Chenodiol

FOSTER CITY, Calif.--(BUSINESS WIRE)--Mirum Pharmaceuticals, Inc. (Nasdaq: MIRM), a leading rare disease company, today provided its preliminary and unaudited estimates for full-year 2025 net product sales, year-end cash balance, corporate updates and full-year 2026 outlook. “2025 was an excellent year for Mirum, reflecting the strength and scalability of our purpose-built rare disease operating model,” said Chris Peetz, Chief Executive Officer of Mirum. “We delivered strong global commercial growth, advanced multiple late-stage clinical programs and are expanding our pipeline with the proposed acquisition of Bluejay Therapeutics and brelovitug for HDV. With a strong financial foundation, deep commitment to patients and multiple upcoming clinical catalysts, we enter 2026 well positioned to drive continued execution and value creation.” 2026 Expectations and Milestones: Commercial growth and pipeline advancement 2026 guidance: expect global net product sales of approximately $630 million to $650 million Volixibat VISTAS study in PSC topline data expected in Q2 2026 Accelerated study timing for LIVMARLI EXPAND Phase 3 study for pruritus in rare cholestatic conditions; now expected to complete enrollment H1 2026, topline data expected in Q4 2026 Volixibat VANTAGE study in primary biliary cholangitis (PBC) expected to complete enrollment in H2 2026 Acquisition of Bluejay Therapeutics and brelovitug for chronic hepatitis delta (HDV) expected to close in mid-to-late January 2026 Bluejay Therapeutics’ AZURE-1 study in HDV interim data expected in Q2 2026 and topline Phase 3 data expected in H2 2026 assuming closing of proposed acquisition 2025 Highlights Commercial: Accelerating global rare disease impact 2025 estimated LIVMARLI net product sales of approximately $359 million, including approximately $243 million in US net product sales, representing 69% year-over-year growth from 2024 2025 estimated CHOLBAM ® and CTEXLI ® net product sales of approximately $161 million representing 31% year-over-year growth from 2024 Q4 2025 total estimated net product sales of approximately $149 million including approximately $106 million in LIVMARLI net sales and