Exposure to the Harmful Algal Bloom (HAB) Toxin Microcystin-LR (MC-LR) Prolongs and Increases Severity of Dextran Sulfate Sodium (DSS)-Induced Colitis

Abstract

Inflammatory Bowel Disease (IBD) represents a collection of gastrointestinal disorders resulting from genetic and environmental factors. Microcystin-leucine arginine (MC-LR) is a toxin produced by cyanobacteria during algal blooms and demonstrates bioaccumulation in the intestinal tract following ingestion. Little is known about the impact of MC-LR ingestion in individuals with IBD. In this study, we sought to investigate MC-LR’s effects in a dextran sulfate sodium (DSS)-induced colitis model. Mice were separated into four groups: (a) water only (control), (b) DSS followed by water (DSS), (c) water followed by MC-LR (MC-LR), and (d) DSS followed by MC-LR (DSS + MC-LR). DSS resulted in weight loss, splenomegaly, and severe colitis marked by transmural acute inflammation, ulceration, shortened colon length, and bloody stools. DSS + MC-LR mice experienced prolonged weight loss and bloody stools, increased ulceration of colonic mucosa, and shorter colon length as compared with DSS mice. DSS + MC-LR also resulted in greater increases in pro-inflammatory transcripts within colonic tissue (TNF-α, IL-1β, CD40, MCP-1) and the pro-fibrotic marker, PAI-1, as compared to DSS-only ingestion. These findings demonstrate that MC-LR exposure not only prolongs, but also worsens the severity of pre-existing colitis, strengthening evidence of MC-LR as an under-recognized environmental toxin in vulnerable populations, such as those with IBD.

CD40 Receptor Knockout Protects against Microcystin-LR (MC-LR) Prolongation and Exacerbation of Dextran Sulfate Sodium (DSS)-Induced Colitis

“…One of the most notable findings we observed from our previous study was that the CD40 receptor was significantly upregulated in the colons of mice with pre-existing colitis that were exposed to MC-LR [23]. Furthermore, we found that downstream products of CD40 activation, monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1), were also upregulated in the same group [23]. Because CD40 is a prominent immunomodulatory receptor found on antigen-presenting immune cells and has recently been extensively linked to IBD pathogenesis [24,25], we hypothesized that CD40 might play a key role in mediating MC-LR induced exacerbation of IBD.…”

“…We have recently reported the first investigation studying the effects of MC-LR within the intestines in both healthy settings and in the setting of pre-existing IBD, as MC-LR is one of the several potential environmental factors that have not been studied in the setting of IBD [23]. We observed that MC-LR has limited effects within the intestines of healthy C57BL/6 mice, yet had significant toxicity within the intestines of C57BL/6 mice with pre-existing colitis as induced by dextran sulfate sodium (DSS) [23]. One of the most notable findings we observed from our previous study was that the CD40 receptor was significantly upregulated in the colons of mice with pre-existing colitis that were exposed to MC-LR [23].…”

“…We observed that MC-LR has limited effects within the intestines of healthy C57BL/6 mice, yet had significant toxicity within the intestines of C57BL/6 mice with pre-existing colitis as induced by dextran sulfate sodium (DSS) [23]. One of the most notable findings we observed from our previous study was that the CD40 receptor was significantly upregulated in the colons of mice with pre-existing colitis that were exposed to MC-LR [23]. Furthermore, we found that downstream products of CD40 activation, monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1), were also upregulated in the same group [23].…”

Synergistic Effect of MC-LR and C-Terminal Truncated HBx on HepG2 Cells and Their Effects on PP2A Mediated Downstream Target of MAPK Signaling Pathway

“…The toxic effects of MC-LR shows obvious organ selectivity, with the liver being the primary target organ (Su et al, 2019). According to research reports, long-term exposure to MC-LR can induce human hepatitis and HCC (Ma et al, 2018a).…”

Freshwater Algal Toxins: Monitoring and Toxicity Profile

“…Finally, two articles pointed out that MC-LR exacerbated the severity of illnesses such as non-alcoholic fatty liver disease [ 10 ] and dextran sulfate sodium (DSS)-induced colitis [ 11 ] in animal models. This is an important aspect, as the exposure to MC-LR, even at levels that are below the no observed adverse effect level (NOAEL) established in healthy animals, can worsen pre-existing pathologies.…”