Curcumin prodrug CMG has beneficial effects on a mouse model of multiple sclerosis by modulating the gut flora

Curcumin well-known as “a major component of curry” is a polyphenol derived from turmeric, Curcuma longa. The Department of Microbiology, Kindai University Faculty of Medicine (Professor Ikuo Tsunoda), demonstrated the benefits of curcumin monoglucuronide (CMG) treatment in an autoimmune model of multiple sclerosis with changes of the gut flora. This work was conducted by Sundar Khadka, M.S. and Seiichi Omura, Ph.D. collaborating with Graduate School of Pharmaceutical Sciences, Kyoto University (Professor Hideaki Kakeya).
This paper was published online in Frontiers in Immunology on December 3rd, 2021 (JST).
URL： https://www.frontiersin.org/articles/10.3389/fcimb.2021.772962/full

1. Highlights of Study
● CMG treatment for a mouse model of multiple sclerosis (MS) suppressed motor paralysis clinically and inflammation in the central nervous system (CNS) microscopically.
● CMG treatment altered the gut flora in the intestine and feces.
● Increases in several bacterial species correlated with the disease severity.

2. Research Background
Curcumin has multiple functions, including antioxidant, antitumor, and anti-inflammation; curcumin has been suggested to be beneficial in several disease conditions, including cardiovascular diseases, cancers, and inflammatory diseases. In the clinical trials, however, oral administration of free-form curcumin did not provide the desired effects. This can be explained by its rapid metabolism in the body. Curcumin is metabolized to an inactive form after it is taken from the intestine, although only the free-form of curcumin has pharmacological activities. In addition, the bioavailability of curcumin within the body is low due to the poor absorption from the intestine, insolubility in body fluids, and rapid elimination and clearance from the body. In the previous study, the research team developed a prodrug type of curcumin, curcumin monoglucuronide (CMG), and found that intravenous/intraperitoneal CMG injection achieved a high serum concentration of free-form curcumin.

3. Summary of the Research
Curcumin has been reported to alter the gut flora and immune responses potentially. The purpose of this study was to determine if CMG treatment could 1) affect the gut flora at three different locations (feces, intestinal contents, and the intestinal mucosa), and 2) suppress inflammation in the central nervous system (CNS) using an autoimmune model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). The research team treated EAE mice with CMG and analyzed the gut flora using a molecular biological method called “16S rRNA sequencing”. CMG treatment ameliorated EAE and altered the overall gut flora compositions in feces and intestinal contents, but not the intestinal mucosa. Computational analyses of the gut flora showed that the altered gut flora in intestinal contents, but not in feces, correlated with the reduced disease scores. The research team also found that the disease severities correlated with significant increases in certain gut bacterial species, for example, Turicibacter sp. and Alistipes finegoldii in intestinal contents. Therefore, CMG treatment altered the gut flora which was associated with the amelioration of EAE. These findings will give insights into the development of novel drugs for inflammatory CNS diseases, including multiple sclerosis.

4. About Publication
Research paper title: Curcumin monoglucuronide (CMG) treatment differentially affects the gut microbiota at three anatomical sites, modulating neuroinflammation
Journal name: Frontiers in Immunology (IF: 5.085)
Authors: Sundar Khadka1,*, Seiichi Omura1,*, Fumitaka Sato1,*, Kazuto Nishio2, Hideaki Kakeya3, Ikuo Tsunoda1
Departments of 1Microbiology and 2Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan
3Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
*These authors contributed equally.

5. Profiles of Researchers
Name: Sundar Khadka, M.S. (Graduate Student)
Affiliation: Dept. Microbiology, Kindai University Faculty of Medicine
Specialty: Neuroimmunology, Neurovirology, Bioinformatics

Name: Seiichi Omura, Ph.D. (Associate Professor)
Affiliation: Dept. Microbiology, Kindai University Faculty of Medicine
Specialty: Neuroimmunology, Microbiota, Bioinformatics
Awards: Award for Best Abstract-Poster, the 6th International Society for Neurovascular Disease Meeting
Travel Grant, the 55th Annual Meeting of the Japanese Society of Neurology
Medical Virology Club Travel Grant, the 32nd American Society for Virology Annual Meeting