approximately $43 million in CHOLBAM and CTEXLI net sales Expanded global footprint; 33 countries with commercial access Regulatory and Pipeline: Momentum across rare and orphan indications Received FDA approval of LIVMARLI tablets Completed enrollment in the volixibat VISTAS study in PSC Announced proposed acquisition of Bluejay Therapeutics, to add worldwide rights to brelovitug, a late-stage fully human monoclonal antibody for HDV that is well aligned with Mirum’s deep expertise in rare liver disease Received FDA approval of CTEXLI for cerebrotendinous xanthomatosis (CTX) LIVMARLI oral solution approved in Japan for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) Initiated MRM-3379 BLOOM Phase 2 study in Fragile X syndrome (FXS) Corporate and Financial: Sustained financial strength and capital discipline Achieved positive cash flow from operations in 2025 As of December 31, 2025, cash, cash equivalents and investments are expected to be approximately $392 million, compared to $292.8 million as of December 31, 2024 Two private placements, for aggregate gross proceeds of approximately $268.5 million, expected to be completed concurrently with the closing of the proposed acquisition The foregoing amounts relating to 2025 financial data are unaudited and preliminary and are subject to completion of financial closing procedures. Additional information and disclosure would be required for a more complete understanding of the Company’s financial position and results of operations as of December 31, 2025. Mirum will present at the 44th annual J.P. Morgan Healthcare Conference in San Francisco on Wednesday, January 14, 2026, at 11:15 a.m. PT. The presentation and question and answer session will be webcast live and can be accessed by visiting the Investors section of Mirum’s corporate website. About LIVMARLI® (maralixibat) oral solution and LIVMARLI® (maralixibat) tablets LIVMARLI® (maralixibat) 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 Breakthrough Therapy designation for ALGS and PFIC type 2 and orphan designation for the treatment of 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 ALGS 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 