Harmful algal bloom (HAB) incidence has been increasing over the past decades, particularly in various inland lakes and rivers in the United States. Human activities such as wastewater discharge and fertilizer, pesticide and urban water runoff into water bodies leads to algal proliferation and HABs. HABs secrete diverse cyanotoxins as secondary metabolites which may come into contact with humans through ingestion of contaminated water or food, inhalation, and dermal contact while swimming. There is a vast number of different HAB-secreted cyanotoxins and microcystins (MC) are the most prevalent and well-studied. MC are known to cause multiple adverse effects in the murine model, including hepatic inflammation and fibrosis, altered glucose metabolism, hyperinsulinemia, insulin resistance, renal toxicity, blood-brain barrier dysfunction, and neuronal apopotosis. In addition, microbiome dysbiosis due to MC is well documented, but resistome dynamics remained understudied. Given the contribution of pesticides, insecticides and heavy metal accumulation in water to rising antimicrobial resistance (AMR) in aquatic ecosystems, and those factors also driving HAB, Saha et al. hypothesized that HABs may be AMR reservoirs. Further, they may pose a risk to humans through direct exposure and within the food chain. To investigate MC effects on the gut resistome and immunity, the research group dosed wild type (WT) and humanized NSG™ mice (engrafted with CD34+ hematopoietic stem cells) with MC and compared their microbiome, resistome, overall gene expression and interleukin-6 (IL-6) levels. Comparing the bacteriomes of MC-exposed and -free mice on the CosmosID-HUB microbiome illustrated a significant decrease of Bacteroidetes and Proteobacteria, and an increase of Actinobacteria and Verrucomicrobia in MC-exposed mice. At species-level resolution, the exposed cohort showed a marked decrease of gut commensals Akkermansia muciniphilia, Lactobacillus johnsonii and Lactobacillus lactis, while Bacteroides thetaiotaomicron, which is an opportunistic pathogen, increased. According to the findings on the HUB, bacteriome dysbiosis was accompanied by resistome variation. MC-exposed mice harbored 22 unique AMR genes while MC-free mice harbored 17. Furthermore, MC-exposed mice were found to be significantly more AMR gene rich and even than MC-free mice using both Simpson’s and Shannon’s Indexes. Performing a principal coordinates analysis over the Bray-Curtis dissimilarity matrix of AMR genes in the two mouse cohorts illustrated clear divergence of MC-exposed and MC-free mice in AMR gene composition. In addition to shifts in the bacteriome and resistome, MC exposure also showed an impact on the host immune system. MC-exposed mice showed marked decreases in TLR2, TLR4, and REG3G expression, as well as increased IL-6 levels. Altogether, the findings of the study illustrate the complex interplay between the host bacteriome, resistome and immunity, which could lead to insights that aid in treating microcystin exposure in clinical settings.
Saha et al. 2022. Prior exposure to microcystin alters host gut resistome and is associated with dysregulated immune homeostasis in translatable mouse models.