Intestinal bacteria are necessary for doxorubicin-induced intestinal damage but not for doxorubicin-induced apoptosis

Abstract

(2016) Intestinal bacteria are necessary for doxorubicin-induced intestinal damage but not for doxorubicin-induced apoptosis, Gut Microbes, 7:5, 414-423, DOI: 10.1080/19490976.2016 To link to this article: https://doi.org/10. 1080/19490976.2016 ABSTRACT Doxorubicin (DOXO) induces significant, but transient, increases in apoptosis in the stem cell zone of the jejunum, followed by mucosal damage involving a decrease in crypt proliferation, crypt number, and villus height. The gastrointestinal tract is home to a vast population of commensal bacteria and numerous studies have demonstrated a symbiotic relationship between intestinal bacteria and intestinal epithelial cells (IEC) in maintaining homeostatic functions of the intestine. However, whether enteric bacteria play a role in DOXO-induced damage is not well understood. We hypothesized that enteric bacteria are necessary for induction of apoptosis and damage associated with DOXO treatment. Conventionally raised (CONV) and germ free (GF) mice were given a single injection of DOXO, and intestinal tissue was collected at 6, 72, and 120 h after treatment and from no treatment (0 h) controls. Histology and morphometric analyses quantified apoptosis, mitosis, crypt depth, villus height, and crypt density. Immunostaining for muc2 and lysozyme evaluated Paneth cells, goblet cells or dual stained intermediate cells. DOXO administration induced significant increases in apoptosis in jejunal epithelium regardless of the presence of enteric bacteria; however, the resulting injury, as demonstrated by statistically significant changes in crypt depth, crypt number, and proliferative cell number, was dependent upon the presence of enteric bacteria. Furthermore, we observed expansion of Paneth and goblet cells and presence of intermediate cells only in CONV and not GF mice. These findings provide evidence that manipulation and/or depletion of the enteric microbiota may have clinical significance in limiting chemotherapy-induced mucositis.

The role of the microbiome in cancer development and therapy

“…Other chemotherapeutic agents also have adverse effects in the GI tract. For example, doxorubicin is similar to irinotecan in that GI damage requires microbiota 125 . These findings suggest that targeting microbiota may diminish the toxicity of multiple chemotherapeutics.…”

Gut microbiota‐immune‐brain interactions in chemotherapy‐associated behavioral comorbidities

“…42 This field would benefit from further research characterizing the effects of chemotherapeutic drugs on the intestinal microbiota and determining how chemotherapy-associated microbial changes alter the structure and function of the intestines and CNS.…”

Emerging Insights on the Interaction Between Anticancer and Immunosuppressant Drugs and Intestinal Microbiota in Pediatric Patients

“…The involvement of gut microbiota in modulating doxorubicin toxicity at the intestinal level has long been known and was mainly ascribed to an increase of epithelial permeability, as described above. However, the different effects exerted by gut bacteria at different levels of the intestinal tracts remained unexplained: apparently protective for the colonic epithelium, damaging for the small intestine . The identification of some doxorubicin inactivating enzymes produced by different bacterial species recently helped to explain this difference.…”

“…20 Doxorubicin-induced cytotoxicity within the gastrointestinal tract manifests as an increase in apoptosis in the stem cell zone of the jejunum and as mucosal damage, including a decrease in crypt number and villus height. Recently, Rigby et al 21 demonstrated that mucosal damage is dependent on enteric bacteria. The authors observed that doxorubicin chemotherapy caused similar levels of apoptosis in both conventionally raised and germ-free (GF) mice's small intestine but alterations in crypt depth and number were observed only in conventionally raised mice, suggesting that the presence of enteric bacteria could cause an increase of epithelial barrier permeability due to their translocation.…”

“…The authors observed that doxorubicin chemotherapy caused similar levels of apoptosis in both conventionally raised and germ-free (GF) mice's small intestine but alterations in crypt depth and number were observed only in conventionally raised mice, suggesting that the presence of enteric bacteria could cause an increase of epithelial barrier permeability due to their translocation. 21 Gut epithelial barrier alterations are characterized by shortening of small intestinal villi, interstitial edema, epithelial discontinuities, and focal invasion of mononuclear cells in lamina propria after therapy with both doxorubicin and cyclophosphamide. 22 Several studies on mouse models validated the role of the chemotherapeutic agent cyclophosphamide in increasing intestinal permeability and in the resulting bacterial translocation.…”