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 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 Brelovitug Brelovitug is an investigational, highly potent, pan-genotypic, fully human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that targets the surface antigen (anti-HBsAg) on both the chronic hepatitis D virus (HDV) and the hepatitis B virus (HBV). Brelovitug is designed to neutralize and remove hepatitis B and hepatitis D virions and deplete HBsAg-containing subviral particles. Brelovitug has FDA Breakthrough Therapy designation for the treatment of HDV and PRIME and Orphan designations from the European Medicines Agency. Following the anticipated close of the Bluejay Therapeutics acquisition, Mirum will own worldwide rights to brelovitug. About MRM-3379 MRM-3379 is an in-licensed investigational oral therapy being evaluated for the treatment of Fragile X syndrome (FXS). It is a selective phosphodiesterase-4D (PDE4D) inhibitor designed to enhance cAMP signaling. MRM-3379 may offer a novel approach to improving cognition, language, and daily function in individuals with FXS. The BLOOM Phase 2 clinical study of MRM-3379 is currently underway in FXS. Males ages 16 to 45 will be randomly assigned to receive one of three dose levels of MRM-3379 or placebo for 12 weeks. An open-label cohort of boys ages 13 to 16 will receive the lowest dose, in order to explore effects of treatment in younger boys, closer to the age of diagnosis. The study’s primary endpoint is safety and tolerability, the key secondary endpoint is the NIH Toolbox Crystallized Cognition Composite (CCC), and several exploratory endpoints will assess potential effects on mood, behavior, and other symptoms that are relevant to this population. About Mirum Pharmaceuticals Mirum Pharmaceuticals (NASDAQ: MIRM) is a leading rare disease company with a global footprint of approved products and a broad pipeline of investigational medicines. Purpose-built to bring forward breakthrough medicines for people with overlooked conditions, Mirum combines deep expertise with strong connections to the rare disease community. The company’s commercial portfolio includes