’ equity: Preferred stock — — Common stock 5 5 Additional paid-in capital 892,367 870,189 Accumulated deficit (658,858 ) (644,181 ) Accumulated other comprehensive loss (258 ) (373 ) Total stockholders’ equity 233,256 225,640 Total liabilities and stockholders’ equity $ 690,245 $ 670,754 Investor Contact: Andrew McKibben ir@mirumpharma.com Media Contact: Erin Murphy media@mirumpharma.com

引言在体内深处，数以万亿计的微生物正在忙碌地生活。它们组成了肠道菌群，一个复杂而充满活力的“第二基因组”，对消化、免疫甚至情绪都起着至关重要的作用。长期以来，研究人员一直在探索这个微观世界与人类健康之间的联系，我们知道不同种类的细菌与各种健康状况有关。但即使是同一种类的细菌，它们内部也存在巨大的差异，就像我们人类一样，虽然同属智人物种，但每个个体都是独特的。这些更精微的、菌株水平（strain-level）的差异，是否也隐藏着与健康和我们生活环境相关的秘密？它们如何分布在全球各地？又如何影响着不同人群的健康？4月30日一项发表在《Cell》上的重磅研究“Global genetic structure of human gut microbiome species is related to geographic location and host health”，以前所未有的规模和深度，回答了这些问题。这项研究汇集了来自全球 42个国家 的 32,152份 人类肠道样本，构建了数百种肠道细菌的菌株系统发育树（strain phylogenies）。研究发现，肠道里特定菌株的组成，竟然与居住的地理位置紧密相连，仿佛肠道居民也有自己的“护照”。更令人兴奋的是，这些看似细微的菌株差异，被发现与一系列重要的人类表型和疾病存在显著关联，从婴儿的生长发育，到老年人的健康衰老，甚至是像黑色素瘤和前列腺癌这样的严重疾病。 菌株分支在特定人群或疾病状态下表现出惊人的富集。这项研究不仅仅是增加了我们对肠道菌群的认识，它正在颠覆我们过去仅停留在物种层面的理解，揭示了菌株多样性如何作为连接地理、传播和人类健康的桥梁。肠道菌群“有护照”？菌株分布与地理位置紧密相关这项研究首先确认了一个重要发现：我们肠道里同一种细菌的不同菌株，它们的地理分布并非随意，而是与宿主的地理位置高度相关。通过将样本的地理距离与对应菌株的系统发育距离进行比较，研究发现，在分析的583个物种中，有456个表现出显著的地理差异（Mantel检验，FDR < 0.05）。这意味着，来自不同国家的人，他们肠道里同一种细菌的菌株往往在遗传上差异更大。有些物种的地理分层尤其明显，比如Eubacterium ventriosum，其系统发育树与地理位置的相关性高达0.57（分析了2582个样本）。又比如Lachnospiraceae家族的一个未知物种，相关性为0.46（分析了6553个样本），而Ruminococcus torques的相关性为0.38（分析了7063个样本）。相比之下，像Alistipes onderdonkii这样的物种，其菌株地理分层就非常弱，相关性仅为0.02（分析了12042个样本）。进一步分析发现，Lachnospiraceae家族的物种整体上表现出更高的地理分层效应（基因集富集分析，NES=1.44，FDR=0.01）。这提示我们，某些特定的微生物类群可能与宿主共享了更强的进化历史，或者受到了地理环境的更深刻影响。“社交达人” vs. “宅家菌”：传播能力塑造地理格局那么，为什么有些菌株全球分布广泛，有些却高度局限在特定地区呢？研究人员提出了一个有趣的假说：这可能与菌株的水平传播（horizontal transmission）能力有关。那些更容易在人与人之间传播的菌株，可能更容易跨越地理障碍，从而降低其地理分层。为了验证这一点，研究团队估计了这583个物种在同一国家但不同研究人群中的菌株共享率（作为传播性的代理指标）。结果发现，物种的传播性与地理分层效应呈负相关（Pearson相关系数为-0.21，p值为3×10^-7）。也就是说，传播性越强的物种，其菌株地理差异越小。这个发现非常直观：那些喜欢“出门旅行”的菌株，自然不会只待在同一个地方，而那些“宅家”的菌株，则更容易在特定地理区域内形成独特的遗传群体。