Natural Anthraquinone Emodin May Protect Immune and Gastrointestinal Health During Chemotherapy Treatment
Authors: Sougiannis Alexander T. , Vanderveen Brandon N. , Kelley Brittany , Enos Reilly T. , Velazquez Kandy T. , Chatzistamou Ioulia , Nagarkatti Mitzi , Fan Daping , Murphy E. Angela 
Published: April 2020

The clinical utility of 5‐fluorouracil (5FU) chemotherapy remains hampered by hematopoietic and gastrointestinal toxicities. Emodin, a natural anthraquinone, has been shown to have anti‐inflammatory potential and may be an effective complementary therapeutic. The purpose of this study was to investigate the ability of emodin to reduce non‐specific toxicities, especially inflammation, associated with 5FU treatment. We evaluated acute and chronic exposure to 5FU utilizing tumor‐free mice. In the chronic phase, we randomized male C57BL/6 mice into four groups; Control + Vehicle (n=10), Control + Emodin (n=10), 5FU + Vehicle (n=15), 5FU + Emodin (n=15). 5FU was administered via I.P. for 3 cycles (5 consecutive days of 5FU at 35mg/kg followed by 9 days of recovery). Emodin was administered via oral gavage 3x/week at 40mg/kg throughout the entire 3 cycles of 5FU treatment. 5FU + Emodin treated mice showed improved grip strength (p<0.05), run‐to‐fatigue time (p<0.05), and reduced sensitivity to peripheral nociception (p<0.05) compared to 5FU + Vehicle mice. Gene expression of the small intestine showed increased TNFα expression in 5FU + Vehicle treated mice which was decreased (p<0.05) with emodin treatment. 5FU + Emodin treated mice show decreased colonic NOS2 expression (p<0.05) but did not decrease MCP‐1, IL‐6, and TNFα expression compared to 5FU + Vehicle treated mice. To investigate the acute benefits of Emodin, male and female mice (n=125/sex) were randomized into four groups; 5FU + Vehicle, 5FU + 20mg/kg, 5FU + 40mg/kg, 5FU + 80mg/kg. Emodin treatment prevented body weight loss (p<0.05) during one cycle of 5FU and was able to prevent performance loss during run‐to‐fatigue (p<0.05). In male mice only, we observed a maintenance of the hematopoietic system, specifically in circulating lymphocytes, with increased emodin dosage (p<0.05). Complementary to this trend, we found that bone marrow cells of 5FU + Emodin treated mice had greater percentage of cells in S (p<0.05) and G2 (p<0.05) phases, compared to 5FU + Vehicle mice. Flow cytometric analysis of spleen, mesenteric lymph node, and colon lamina propria did not show differences in total macrophages or neutrophils. Gene expression analysis of the colon did not show significant differences between all groups. Chronic exposure to 5FU causes increased production of Muc5ac, an indication of dysplasia in the colon, which is ameliorated with complementary emodin. Despite this, we did not see decreased Muc5ac from emodin treatment acutely. However, utilizing 16S rRNA FISH, we can see that 5FU can cause pockets of mucus disruption, gut barrier damage, and alterations in bacterial spatial arrangement, all of which was mitigated with increased dosage of emodin treatment. Taken together, emodin treatment may contribute to improved GI health by reducing damaging inflammation which may improve overall quality of life. Future analysis will expand on the inflammatory signaling pathways involved in emodin signaling and will investigate the potential role of the gut microbiome in reducing GI inflammation in this model of 5FU treatment.Support or Funding Information(AT009964) (F31AT009820)