LIVMARLI® (maralixibat) for Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC), CHOLBAM® (cholic acid) for bile-acid synthesis disorders, and CTEXLI® (chenodiol) for cerebrotendinous xanthomatosis (CTX). Mirum’s clinical-stage pipeline includes volixibat, an IBAT inhibitor in late-stage development for primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), brelovitug, a fully human monoclonal antibody in late-stage development for chronic hepatitis delta virus (HDV), subject to the completion of the proposed acquisition of Bluejay Therapeutics, and MRM-3379, a PDE4D inhibitor being evaluated for Fragile X syndrome (FXS). Mirum’s success is driven by a team dedicated to advancing high impact medicines through strategic development, disciplined execution and purposeful collaboration across the rare disease ecosystem. Learn more at www.mirumpharma.com and follow Mirum on Facebook, LinkedIn, Instagram and 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, commercial results for our approved products, including continued growth in year-over-year net product sales, being on track to achieve our revised financial guidance, our expected financial results as of December 31, 2025, including our net product sales, cash flow from operations, and cash, cash equivalents and investments, our expectations regarding our financial results in 2026 and 2027, the anticipated occurrence, manner and timing of the closing of the proposed acquisition of Bluejay Therapeutics, the anticipated occurrence, manner and timing of the closing of the private placements expected to close concurrently with the proposed acquisition of Bluejay Therapeutics and the gross proceeds expected to result from such private placements, delivering life changing medicines for patients suffering from rare diseases, the results, enrollment, conduct and progress of Mirum’s ongoing and planned studies for its product candidates, including in-licensed product candidates, our expectations regarding the development of Bluejay Therapeutics’ brelovitug, including the potential successful results from the pivotal Phase 3 studies for HDV, the timing and results of interim analyses of our ongoing studies and additional international launches expected in 2026. 