这种传播能力与地理分层的反向关系，为理解肠道微生物的生物地理学（biogeography）提供了新的视角。菌株记录我们的生命轨迹，特别是年龄除了地理位置，肠道菌株的差异还与广泛的人类表型相关。在本次分析的256个表型中，年龄是与菌株系统发育差异关联最普遍的因素，共关联了253个物种的系统发育。其次是身体质量指数（BMI），关联了12个物种；性别关联了6个物种。一个最重要的年龄相关发现是关于长双歧杆菌（Bifidobacterium longum）。研究发现，在欧洲和非洲样本中，长双歧杆菌的系统发育树都呈现出明显的婴儿特异性菌株（infant-specific clades）。系统发育分析显示，婴儿（定义为小于2岁）和成人之间存在清晰的菌株分离。研究进一步揭示，婴儿特异性菌株中包含两个主要分支：一个主要富集了B. longum subsp. infantis的参考基因组，在欧洲和非洲婴儿中都有出现；另一个较小的分支富集了B. longum subsp. suis的参考基因组，在非洲样本中显著富集（泛化线性模型GLM在非洲样本中的log-odds值为-3.32，p值为8.13×10^-5），这与先前在孟加拉国婴儿中观察到的结果一致。通过平均核苷酸同一性（average nucleotide identity, ANI）分析和碳水化合物活性酶（carbohydrate-active enzymes, CAZymes）预测，研究证实了不同分支在代谢能力上的差异，例如婴儿特异性菌株富集了分解母乳中复杂糖类所需的酶，这与它们在婴儿期独特的饮食结构相适应。这些结果有力地支持了不同生命阶段对应独特的菌株组成。探索“长寿菌株”：瘤胃球菌与衰老及胆汁酸随着年龄的增长，肠道菌群也会发生变化。研究发现，在亚洲样本中，有5个物种的系统发育树中存在富集在百岁老人（>90岁）中的菌株分支，其中就包括瘤胃球菌（Ruminococcus gnavus）。特别是在一项专注于中国百岁老人的研究（XuQ_2021）中，瘤胃球菌的一个分支在百岁老人中显示出很强的富集信号（elpd_diff值为-65.5），该研究中148位非百岁老人中有47位是百岁老人。即使仅使用XuQ_2021研究的数据，该关联也得到了证实（elpd_diff值为-20.1，96个样本中有47个非百岁老人是百岁老人）。在包含所有亚洲研究的样本中，这种富集在老年个体中的菌株分支在系统发育上与年龄显著相关（泛化线性混合模型GLMER PAsian_tree值为1.75×10^-11）。更令人振奋的是，这种关联在欧洲样本中也得到了复制（elpd_diff值为-34.99）。在包含所有欧洲样本的系统发育树中，富集在老年个体中的菌株分支的平均年龄显著更高（GLMER，log-odds age = 0.03，p值为1.88×10^-9）。这表明，瘤胃球菌的特定菌株倾向于更常见于老年个体，且这种趋势独立于地理位置。瘤胃球菌此前已被发现与炎症和胆汁酸代谢有关。研究利用荷兰队列（ZhernakovaA_2016 和 KurilshikovA_2019）中有限的胆汁酸数据（共69个样本，其中13个在该老年富集分支中），发现在该分支中初级胆汁酸（primary bile acids）的丰度更高，包括胆酸（cholic acid, CA，FDR=1.39×10^-4）和鹅去氧胆酸（chenodeoxycholic acid, CDCA，FDR=2.33×10^-4）。对瘤胃球菌宏基因组组装基因组（metagenome-assembled genomes, MAGs）的功能分析进一步揭示，该老年富集分支中的菌株显著耗尽了产生7β-羟基类固醇脱氢酶（7βHSDH，FDR=3×10^-8）的基因，而富集了产生3α-羟基类固醇脱氢酶（3αHSDH，FDR=0.02）、BaiA（FDR=0.02）和胆盐水解酶（BSH，FDR=3×10^-8）的基因。这些发现提示，该瘤胃球菌菌株可能在老年人的胆汁酸代谢中扮演着重要角色。解锁肠道与癌症的“菌株密码”：柯林斯氏菌这项研究还深入探索了菌株水平系统发育与疾病的关联。在分析的37个与疾病相关的物种中，柯林斯氏菌（Collinsella aerofaciens）引起了关注。在欧洲样本中，柯林斯氏菌的系统发育与四种不同的健康状况相关：黑色素瘤（melanoma）、炎症性肠病（IBD）、高血压（hypertension）和哮喘（asthma）。其中最强的关联是黑色素瘤。在欧洲（elpd_diff值为-141）和北美（elpd_diff值为-49.9）的样本中，黑色素瘤患者的肠道菌群显著富集了柯林斯氏菌的一个特定分支。