Drosophila melanogaster Models for Inflammatory Bowel Disease: Mechanisms and Therapeutic Insights

Drosophila melanogaster Models for Inflammatory Bowel Disease: Mechanisms and Therapeutic Insights

October 20, 2025 Author Summary 0

Inflammatory bowel disease

Inflammatory bowel disease is a chronic, non-specific inflammation of the gastrointestinal tract that mainly includes ulcerative colitis and Crohn’s disease. Its global burden has increased from 3.3 million in 1990 to 4.9 million in 2019, with projections exceeding 10 million by 2030. Many patients face a long disease course and disability that translate into substantial medical costs and societal impact. Because the gut communicates with other organs through brain–intestine and lung–intestine axes, people with inflammatory bowel disease show higher rates of certain neurodegenerative and respiratory conditions.

Etiology is multifactorial, involving environmental, genetic, infectious, and immune factors. Current therapies range from non-targeted drugs (aminosalicylates, corticosteroids, immunomodulators) to targeted agents (anti-TNF, anti-IL-12/23, JAK inhibitors, anti-integrins). Yet a considerable proportion of patients do not respond initially or show delayed responses and may experience side effects. These realities motivate fast, tractable models that clarify mechanisms and help prioritize therapeutic candidates.

Why use Drosophila melanogaster?

The fruit fly combines speed, low cost, and a versatile genetic toolkit (Gal4/UAS, CRISPR/Cas9). Many human disease-related genes have fly homologs, and the fly gut mirrors key organizational features of the human intestine. The midgut contains four principal cell types—intestinal stem cells (ISCs), enteroblasts (EBs), enterocytes (ECs), and enteroendocrine cells (EEs)—and includes an acid-secreting copper cell region. These parallels support rapid, mechanistic studies of epithelial damage, inflammation, and repair.

Modeling inflammatory bowel disease in flies

The most widely used inducer is dextran sulfate sodium (DSS). In flies, DSS disrupts gut integrity and triggers inflammatory signaling, yielding a reproducible suite of physiological and intestinal changes: shortened lifespan, reduced movement, weight loss, decreased food intake and excretion, shortened intestinal length, barrier damage, disturbed acid–base balance in the copper cell region, ISC overproliferation, and dysbiosis.

Other approaches broaden the toolkit: feeding sodium dodecyl sulfate (SDS), bleomycin, or paraquat to elevate oxidative stress; oral infection with pathogens such as Pseudomonas aeruginosa or Erwinia carotovora carotovora 15; and sleep deprivation, which increases peroxides and provokes gut inflammation. Together these paradigms offer complementary ways to model disease-relevant injury and repair.

Mechanistic insights: an ISC-centered network

In a healthy midgut, ISCs divide to maintain the epithelium. Asymmetric divisions generate EBs that differentiate into absorptive ECs or hormone-secreting EEs. DSS shifts this balance toward excessive ISC proliferation, EB accumulation, and increased EE differentiation without proper EC maturation.

Conserved pathways coordinate this response:

  • JAK/STAT: Damage elevates cytokines (Unpaireds), activating JAK/STAT in ISCs and EBs to drive division and repair.

  • EGFR: EGF-like ligands stimulate ISC proliferation; disrupting EGFR signaling prevents this expansion.

  • JNK: Activated by stress in ISCs and ECs; in ECs it induces Unpaireds and EGF ligands, amplifying JAK/STAT and EGFR.

  • Wnt/Wg: Supports ISC maintenance and regeneration; loss of Wg/Fz impairs self-renewal.

  • Hedgehog: Contributes to damage-induced ISC proliferation through crosstalk with other pathways.

  • Hippo/Yki: Required in precursor cells for DSS-induced ISC proliferation; Yki activity increases Unpaireds and EGF ligands, feeding back into JAK/STAT and EGFR.

This network explains how the epithelium attempts repair yet can tip into pathology when signals are mis-regulated.