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 “anticipate,” “expected,” “will,” “could,” “would,” “guidance,” “potential” 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 Quarterly Report on Form 10-Q for the quarter ended September 30, 2025 and subsequent filings with the Securities and Exchange Commission. 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.

炎症性肠病（inflammatory bowel disease，IBD）是一组以胃肠道慢性炎症复发缓解交替为特征的疾病总称，主要包括溃疡性结肠炎（ulcerative colitis，UC）和克罗恩病（Crohn’s disease，CD）2种[1]。UC病变局限于结肠黏膜层，CD则可累及全消化道，呈现节段性、透壁性炎症特征[2]。IBD发病机制复杂，涉及肠道微生态失衡、肠黏膜屏障功能障碍、免疫调控异常、遗传易感性及环境-饮食因素交互作用[3]。值得注意的是，肠道菌群及其关键代谢产物——胆汁酸构成的双向调节系统，在IBD的发生发展过程中具有核心病理意义[4]。肠道菌群通过胆汁酸代谢重塑影响局部免疫微环境，而胆汁酸代谢异常又反向调控菌群平衡，形成正反馈环路，加剧炎症[5]。 当前临床治疗以药物干预为主，涵盖氨基水杨酸制剂、糖皮质激素、免疫抑制剂及生物制剂等。尽管治疗方案不断革新，但仍面临显著的疗效瓶颈与安全性挑战：30%～40%的患者对传统治疗无应答或出现继发性失效[6]；长期使用免疫抑制剂或生物制剂可能引发机会性感染、肝肾功能损伤，且高额费用限制了普及应用[7-8]。更关键的是，现有疗法多聚焦于“下游”免疫通路的广谱抑制，未能从根本上纠正肠道微生态失衡这一核心病理环节，导致疾病易反复、难根治。在此背景下，微生物-代谢调控策略因其精准靶向性成为研究新焦点[9]。近年来，研究揭示了中药通过“微生物群-代谢物轴”发挥治疗作用的新机制：中药活性成分既可直接调节肠道菌群结构，又能通过次级代谢产物干预胆汁酸代谢通路。这种双重调控特性使中药成为修复肠道微生态、重建免疫稳态的潜在治疗工具。本文系统阐述了肠道菌群-胆汁酸轴的互作机制，分析了该轴在IBD发生发展过程中的特征性变化，并总结了中药基于该轴干预策略的研究进展，为IBD的精准防治提供了新思路。 1 肠道菌群-胆汁酸轴在IBD中的作用 肠道菌群与胆汁酸的相互作用在IBD进程中扮演重要角色，一方面菌群调节胆汁酸的合成、重吸收和代谢，另一方面胆汁酸影响菌群的多样性和稳态。 1.1 胆汁酸的合成及与肠道菌群的相互作用 胆汁酸是胆汁的主要成分，由肝细胞以胆固醇为原料合成，经胆盐输出泵（bile salt export pump，BSEP）泵入胆囊并分泌至小肠，促进脂质消化[10]。95%的胆汁酸通过回肠末端重吸收，再经门静脉返回肝脏形成肠肝循环[10]，剩余5%在结肠经微生物转化为次级胆汁酸（secondary bile acids，SBA），后者被重吸收或随粪便排出[11]。胆汁酸的合成和运输受肝细胞和肠上皮细胞中激素样信号的复杂网络调节[10]，其作为信号分子可激活法尼醇X受体（farnesoid X receptor，FXR）、G蛋白偶联胆汁酸受体1（takeda G-protein-coupled receptor 5，TGR5）等核受体，参与调控胆汁酸合成、肠道稳态及炎症免疫反应。 肠道菌群通过直接参与生物转化和间接调控宿主信号通路，影响胆汁酸组成及功能[12]。胆盐水解酶（bile salt hydrolase，BSH）是初始“入口”反应——解偶联反应的核心酶[13]，催化结合型胆汁酸水解为非结合形式，其分布于革兰阳性菌、革兰阴性菌和古菌中。在解偶联后，7α-去羟基化是非结合初级胆汁酸（primary bile acids，SBA）转化为SBA的重要代谢途径，由Clostridium等菌属主导[14]，胆汁酸诱导型操纵子（bile-acid-induced operon，bai）执行[15]。羟基类固醇脱氢酶能可逆催化胆汁酸在C-3、C-7和C-12位的羟基化反应[16]，通过差向异构化和氧化反应生成亲水性胆汁酸，降低毒性并维持肠道稳态[17]。此外，肠道菌群催化胆汁酸与脂肪酸、二元羧酸、氨基酸[18-20]等形成酯化或酰胺化偶联物。特定氨基酸-胆汁酸偶联物（如苯丙氨酸胆酸）在CD患者中升高，或可作为IBD分型诊断标志[12]。除经典代谢途径外，硫酸化和葡萄糖醛酸化也是肠道的重要代谢机制[21]。菌群可通过去除硫酸基团或调节葡萄糖醛酸化过程参与胆汁酸循环。另外，近期研究报道了FXR拮抗剂胆汁酸-甲基半胱胺结合物[22]和3-琥珀酰化胆酸等新型代谢产物，前者在体内促进胆汁酸生物合成基因的表达，后者可缓解代谢性脂肪肝炎并调节菌群生态[19]。