这个分支横跨不同的研究和国家，在系统发育树中，该分支的样本中有123个来自黑色素瘤患者（占该分支总样本的181个），而总共有170个黑色素瘤患者的样本出现在系统发育树中，富集在该分支的风险比高达131.843（p值小于2×10^-16）。值得注意的是，该分支的存在与先前的治疗或治疗效果（RECIST分类）无关。更令人惊讶的是，前列腺癌（prostate cancer）患者的样本也显著富集在该柯林斯氏菌分支中。在一个专注于前列腺癌的研究（PernigoniN_2021）中，该分支包含了14位前列腺癌患者中的12位（Fisher精确检验富集p值为4.97×10^-14）。这些结果表明，柯林斯氏菌的一个特定菌株分支在两种不同类型的癌症患者（黑色素瘤和前列腺癌）中更为普遍。虽然这项研究是关联性的，不能确定因果关系，但它提供了一个重要的线索，提示该菌株可能在癌症的发生或发展中扮演某种角色。癌症相关菌株的“秘密武器”：功能基因分析为了理解这个癌症相关柯林斯氏菌分支为何特殊，研究人员对其基因组进行了功能分析。通过构建高质量的宏基因组组装基因组（MAGs），并比较癌症相关分支与系统发育树其余部分的基因内容，发现该分支中显著富集了218个基因，比其他菌株更常见。进一步的通路富集分析揭示，该分支中叶酸（维生素B12）的生物合成通路显著过代表（5个通路富集）。维生素B12此前被一些研究关联到癌症风险，但这种关联尚不一致。这些功能基因的差异提示，这个特殊的柯林斯氏菌分支可能具有不同于其他菌株的代谢能力，例如影响维生素B12的利用或合成。未来的研究需要深入探究这些功能差异如何影响宿主环境，以及它们是否直接参与了癌症的发生或进展。未来：绘制更精细的微生物健康地图这项大规模研究首次在全球菌株水平上揭示了人类肠道菌群的遗传结构与地理位置、传播和宿主健康之间的复杂关系。它强调了只关注物种水平是不够的，菌株水平的差异对于理解微生物与健康的相互作用至关重要。研究发现，许多微生物与表型的关联是由小的菌株分支驱动的，而不是整个物种或大的亚种群体。这提示我们需要更大的样本量和更高的分辨率来识别这些隐藏在物种内部的、与健康相关的菌株分支。虽然研究具有关联性和观察性的局限性，无法直接推断因果，但它为未来的机制研究指明了方向。例如，可以进一步研究柯林斯氏菌的癌症相关菌株如何与宿主相互作用，以及它们是否影响免疫系统或维生素B12代谢，从而促进癌症发展。类似地，对瘤胃球菌老年富集菌株胆汁酸代谢功能的深入研究，可能揭示衰老相关疾病的新机制。未来的研究需要更多样本量更大的、包含多种族群的、深度表型的队列，特别关注那些难以通过现有方法检测到的、丰度较低但可能具有重要功能的菌株。通过绘制更精细的微生物健康地图，我们将更有可能开发出基于肠道菌群的精准诊断和干预手段，最终改善人类健康。所以，下一次想到你的肠道菌群时，不妨思考一下：你的肚子里住着的，是带着“全球旅行签证”的菌株，还是深深扎根于本土的“本地菌”？而这些微小的差异，或许正悄悄影响着你的健康轨迹。参考文献Andreu-Sánchez S, Blanco-Míguez A, Wang D, Golzato D, Manghi P, Heidrich V, Fackelmann G, Zhernakova DV, Kurilshikov A, Valles-Colomer M, Weersma RK, Zhernakova A, Fu J, Segata N. Global genetic structure of human gut microbiome species is related to geographic location and host health. Cell. 2025 Apr 29:S0092-8674(25)00416-7. doi: 10.1016/j.cell.2025.04.014. Epub ahead of print. PMID: 40311618.声明：本文仅用于分享，不代表平台立场，如涉及版权等问题，请尽快联系我们，我们第一时间更正，谢谢！往期热文：Cell | 颠覆认知！不是被动扩散，CD36介导内吞才是许多“大块头”药物入胞的秘密通道Nature Methods | mScarlet3-H：红色荧光蛋白的新一代王者！Nature Methods | 告别“平面时代”！光学显微镜如何带你看清3D细胞世界的秘密？Nature | 帕金森病新曙光！iPS细胞人体试验结果揭晓，安全有效性初显！Cell | 实时见证“基因之吻”：Oligo-LiveFISH高精度追踪增强子-启动子动态互作Nature Biotechnology | 重磅综述：不止CAR-T！唤醒免疫“特种部队”，工程化先天细胞开启抗癌新纪元