Microbiota–immunity interactions

The fly gut hosts relatively low microbial diversity—often 5–30 species—with Lactobacilli and Acetobacter dominant. DSS disrupts this balance, typically increasing Firmicutes and decreasing Proteobacteria and Actinobacteria. Innate immune defenses include DUOX-generated reactive oxygen species and antimicrobial peptides controlled by NF-κB pathways (Toll and Imd). A key NF-κB transcription factor (Relish) was not activated when DSS was provided to sterile flies, indicating that disordered flora are required for this aspect of immune activation. At the same time, certain protective interventions reduce inflammation even under germ-free conditions, showing that not all benefits rely on the microbiota. Clarifying when microbiota-dependent versus microbiota-independent mechanisms dominate remains a priority.

Candidate therapeutics and mechanisms

The review organizes natural products by mechanism, highlighting four broad themes:

Inflammation-related pathways

  • A classical multi-component formula alleviates intestinal damage by inhibiting JAK/STAT.

  • Acanthopanax senticosus polysaccharides improve survival by modulating EGFR, JNK, and Notch, reducing ISC overproliferation and abnormal differentiation.

  • Silybin curbs ISC overgrowth via JNK.

  • Flos puerariae extract appears to protect by inhibiting JAK/STAT and Wnt.

  • Total ginsenosides aid survival and repair through MAPK.

  • Additional botanicals, including ursolic acid and safranal, dampen ISC hyperproliferation by acting on JNK, EGFR, and JAK/STAT.

Oxidative stress control
Excess reactive oxygen species are central to injury in these models. Antioxidants and boosts to endogenous defenses mitigate damage and restore homeostasis.

Microbiota modulation
Oligo- and polysaccharides such as agar and chitosan oligosaccharides, and carrageenan-derived compounds, improve physiology while shifting microbial composition and immune tone toward balance.

Autophagy tuning
Some agents relieve injury by down- or up-regulating autophagy-related genes, offering a route to restore epithelial equilibrium.

Across these categories, many effects observed in flies align with findings in mammalian models and clinical observations, supporting the use of Drosophila to screen candidates and map mechanisms before advancing to higher organisms.

Practical implications for research programs

  • Multiple quantitative endpoints: The DSS paradigm supports multidimensional profiling—lifespan, locomotion, feeding, excretion, intestinal length, barrier integrity, copper cell region acid–base balance, ISC proliferation, and microbiota composition.

  • Pathway-anchored experimentation: Converging signals (JAK/STAT, EGFR, JNK, Wnt/Wg, Hedgehog, Hippo) provide clear entry points for genetic epistasis and drug–gene interaction studies focused on regeneration without maladaptive proliferation.

  • Translational triage: Compounds with defined mechanisms in flies can be prioritized for validation in higher organisms, especially where concordant evidence already exists.

Outlook

Open questions center on the microbiota–epithelium interface: how dysbiosis causally shapes ISC behavior and repair; how beneficial taxa preserve barrier function; and how pathogens disrupt immune regulation. Aging flies exhibit barrier dysfunction and dysbiosis reminiscent of disease-like states, but equating age-related changes with inflammatory bowel disease requires further study. Clarifying these relationships should guide targeted interventions that pair microbiota management with precise control of inflammatory and regenerative signaling.

Key messages

  • Inflammatory bowel disease is rising globally and remains difficult to treat for many patients.

  • Drosophila melanogaster provides a fast, ethical, and genetically tractable platform to study intestinal injury, immunity, and repair.

  • DSS and complementary paradigms generate robust, disease-relevant phenotypes and quantitative endpoints.

  • An ISC-centered signaling network—JAK/STAT, EGFR, JNK, Wnt/Wg, Hedgehog, Hippo—coordinates damage responses.

  • Natural products show mechanism-based benefits across inflammation, oxidative stress, microbiota balance, and autophagy, offering leads for downstream validation.