但新型胆汁酸与FXR的关系及其在疾病中的具体机制仍需深入探索。 胆汁酸对菌群的调控呈现双重特性：一方面，其抗菌活性具有浓度和结构依赖性，低浓度胆汁酸仅在生理与生存力上轻微下降，而高浓度胆汁酸通过破坏细胞膜、诱导胞内酸化及DNA损伤抑制细菌生长。非结合型胆汁酸抗菌性强于结合型，革兰阳性菌相对于革兰阴性菌更敏感[23]，具BSH的菌株可增强耐受性。如胆酸能够促使梭状芽胞杆菌分泌抗菌药物，而这些抗菌药物反过来抑制艰难梭菌并改善腹泻和UC症状[24]。另一方面，胆汁酸可富集特定功能菌，如具有7α-去羟基化代谢酶的细菌丰度与SBA水平呈正相关[25]，脱氧胆酸可促进拟杆菌属细菌增殖，使其分泌抗炎代谢物[26]，接受熊去氧胆酸（ursodeoxycholic acid，UDCA）治疗的患者肠道内，拟杆菌属、萨特氏菌属和颤螺旋菌属显著增加[27]。此外，外源性胆汁酸的干预亦能影响菌群动态，添加熊胆粉可降低葡聚糖硫酸钠（dextran sulfate sodium salt，DSS）诱导的小鼠菌群丰度和多样性[28]。 多项研究证明，FXR信号通路是菌群与胆汁酸相互调控的重要媒介[29]。肠道菌群可通过FXR信号通路间接调控胆汁酸代谢。特定菌株（如多氏拟杆菌和黏液真杆菌）可直接激活FXR[30]，抑制肝脏胆汁酸合成基因表达，并调节转运体[如BSEP[31]、有机溶质转运体α/β（organic solute transporter α/β，OST α/β）[32]等]活性，控制胆汁酸池大小。另外，FXR激动剂（如奥贝胆酸）可增加革兰阳性菌丰度[33]，拮抗剂（如甘氨β胆酸）会降低厚壁菌门/拟杆菌门的值，且甘氨β鼠胆酸药效作用在其与FXR激动剂（GW4064）联用或在缺乏FXR的小鼠中均会消失，表明该药效须通过抑制FXR通路才能实现[34]。这些结果有助于了解胆汁酸治疗后微生物谱的变化[35]，并开发针对肠道微生物组的胆汁酸治疗新方法。 综上，肠道菌群通过多元代谢途径重塑胆汁酸谱，胆汁酸则通过结构特异性控菌效应及受体介导的信号网络，双向调控菌群组成与功能（图1）。未来需进一步解析菌群-胆汁酸轴的互作网络，开发基于胆汁酸代谢酶的工程菌株，结合多组学筛选疾病特异性胆汁酸-菌群标志物，为个性化治疗提供新靶点。 1.2 IBD 中失衡的肠道菌群和胆汁酸 IBD是一种由宿主与肠道微生物相互作用失衡引发的慢性肠道炎症性疾病[36]。肠道菌群通过代谢短链脂肪酸、胆汁酸等物质维持共生稳态，但其失调可导致毒性代谢物增加、有益产物减少，肠屏障功能破坏并诱发疾病[37]。胆汁酸与肠道菌群的互作在IBD发病中起关键作用。临床研究发现，IBD患者肠道菌群呈现多样性降低、有益菌减少和致病菌富集，厚壁菌门（如毛螺菌科、粪杆菌属）和放线菌门（如罗斯伯利亚属）丰度显著下降，而变形菌门（如肠杆菌科）及梭杆菌门等致病菌比例升高[38-39]。UC患者表现为拟杆菌科减少、放线菌门增加及条件致病菌富集[40]；CD患者则以厚壁菌门锐减、肠杆菌科扩张为特征[41]。菌群结构变化与胆汁酸代谢紊乱密切相关，IBD患者粪便中PBA比例上升，SBA显著减少，结合型胆汁酸蓄积，提示解偶联和7α-去羟基化功能减弱[4,42]。具有胆汁酸代谢酶（如BSH）的厚壁菌门减少，导致异别石胆酸和牛磺石胆酸等SBA生成不足，而硫酸化胆汁酸（如3-磺基脱氧胆酸）异常升高[43-44]。菌群失调直接抑制胆汁酸转化，而异常胆汁酸谱 [如脱氧胆酸/（脱氧胆酸＋胆酸）的值降低] 可损害肠屏障并产生炎症[37]。此外，宿主与菌群衍生的结合型胆汁酸能通过恢复上皮屏障功能及杯状细胞分泌改善肠道炎症[44]，也能通过激活BAR家族调控免疫反应[45]。在先天免疫中，FXR激活过氧化物酶体增殖物激活受体γ通路纠正辅助性T细胞17（T helper 17 cells，Th17）/调节性T细胞（regulatory T cells，Treg）失衡这一IBD核心机制[46]。TGR5通过环磷酸腺苷信号激活，抑制白细胞介素-6（interleukin-6，IL-6）、IL-1β等炎症因子表达[47]，并促进肠道干细胞增殖[48]。而在适应性免疫中，石胆酸及其代谢物通过抑制视黄酸受体相关孤儿受体γt调控Th17/Treg平衡，从而直接对宿主免疫应答进行精细调控[49]。 综上，IBD中肠道菌群与胆汁酸的双向调控异常是疾病进展的核心机制（图2）。未来需深入解析其互作网络，探索基于菌群-胆汁酸轴的精准治疗策略。 2 中药干预肠道菌群-胆汁酸轴的抗肠炎作用研究 临床研究和动物实验证明，IBD的发展与宿主肠道菌群及代谢物改变有密切的联系。因此，调节肠道菌群-胆汁酸轴，可在IBD治疗中有所裨益。近年来，中药作为治疗和预防IBD复发的重要干预手段，凭借多靶点、多通路的调节特性，在临床实践中展现出显著疗效，受到国内外高度重视。基于此，本综述系统归纳了中药通过调控肠道菌群-胆汁酸轴干预IBD的潜在作用机制（图3）及研究进展。 2.1 中药复方 近年来，研究者从不同角度对中药复方延缓IBD进行了基础研究，发现其不仅有助于维持肠道完整性、减少炎症、降低氧化应激，还对IBD的治疗具有积极作用[50]。