Abstract

We developed a prodrug type of curcumin, curcumin monoglucuronide (CMG), whose intravenous/intraperitoneal injection achieves a high serum concentration of free-form curcumin. Although curcumin has been reported to alter the gut microbiota and immune responses, it is unclear whether the altered microbiota could be associated with inflammation in immune-mediated diseases, such as multiple sclerosis (MS). We aimed to determine whether CMG administration could affect the 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 MS, experimental autoimmune encephalomyelitis (EAE). We injected EAE mice with CMG, harvested the brains and spinal cords for histological analyses, and conducted microbiome analyses using 16S rRNA sequencing. CMG administration modulated EAE clinically and histologically, and altered overall microbiota compositions 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 ileal contents, but not in feces, correlated with the clinical and histological EAE scores. On the other hand, when we analyzed the individual bacteria of the microbiota, the EAE scores correlated with significant increases in the relative abundance of two bacterial species at each anatomical site: Ruminococcus bromii and Blautia (Ruminococcus) gnavus in feces, Turicibacter sp. and Alistipes finegoldii in ileal contents, and Burkholderia spp. and Azoarcus spp. in the ileal mucosa. Therefore, CMG administration could alter the gut microbiota at the three different sites differentially in not only the overall gut microbiome compositions but also the abundance of individual bacteria, each of which was associated with modulation of neuroinflammation.

Highlights

  • Polyphenol curcumin is the principal active component of turmeric, Curcuma longa (Ozawa et al, 2017)

  • Fecal samples are widely used for microbiome studies as a representative of the gut microbiota throughout the GI tract (Durbán et al, 2011), the microbial compositions have been shown to be different depending on the anatomical sites (Durbán et al, 2011; Durbán et al, 2012; Dieterich et al, 2018; Lee et al, 2018)

  • Bacterial diversities have been reported to increase gradually along the GI tract (Lee et al, 2018) and differ between the GI lumen versus mucosa (Durbán et al, 2011; Durbán et al, 2012). Consistent with these findings, in the current study, we found that bacterial compositions in EAE mice differed among the three anatomical sites whose diversities were higher in feces than in ileum contents, and between ileal contents and the ileal mucosa

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Summary

Introduction

Polyphenol curcumin is the principal active component of turmeric, Curcuma longa (Ozawa et al, 2017). The oral administration of freeform curcumin did not provide the desired effects in clinical trials This can be explained by its rapid metabolism in the body; curcumin is metabolized to an inactive conjugated form after it is taken from the intestine (Asai and Miyazawa, 2000), only a free-form of curcumin is associated with the pharmacological activity. We demonstrated that intravenous CMG administration had an anticancer effect on mice transplanted with human colorectal cancer cells by achieving the blood concentration of free-form curcumin 1000-fold more than oral administration of curcumin (Ozawa et al, 2017). Intraperitoneal CMG administration had anti-tumor effects on oxaliplatinresistant colon cancer with less toxicity in mouse xenograft models (Ozawa-Umeta et al, 2020)

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