Prolonged oral antimicrobial administration prevents doxorubicin-induced loss of active intestinal stem cells

Abstract

Acute intestinal mucositis is a common off-target effect of chemotherapy, leading to co-morbidities such as vomiting, diarrhea, sepsis, and death. We previously demonstrated that the presence of enteric bacteria modulates the extent of jejunal epithelial damage induced by doxorubicin (DXR) in mice. Despite conventional thinking of the crypt as a sterile environment, recent evidence suggests that bacterial signaling influences aISC function. In this study, we labeled aISCs using transgenic Lgr5 -driven fluorescence or with immunostaining for OLFM4. We examined the effect of DXR in both germ free (GF) mice and mice depleted of microbiota using an established antimicrobial treatment protocol (AMBx). We found differences in DXR-induced loss of aISCs between GF mice and mice treated with AMBx. aISCs were decreased after DXR in GF mice, whereas AMBx mice retained aISC expression after DXR. Neither group of mice exhibited an inflammatory response to DXR, suggesting the difference in aISC retention was not due to differences in local tissue inflammation. Therefore, we suspected that there was a protective microbial signal present in the AMBx mice that was not present in the GF mice. 16S rRNA sequencing of jejunal luminal contents demonstrated that AMBx altered the fecal and jejunal microbiota. In the jejunal contents, AMBx mice had increased abundance of Ureaplasma and Burkholderia . These results suggest pro-survival signaling from microbiota in AMBx-treated mice to the aISCs, and that this signaling maintains aISCs in the face of chemotherapeutic injury. Manipulation of the enteric microbiota presents a therapeutic target for reducing the severity of chemotherapy-associated mucositis.

Experimental Chemotherapy-Induced Mucositis: A Scoping Review Guiding the Design of Suitable Preclinical Models

“…Doxorubicin: a mouse model was used in 10 publications [ 12 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 ], with a dosage ranging from 10 to 20 mg/kg intraperitoneally. Two articles documented the use of a rat model with a dosage of 20 mg/kg i.p.…”

From birth to death: The hardworking life of Paneth cell in the small intestine

“…Chemotherapy such as 5-fluorouracil and doxorubicin (Dox) treatments can induce intestinal bacterial translocation and the apoptosis of PCs and ISCs in mice (125). Antimicrobial administration rescues Dox-induced ISC loss (126), implying that sterile crypts protect ISCs from excessive apoptosis. Based on these findings, it could be speculated that PC disruption-mediated bacterial colonization in crypts might bring about ISC apoptosis and loss.…”

The Link Between the Microbiota and HER2+ Breast Cancer: The New Challenge of Precision Medicine

“…Methotrexate bioavailability is reduced by its conversion into a downstream metabolite by bacteria (75) whereas doxorubicin can be inactivated by The microbiota is also critical in mediating chemotherapeutic toxicity. For instance, doxorubicin-induced intestinal injury and cardiac dysfunction are associated with an imbalance in the microbiome (90,91), whereas treatment with taxanes and antimicrotubule agents decrease the abundance of A. muciniphila and consequently disrupt gut barrier integrity, resulting in enhanced neuropathy and altered brain function (92). Also, the toxicity of methotrexate is influenced by the gut microbiota's immunomodulatory properties: gut microbes alleviate chemotherapy-induced small intestinal injury through the regulation of the multidrug transporter ABCB1/MDR1 p-gp…”