经典方剂如白头翁汤可显著抑制炎症因子，上调总胆汁酸和总胆固醇水平，并通过TGR5/FXR通路调节菌群组成和胆汁酸代谢，发挥抗肠炎作用[51]。葛根芩连汤可通过富集有益菌如罗斯氏菌属的相对丰度，减少有害菌埃希氏菌属-志贺氏菌的相对丰度，调控胆汁酸代谢与炎症因子，缓解结肠炎症[52]；其加味方则通过调节紫单胞菌科与穆氏菌科的比例，恢复牛磺酸结合型胆酸、脱氧胆酸等水平，促进黏蛋白分泌与隐窝干细胞增殖，发挥免疫调节作用[53]。四君子汤通过抑制BSH相关菌属，升高结合与非结合胆汁酸比值，缓解肠道炎症[54]。理中汤则通过减少条件致病菌（如梭状芽胞杆菌、肠杆菌属和埃希氏菌-志贺氏菌）丰度，提升益生菌丰度来重塑菌群结构，调控脱氧胆酸/胆酸代谢，促进抗炎因子释放，从而缓解结肠炎症[55]。清肠化瘀方对DSS诱导的急慢性UC小鼠模型有显著疗效，方中白芷作为主要组成药味，在维持肠道微生物群稳态及调控代谢功能方面发挥关键作用。值得注意的是，结肠组织中拟杆菌属特异性水解酶活性的显著增强，可能是驱动优势菌群丰度、非结合牛磺胆酸水平升高的重要分子机制[56]。此外，研究发现，中药制剂片仔癀具有抑制炎症性疾病的作用，其可通过富集有益菌来恢复肠道微生物群，促进结合型胆汁酸累积[57]，其中牛磺熊去氧胆酸（tauroursodeoxycholic acid，TUDCA）通过调节肠道菌群和改善肠屏障功能减轻炎症[58]，抑制肠道FXR-FGF15信号通路，改善肝肠代谢[59]。清肠消澼饮可通过上调肠道内脱氧胆酸和石胆酸代谢相关菌群的丰度，显著抑制肠道炎症级联反应，有效改善结肠组织病理损伤[60]。这些研究系统阐明了复方制剂基于“菌群-胆汁酸轴”调控IBD的治疗机制，为中医药精准干预提供了科学支撑。 2.2 单味中药及其提取物 单味中药及其提取物也可通过多途径调控肠道菌群-胆汁酸轴，发挥抗肠炎作用。如牛头草可增加拟杆菌丰度，促进胆汁酸吸收，同时通过磷脂酰肌醇信号系统降低炎症因子水平，修复肠道屏障功能，维持黏膜免疫稳态[61]。木犀蜜环菌是一种珍稀的野生药用和食用担子菌，其通过富集乳酸杆菌科等抗炎菌，激活FXR信号，抑制丝裂原活化蛋白激酶/NF-κB通路，恢复肠内稳态，发挥抗肠炎作用[62]。大麦叶可提升副萨特氏菌属和另枝菌属等有益菌丰度，调节结合型与非结合型胆汁酸比例，使异石胆酸浓度恢复正常[63]。清热燥湿类中药（如黄连、黄芩、黄柏、苦参）可使小鼠肠道微生物群落组成与其胆汁酸相关性存在显著性差异，如拟杆菌属和链球菌属丰度一降一升，与胃肠道中鹅脱氧胆酸（chenodeoxycholic acid，CDCA）、UDCA和TUDCA升高显著相关[64]。杜仲叶提取物通过下调TLR4/IL-6基因表达，影响肠道菌群-胆汁酸-TGR5轴（其特征分类群阿克曼菌属与TUDCA呈显著正相关），促进紧密连接蛋白表达，缓解IBD[65]。上述发现不仅为阐述单味中药及其提取物治疗IBD的发病机制提供了新视角，更为开发基于微生态-代谢调控的中药复方制剂奠定了理论基础。 2.3 中药活性成分 研究表明，中药活性成分可通过重塑肠道菌群结构恢复微生态平衡，同时干预胆汁酸代谢通路，显著降低炎症因子水平并增强肠道屏障功能，从而发挥对IBD的治疗作用[66-68]。相关成分作用机制如下。 2.3.1 多酚类 植物多酚作为具有苯酚结构的次生代谢产物，可通过直接抗菌或益生元效应选择性调控特定菌群，实现胆汁酸谱精细化调控，进而通过代谢-免疫轴的系统调控影响宿主健康。葡萄籽原花青素的干预可显著增加具有潜在抗炎特性且参与胆汁酸代谢的菌群丰度，从而激活FXR通路，引起粪便中CDCA及其产物石胆酸含量升高，缓解肠道炎症[69]。类似地，没食子酸促进乳杆菌科、普雷沃氏菌等益生菌增殖，抑制以厚壁菌门和变形菌门为主的病原菌，通过加速胆汁酸代谢，维持胆汁酸稳态，减少毒性代谢产物积累，从而缓解炎症损伤[70]。茶多酚成分如表没食子儿茶素-3-没食子酸酯则通过富集拟杆菌属等产SBA功能菌，增强免疫调节作用[71]。苹果多酚提取物特异性调节BAR活性，使β-鼠胆酸升高而猪去氧胆酸降低，同时促进疣微菌门、阿克曼氏菌属和拟杆菌属等扩增，通过TGR5介导的NF-κB通路实现抗炎效应[72]。反式茴香酚则通过抑制脱硫弧菌、副普雷沃菌属和幽门螺杆菌等促炎菌丰度，降低Th17/Treg细胞的值及特定胆汁酸水平，改善UC炎症[73]。丹参茎叶酚酸可通过下调副拟杆菌属丰度抑制芳香族氨基酸代谢，上调瘤胃菌属丰度增加7-磺酸化胆酸和脱氧胆酸，形成“抑致病菌-促胆汁酸生成”的双重调控机制，其对潜在致病菌（链球菌属、肠球菌属和大肠杆菌等）相对丰度降低作用最为明显，同时恢复促炎/抗炎因子平衡[74]。菊苣酸则通过降低拟杆菌门、黄杆菌科和玫瑰属等丰度，增加毛螺菌科丰度，恢复下调的石胆酸水平，构建抗肠炎微环境[75]。这些研究揭示了植物多酚通过“菌群-胆汁酸轴”的级联调控网络，实现对肠道炎症的多靶点干预，为开发基于微生物-代谢互作的抗炎策略提供了重要理论依据。 2.3.2 多糖 多糖作为肠道菌群的能量来源，能促进有益菌群生长，并通过其代谢产物调节菌群构成，发挥益生元作用[76]。