 

The translation of the preceding English text in Chinese:

 

炎症性肠病

炎症性肠病（Inflammatory bowel disease, IBD）是一种胃肠道的慢性、非特异性炎症，主要包括溃疡性结肠炎和克罗恩病。其全球患病负担已从1990年的330万人增加到2019年的490万人，预计到2030年将超过1000万人。许多患者经历漫长的病程和功能障碍，带来巨大的医疗支出和社会影响。由于肠道通过脑–肠轴和肺–肠轴与其他器官交流，IBD患者出现某些神经退行性疾病和呼吸系统疾病的风险也更高。

病因多因素相关，涉及环境、遗传、感染和免疫等多方面因素。当前治疗从非靶向药物（如氨基水杨酸、糖皮质激素、免疫调节剂）到靶向药物（如抗TNF、抗IL-12/23、JAK抑制剂、抗整合素）不等。然而，仍有相当一部分患者起初无反应或反应延迟，并可能出现副作用。这些现实促使研究者寻求快速、可操作的模型，以阐明机制并帮助优先筛选治疗候选物。

为什么使用黑腹果蝇（Drosophila melanogaster）？

果蝇兼具实验速度快、成本低和遗传工具丰富的优势（如Gal4/UAS系统和CRISPR/Cas9）。许多与人类疾病相关的基因在果蝇中存在同源基因，而果蝇肠道在组织结构上与人类肠道有重要相似之处。中肠主要由四种细胞类型组成——肠干细胞（ISCs）、肠母细胞（EBs）、肠上皮细胞（ECs）和肠内分泌细胞（EEs），并包含一个分泌酸的铜细胞区。这些相似性支持快速、机制性地研究上皮损伤、炎症和修复过程。

在果蝇中模拟炎症性肠病

最常用的诱导剂是硫酸葡聚糖钠（DSS）。在果蝇中，DSS会破坏肠道完整性并激活炎症信号，产生一系列可重复的生理和肠道变化：寿命缩短、运动减少、体重下降、进食和排泄减少、肠道缩短、屏障受损、铜细胞区酸碱平衡紊乱、肠干细胞过度增殖以及肠道菌群失调。

其他方法扩展了研究工具箱：喂食十二烷基硫酸钠（SDS）、博莱霉素或对氧化物（paraquat）以增强氧化应激；经口感染病原体如铜绿假单胞菌或胡萝卜软腐欧文氏菌15株；以及睡眠剥夺，这些都可增加过氧化物水平并诱发肠道炎症。这些范式共同提供了多种互补方式来模拟疾病相关的损伤与修复。

机制性洞察：以ISC为中心的信号网络

在健康的中肠中，ISCs通过分裂维持上皮稳态。不对称分裂产生EBs，后者分化为吸收性ECs或分泌激素的EEs。DSS使这种平衡偏向于过度的ISC增殖、EB积累以及EE分化增加，而EC分化不足。

保守信号通路协调这一响应：

JAK/STAT：损伤导致细胞因子（Unpaireds）上调，激活ISCs和EBs中的JAK/STAT通路，驱动分裂与修复。
EGFR：EGF样配体促进ISC增殖；破坏EGFR信号可抑制这种扩增。
JNK：在ISCs和ECs中由应激激活；在ECs中诱导Unpaireds和EGF配体，从而放大JAK/STAT和EGFR信号。
Wnt/Wg：维持ISC稳态与再生；Wg/Fz缺失会削弱自我更新。
Hedgehog：通过与其他通路的交叉作用促进损伤诱导的ISC增殖。
Hippo/Yki：在前体细胞中介导DSS诱导的ISC增殖；Yki活性增强Unpaireds和EGF配体的表达，形成对JAK/STAT和EGFR的正反馈。

