Good Bug, Bad Bug: Breaking through Microbial Stereotypes

Cirstea, Mihai; Radisavljevic, Nina; Finlay, B. Brett

doi:10.1016/j.chom.2017.12.008

Cited by 63 publications

(67 citation statements)

References 14 publications

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“…Thus, in our study, the intestinal bacteria structures between groups were further evaluated. The overall structure of the gut microbiota in CTX-treated 4T1-bearing mice was significantly changed, which was consistent to CTX-treated normal and pathological animals in previous studies [ properties, has been proposed as the gatekeeper of our mucosa promoting immune responses and beneficial interactions in the intestinal tract [53], however, in our study, Akkermansia is not the key factor to alleviate the intestinal mucositis. Previous studies have indicated that Akkermansia has an active cross-talk with host cells [54] and thus mediate many acute and chronic diseases [55,56].…”

Section: Discussionsupporting

confidence: 90%

Ginsenosides facilitate the anti-cancer efficacy of cyclophosphamide via modulating intestinal bacteria and alleviating intestinal mucositis in mammary carcinoma mice

Zhou

et al. 2019

Preprint

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Background: Ginsenosides has been reported to facilitate the chemotherapy of cyclophosphamide (CTX), but the underlying mechanism is still elusive. Here, ICR mice bearing subcutaneous 4T1 tumor (mouse mammary carcinoma cells) were used to investigate the enhanced chemotherapeutic effects and underlying the mechanism of concurrent administration of ginsenosides and CTX. Results: Combinational treatment with ginsenosides in mice enhanced the anti-cancer efficacy of CTX as observed by elevated tumor growth inhibition rate, prolonged survival rate, decreased tumor burden and increased apoptosis in tumor tissues. The mechanism underlying the enhancing effects involved the elevation of the anti-cancer immunity, which manifested as accelerating anti-cancer cytokines (IL-2, IL-6, IL-17, TNF-α and INF-γ) that was further ascribed to the ginsenosides-induced generation of intestinal probiotics including Bifidobacterium, Akkermansia and Lactobacillus. Moreover, through activating Nrf2 and inhibiting NFκB pathways, ginsenosides reversed CTX-induced intestinal mucositis by maintaining normal intestinal permeability and junction proteins function. Conclusion: Ginsenosides ameliorate CTX-induced intestinal mucositis and promote anti-cancer immunity via maintaining intestinal homeostasis, consequently enhancing the anti-cancer efficacy of CTX.

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Section: Discussionsupporting

confidence: 90%

Ginsenosides facilitate the anti-cancer efficacy of cyclophosphamide via modulating intestinal bacteria and alleviating intestinal mucositis in mammary carcinoma mice

Zhou

et al. 2019

Preprint

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“…5B). The increase in levels of Verrucomicrobia, which do not encode L1 GUS enzymes, is associated with a significant increase in Akkermansia muciniphila, a microbe that is typically linked with a healthy gut and the processing of host mucins (32,33). These first data on the effects of gut microbial GUS inhibitor on the GI microbiota composition reveal differential effects depending on the immune function of the mouse model used.…”

Section: Gus Inhibition Does Not Alter Gut Microbial Composition In Thementioning

confidence: 91%

Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy

Bhatt

Pellock

Biernat

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

142

104

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Irinotecan treats a range of solid tumors, but its effectiveness is severely limited by gastrointestinal (GI) tract toxicity caused by gut bacterial β-glucuronidase (GUS) enzymes. Targeted bacterial GUS inhibitors have been shown to partially alleviate irinotecan-induced GI tract damage and resultant diarrhea in mice. Here, we unravel the mechanistic basis for GI protection by gut microbial GUS inhibitors using in vivo models. We use in vitro, in fimo, and in vivo models to determine whether GUS inhibition alters the anticancer efficacy of irinotecan. We demonstrate that a single dose of irinotecan increases GI bacterial GUS activity in 1 d and reduces intestinal epithelial cell proliferation in 5 d, both blocked by a single dose of a GUS inhibitor. In a tumor xenograft model, GUS inhibition prevents intestinal toxicity and maintains the antitumor efficacy of irinotecan. Remarkably, GUS inhibitor also effectively blocks the striking irinotecan-induced bloom of Enterobacteriaceae in immunedeficient mice. In a genetically engineered mouse model of cancer, GUS inhibition alleviates gut damage, improves survival, and does not alter gut microbial composition; however, by allowing dose intensification, it dramatically improves irinotecan's effectiveness, reducing tumors to a fraction of that achieved by irinotecan alone, while simultaneously promoting epithelial regeneration. These results indicate that targeted gut microbial enzyme inhibitors can improve cancer chemotherapeutic outcomes by protecting the gut epithelium from microbial dysbiosis and proliferative crypt damage. microbiome | chemotherapy | cancer | gastrointestinal toxicity I rinotecan (CPT-11) is essential for treating colorectal and pancreatic cancers and is frequently administered as a mixture with 5-fluorouracil and/or oxaliplatin. Ongoing clinical trials seek to extend irinotecan to other forms of cancer. However, irinotecan causes both myelosuppression and gastrointestinal (GI) side effects, including mucositis and late-onset diarrhea, which are often dose limiting: 88% of irinotecan patients develop diarrhea, with 30% experiencing acute grade 3 to 4 diarrhea (1-3). This toxicity is frequently refractory to antimotility drugs. Thus, treating irinotecaninduced diarrhea is a significant clinical need (4, 5).The irinotecan prodrug is activated in vivo to SN38, a potent topoisomerase I inhibitor (6) that retards the growth of rapidly proliferating cells in tumors and the intestinal epithelium, which renews every 5 d. SN38 is detoxified through the addition of glucuronic acid (GlcA) to form SN38-G, a compound marked for elimination via the GI tract. Gut commensal bacterial β-glucuronidase (GUS) proteins remove GlcA from SN38-G. Reactivated SN38 inflicts epithelial damage, resulting in bleeding diarrhea and acute weight loss in animal models (7). We reduced irinotecan-induced gut toxicity using inhibitors that selectively, nonlethally, and potently block the actions of gut bacterial GUS enzymes (8,9). The utility of GUS inhibition also extends to drugs be...

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“…Most of this research has focused on microbiomes of the human body and, although there is still much uncertainty about what constitutes a "normal" or "healthy" human microbiome, microbial "dysbiosis" has already been implicated in a range of non-communicable diseases. This research is also challenging the common understandings of pathogens and the beneficial role of bacteria for human health [1], and increases awareness of how hygiene and antibiotics impact early-life microbial colonisation and exposure, and their effects on human health and development [2]. There is both public health and commercial interest in translating this research that might lead to probiotic applications to improve human and animal health, domestic hygiene, waste management and agricultural productivity, amongst other potential benefits.…”

mentioning

confidence: 99%