芜菁多糖是芜菁块根中主要的营养物质和生物活性成分，在人源化小鼠模型中能显著提升粪便总胆汁酸水平，重塑肠道菌群组成[74]。诺尼果多糖能特异性富集粪杆菌、杜氏乳杆菌、鼠杆菌等益生菌，增强SBA合成能力[77]。此外，不同植物多糖对菌群的调控具有种属特异性，如藤椒多糖能显著改变红蝽菌科等炎症无关菌的丰度，抑制副萨特氏菌属等促炎菌的丰度。此外，其还可以上调BSH活性，促进PBA转化为SBA，调节BAR，减缓脱氧胆酸、石胆酸的下降趋势，发挥治疗作用[78]。水溶性大蒜多糖通过调节7α-脱羟基化反应调控特定胆汁酸，促进Th17/Treg细胞平衡、抑制NF-κB/STAT3等促炎通路，实现免疫微环境优化[79]。岩藻多糖则通过增加毛螺杆菌科丰度，调节胆酸、UDCA浓度，激活FXR/TGR5受体信号，形成三重防护体系[80]。这些研究共同揭示了植物多糖通过“菌群-胆汁酸轴”的多维度作用模式，为开发基于微生态调控的抗炎食品功能因子提供了重要理论依据。 2.3.3 其他 此外，其他活性成分也可通过调控菌群-胆汁酸轴改善IBD。如从黄芩水溶液中分离的新型黄芩苷镁复合物，凭借其优异的水溶性和镁离子配位特性，显著抑制NF-κB和过氧化物酶体增殖物激活受体α信号通路活化，调节炎症因子表达，富集振荡杆菌等有益菌、抑制拟杆菌等致病菌，维持肠道屏障完整性，同时恢复胆汁酸代谢紊乱，有效改善UC症状[81]。从藤茶中提取的二氢杨梅素可通过提升阿克曼氏菌丰度，促进CDCA和石胆酸生成，激活FXR/TGR5信号通路，并上调IL-10，从而减轻结肠炎症浸润[82]。白芍/赤芍中的芍药苷通过多重机制发挥保护作用：首先重构肠道菌群，促进乳酸杆菌增殖，进而增强胆酸/CDCA向脱氧胆酸/石胆酸的转化能力，提升SBA水平，最终激活结肠TGR5/FXR受体，修复屏障损伤并抑制炎症反应[83]。生物碱类成分亦表现突出。苦参总生物碱通过重塑UC小鼠肠道菌群结构，调节菌群介导的胆汁酸代谢紊乱，使与拟杆菌科和脱铁杆菌门增加呈正相关的胆酸显著升高，下调非结合型牛磺-α/β-鼠胆酸水平，进而修复肠屏障损伤、降低肠道炎症[84]。小檗碱可通过富集乳酸杆菌和玫瑰菌，提升非结合型胆汁酸及UDCA/脱氧胆酸浓度，增强了菌群-胆汁酸-FXR/TGR5轴联控效应[85]。值得注意的是，瑟丹内酯通过抑制Janus酪氨酸激酶/STAT和NF-κB通路，下调BSH相关菌属（如副杆菌和肠球菌），调节结合/非结合胆汁酸比例，间接抑制FXR基因表达，缓解UC[86]。苍术挥发油则通过综合调控抗炎因子、菌群稳态及胆汁酸代谢，减轻急性UC炎症[87]，进一步验证了菌群-胆汁酸轴在IBD治疗中的核心地位。 上述研究系统揭示了中药活性成分通过“菌群-胆汁酸轴”的多维调控模式，为开发基于微生态-代谢互作的IBD治疗策略提供了重要科学依据。 3 结语与展望 迄今为止，许多研究已探讨了中药在调节肠道微生物群及其衍生代谢物与治疗IBD之间的关系。类似地，本文集中阐明了IBD中肠道菌群和胆汁酸的动态失衡，菌群与胆汁酸的双向调控机制以及中药干预的潜在影响。然而，当前研究仍存在若干关键科学问题亟待突破。首先，微生物源胆汁酸代谢产物的深度挖掘受限于标准品匮乏的瓶颈，特别是稀有胆汁酸异构体及代谢中间体的对照品匮乏问题突出，这不仅严重制约了高灵敏度定量方法的开发，更导致肠道菌群代谢产物与宿主生理效应之间的量效关系难以精确解析，极大阻碍了胆汁酸代谢通路的机制阐明；其次，当前研究主要依赖16S/宏基因组测序数据与胆汁酸谱的关联性分析，却缺乏对关键菌株的功能性验证，特别是针对胆汁酸修饰酶（如胆盐水解酶、差向异构酶等）的酶学特性研究及基因调控机制解析尚未形成系统化研究体系。值得关注的是，研究表明，除肠道细菌外，真菌、古生菌和病毒等微生物与胆汁酸也可能存在互作，其与IBD等疾病密切相关[88]，但相关了解十分有限。此外，中药治疗IBD的临床证据相对匮乏，且中药口服后胃肠道内未知代谢产物的化学表征、生物合成途径及生理功能仍不明确，特别是肠内菌群介导的“中药黑箱效应”缺乏代谢组学表征，这严重制约了基于代谢组学的新疗法开发；同时，现有动物模型未能复现人类特有的胆盐复合物组成及肠-肝轴紊乱特征，基础研究成果向临床转化的可靠性存疑。 中药（活性成分、单味中药或其提取物与中药复方）靶向肠道菌群-胆汁酸轴的干预策略有望为IBD预防和治疗开辟新方向。为此，需要进一步的研究来加深我们对其潜在机制的理解，并在临床实践中验证其有效性。建议从以下维度深化研究：（1）整合多组学技术解析中药调控菌群-胆汁酸轴的分子图谱，重点阐明活性成分对关键菌株的定向调控机制及代谢通路重塑规律；（2）系统揭示多界微生物在胆汁酸代谢中的生态位分工与信号串扰机制，这可能是揭示其致病/保护效应的关键突破口；（3）开发体外仿生肠道模型与类器官芯片技术，克服物种差异对机制研究的局限。通过揭示“中药-菌群-胆汁酸-免疫”多维互作机制，有望推动中医药现代化研究迈向新高度，为IBD等复杂肠道疾病提供差异化诊疗方案。 来 源：谢译萱，魏雪梅，杨 洋，李 运，吴嘉振，刘 馨，黄泳彤，苏琳祺，张 瑜，果德安，陈琴华．基于肠道菌群-胆汁酸轴探讨中药治疗炎症性肠病的研究进展 [J]. 中草药, 2025, 56(22): 8403-8413.