这一网络解释了上皮如何尝试修复，同时也揭示信号失调如何导致病理变化。

微生物群–免疫相互作用

果蝇肠道的微生物多样性较低，通常为5–30种，以乳酸杆菌属和醋杆菌属为主。DSS会破坏这种平衡，通常表现为厚壁菌门增加，而变形菌门和放线菌门减少。先天免疫防御包括DUOX产生的活性氧以及由NF-κB通路（Toll和Imd）控制的抗菌肽。当在无菌果蝇中提供DSS时，关键的NF-κB转录因子Relish未被激活，说明菌群失调是该免疫激活环节所必需的。同时，一些保护性干预即使在无菌条件下也能减轻炎症，说明并非所有有益效应都依赖微生物群。阐明微生物依赖与非依赖机制的主导条件仍是重点研究方向。

潜在治疗物与机制

本综述按作用机制分类总结了天然产物，突出四个主题：

与炎症相关的通路

  • 经典多组分方剂通过抑制JAK/STAT减轻肠道损伤。

  • 刺五加多糖通过调节EGFR、JNK和Notch改善生存率，减少ISC过度增殖与异常分化。

  • 水飞蓟宾通过JNK抑制ISC过度生长。

  • 葛花提取物通过抑制JAK/STAT和Wnt发挥保护作用。

  • 总人参皂苷通过MAPK促进生存与修复。

  • 其他植物化合物，如熊果酸和藏红醛，通过作用于JNK、EGFR和JAK/STAT减轻ISC过度增殖。

氧化应激调控
过量的活性氧是模型中损伤的核心。抗氧化剂及内源防御增强剂可缓解损伤并恢复稳态。

微生物群调节
琼脂、壳寡糖及卡拉胶衍生物等寡糖和多糖可改善生理状态，同时调整微生物组成和免疫平衡。

自噬调控
部分化合物通过上调或下调自噬相关基因缓解损伤，为恢复上皮平衡提供途径。

在这些类别中，果蝇中观察到的诸多效应与哺乳动物模型和临床研究结果一致，支持利用果蝇筛选候选物并绘制作用机制图谱，再推进至高等生物验证。

对科研工作的实际启示

多维定量指标：DSS模型支持多维度分析，包括寿命、运动、进食、排泄、肠长、屏障完整性、铜细胞区酸碱平衡、ISC增殖和菌群组成。

信号通路锚定实验：JAK/STAT、EGFR、JNK、Wnt/Wg、Hedgehog和Hippo等信号的交汇提供了明确的遗传上位性与药物–基因相互作用研究切入点，聚焦于无异常增殖的再生机制。

转化筛选：在果蝇中具有明确作用机制的化合物可优先在高等生物中验证，尤其在已有一致性证据的情况下。

展望

开放性问题集中于微生物群–上皮界面的作用：菌群失调如何因果性地影响ISC行为与修复；有益菌群如何维持屏障功能；病原体又如何破坏免疫调控。老龄果蝇表现出屏障功能障碍和菌群失调，类似疾病状态，但将衰老相关变化直接等同于IBD仍需进一步研究。阐明这些关系有助于制定同时管理微生物群与精准控制炎症和再生信号的靶向干预策略。

关键信息

  • 炎症性肠病在全球范围内持续上升，仍难以治愈。

  • 黑腹果蝇提供了一个快速、伦理、遗传可操作的平台，用于研究肠道损伤、免疫与修复。

  • DSS及补充模型产生稳健、疾病相关的表型和可量化指标。

  • 以ISC为核心的信号网络（JAK/STAT、EGFR、JNK、Wnt/Wg、Hedgehog、Hippo）协调损伤反应。

  • 多种天然产物通过抗炎、抗氧化、调节菌群与自噬机制产生作用，为后续验证提供线索。

Reference:

Drosophila melanogaster models for investigating inflammatory bowel disease: Methods, pathology, mechanisms, and therapeutic approaches.

Biomol Biomed [Internet]. 2025 Jul. 1 [cited 2025 Oct. 20];26(2):186–199.

Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/12656

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Editor: Merima Hadžić

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