Microcystis toxin-mediated tumor promotion and toxicity lead to shifts in mouse gut microbiome

Lee, Ji-Young; Lee, Seungjun; Mayta, Alba; Mrdjen, Igor; Weghorst, Christopher M.; Knobloch, Thomas J.

doi:10.1016/j.ecoenv.2020.111204

Cited by 18 publications

(11 citation statements)

References 32 publications

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“…Cyanotoxins have a primordial position among the diverse environmental toxins studied due to the increasing exposures among humans and animals. Although MC-LR has prominent adverse effects on various organ systems including the liver, kidney, intestines, MC-LR exposure can also mediate significant changes to the host's gut microbiome as observed by previous studies including our group 25,29,93,94 . We have shown previously that MC-LR treatment led to altered microbiome pattern 25 , resulting in increased lactate-producing bacteria in the gut microenvironment with elevated intestinal and serum lactate levels, which ultimately led to NADP Oxidase 2-dependent activation of TGFβ-mediated Smad2/3-Smad4 fibrotic pathway activation in the intestines of adult mice 26 .…”

Section: Discussionsupporting

confidence: 58%

“…Previous studies by our research group and several others have reported that exposure to MC significantly altered gut bacteriome in experimental murine models 25,28,29 . Gut dysbiosis affects the host health by exacerbating the pathological outcomes in gastrointestinal disorders, liver diseases, and metabolic conditions like obesity and diabetes and increases the risk of anti-microbial resistance, which has been a global health concern 30,31 .…”

Section: Introductionmentioning

confidence: 64%

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Prior exposure to microcystin alters host gut resistome and is associated with dysregulated immune homeostasis in translatable mouse models

Saha

Bose

Stebliankin

et al. 2021

Preprint

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The increased propensity of harmful algal blooms (HABs) and exposure from HABs-cyanotoxin causes human toxicity. It has been associated with the progression of several diseases that encompass the liver, kidneys, and immune system. Recently, a strong association of cyano-HAB toxicity with the altered host gut microbiome has been shown. We tested the hypothesis that prior exposure to cyanotoxin microcystin may alter the microbiome and induce microbiome-host-resistome crosstalk. Using both wild-type and humanized mice, we show that the mice exposed to microcystin had an altered microbiome signature that harbored antimicrobial resistance genes. Host resistome phenotypes such as mefA, msrD, mel, ant6, and tet40 increased in diversity and relative abundance following microcystin exposure. Interestingly, the increased abundance of these genes was traced to resistance to common antibiotics such as tetracycline, macrolides, glycopeptide, and aminoglycosides, crucial for modern-day treatment for several diseases. Increased abundance of these genes was positively associated with increased expression of PD1, a T-cell homeostasis marker, and pleiotropic inflammatory cytokine IL-6 with a concomitant negative association with immunosurveillance markers IL7 and TLR2. Microcystin exposure also caused decreased TLR2, TLR4, and REG3G expressions, increased immunosenescence, and higher systemic levels of IL-6 in both wild-type and humanized mice. In conclusion, the results show a first-ever characterization of the host resistome of microcystin exposure and its connection to host immune status and antibiotic resistance. The results may be crucial for understanding the ability of exposed subjects to fight future bacterial infections and the progression of the debilitating disease in hospital settings.

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Section: Discussionsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 64%

Prior exposure to microcystin alters host gut resistome and is associated with dysregulated immune homeostasis in translatable mouse models

Saha

Bose

Stebliankin

et al. 2021

Preprint

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“…Among plants that treat water from Lake Erie and other locations in Ohio and neighboring states for consumption, the maximum microcystin concentration detected in finished drinking water was ~10 μg/L at the Celina plant [31] . Based on that finding, the rats were non-invasively exposed to an environmentally appropriate concentration of microcystin-LR (10 μg/L) in drinking water provided ad libitum for 7 weeks as described [32] . None of the rats died; and initial and final body weight as well as total food intake at 7 weeks did not significantly differ between the exposed and control groups ( Table 3 ).…”

