Curcumin monoglucuronide (CMG) treatment differentially affects gut microbiota at three anatomical sites, modulating neuroinflammation

We developed a prodrug type of curcumin, curcumin monoglucuronide (CMG), whose injection achieves a high serum concentration of free-form curcumin. Although curcumin has been reported to potentially alter gut microbiota and immune responses, it is unclear whether the altered microbiota could be associated with inflammation in immune-mediated diseases. We aimed to determine the extent of which CMG treatment could affect gut microbiota at three anatomical sites (feces, ileal contents, and the ileal mucosa), leading to suppression of inflammation in the central nervous system (CNS) in an autoimmune model for multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). We treated EAE mice with CMG, harvested the CNS tissues for histological analyses, and conducted microbiome analyses using 16S rRNA sequencing. CMG treatment ameliorated EAE, clinically and histologically, and altered overall microbiota composition in feces and ileal contents, but not the ileal mucosa. Principal component analysis (PCA) of the microbiome showed that principal component (PC) 1 values in the ileal content, but not feces, were correlated with clinical and histological EAE scores. On the other hand, when we analyzed the individual bacteria of the microbiota, the EAE scores were correlated with significant increases in relative abundance of two bacterial species at each anatomical site. Therefore, CMG treatment could differentially alter gut microbiota at three different sites in not only overall gut microbiome compositions, but also abundance of individual bacteria, each of which associated with modulation of inflammation in the CNS.

本研究开发了一种姜黄素类前体药物——姜黄素单葡糖醛酸苷（curcumin monoglucuronide, CMG），其经注射给药后可获得高浓度的游离型姜黄素血清水平。尽管已有研究报道姜黄素可调控肠道菌群与免疫应答，但目前尚不明确菌群变化是否与免疫介导性疾病中的炎症反应存在关联。本研究旨在明确CMG给药可在粪便、回肠内容物及回肠黏膜三个解剖位点对肠道菌群产生的影响，及其在多发性硬化（multiple sclerosis, MS）自身免疫模型——实验性自身免疫性脑脊髓炎（experimental autoimmune encephalomyelitis, EAE）中对中枢神经系统（central nervous system, CNS）炎症的抑制作用。本研究对EAE小鼠给予CMG干预，采集中枢神经系统组织开展组织学分析，并采用16S rRNA测序技术进行微生物组分析。结果显示，CMG给药可在临床与组织学层面改善EAE病症，并改变粪便与回肠内容物的整体菌群组成，但对回肠黏膜菌群无显著影响。微生物组主成分分析（principal component analysis, PCA）结果表明，回肠内容物的主成分1（principal component 1, PC1）值与EAE的临床及组织学评分呈显著相关，而粪便菌群的PC1值则无此关联。另一方面，当对菌群中的单种细菌进行分析时，三个解剖位点中各有两种细菌的相对丰度显著升高，且该丰度变化与EAE评分呈显著相关。综上，CMG给药可在三个不同解剖位点对肠道菌群产生差异化调控作用：不仅改变整体肠道微生物组组成，还影响单种细菌的丰度，且各类细菌的丰度变化均与中枢神经系统炎症的调控存在关联。