Section: Resultsmentioning

confidence: 99%

Microcystin-LR incorporated into colonic cells through probenecid-sensitive transporters leads to upregulated MCP-1 expression induced by JNK activation

et al. 2022

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“…In our current study, we successfully demonstrated a histopathologic promotion of hepatocellular lesions toward a more malignant phenotype (hepatocellular carcinoma in the Microcystis lysate exposure group). When combined with increased mortality rates due to M. aeruginosa lysate consumption and our previous findings detailing shifts in gut microbiome communities, considerable health status impacts could be associated with low-concentration chronic cyanobacterial and cyanotoxin ingestion [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…The Microcystis aeruginosa cultivation, animal husbandry, and experimental conditions for the current study are outlined in our previous publication [ 34 ]. Briefly, purified MC-LR (99%) was obtained from a commercial supplier (Beagle Bioproducts, Columbus, OH, USA), while M. aeruginosa were cultured, removed from suspension via centrifugation, and lysed to create a concentrated whole cell lysate.…”

Section: Methodsmentioning

confidence: 99%

Impact of Cyanotoxin Ingestion on Liver Cancer Development Using an At-Risk Two-Staged Model of Mouse Hepatocarcinogenesis

Mrdjen

Lee

Weghorst

et al. 2022

Toxins

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Exposure to cyanobacterial hepatotoxins has been linked to the promotion and increased incidence of liver cancer in pre-clinical and epidemiologic studies. The family of hepatotoxins, microcystins (MCs), are produced by over 40 cyanobacterial species found in harmful algal blooms (HABs) worldwide, with MC-LR being the most common and potent MC congener. In the current study, we hypothesized that the low-dose chronic ingestion of Microcystis cyanotoxins via drinking water would promote liver carcinogenesis in pre-initiated mice. Four groups of C3H/HeJ mice received one intraperitoneal (i.p.) injection of diethylnitrosamine (DEN) at 4 weeks of age. Three weeks later, the mice were administered ad libitum drinking water containing one of the following: (1) reverse osmosis, deionized water; (2) water containing 500 mg/L phenobarbital (PB500); (3) water with purified MC-LR (10 µg/L) added; or (4) water containing lysed Microcystis aeruginosa (lysate; 10 µg/L total MCs). The exposure concentrations were based on environmentally relevant concentrations and previously established Ohio EPA recreational water MC guidelines. Throughout the 30-week exposure, mouse weights, food consumption, and water consumption were not significantly impacted by toxin ingestion. We found no significant differences in the number of gross and histopathologic liver lesion counts across the treatment groups, but we did note that the PB500 group developed lesion densities too numerous to count. Additionally, the proportion of lesions classified as hepatocellular carcinomas in the MC-LR group (44.5%; p < 0.05) and lysate group (55%; p < 0.01) was significantly higher compared to the control group (14.9%). Over the course of the study, the mice ingesting the lysate also had a significantly lower survival probability (64.4%; p < 0.001) compared to water (96.8%), PB500 (95.0%), and MC-LR (95.7%) exposures. Using cyanotoxin levels at common recreational water concentration levels, we demonstrate the cancer-promoting effects of a single cyanotoxin MC congener (MC-LR). Furthermore, we show enhanced hepatocarcinogenesis and significant mortality associated with combinatorial exposure to the multiple MCs and bioactive compounds present in lysed cyanobacterial cells—a scenario representative of the ingestion exposure route, such as HAB-contaminated water and food.

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Microcystis toxin-mediated tumor promotion and toxicity lead to shifts in mouse gut microbiome

Cited by 18 publications

References 32 publications

Prior exposure to microcystin alters host gut resistome and is associated with dysregulated immune homeostasis in translatable mouse models

Prior exposure to microcystin alters host gut resistome and is associated with dysregulated immune homeostasis in translatable mouse models

Microcystin-LR incorporated into colonic cells through probenecid-sensitive transporters leads to upregulated MCP-1 expression induced by JNK activation

Impact of Cyanotoxin Ingestion on Liver Cancer Development Using an At-Risk Two-Staged Model of Mouse Hepatocarcinogenesis

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