To further investigate the role of kidney damage in miRNA retention in the consuming animals, we treated mice with cisplatin, a platinum derivative and important chemotherapeutic agent7. A known effect of cisplatin administration is acute renal failure (ARF). Three days after cisplatin administration, kidney damage was confirmed by elevated blood urea nitrogen (BUN) levels resembling those of the most responsive honeysuckle-fed animals (data not shown). When we gavage-fed the cisplatin-treated mice with either honeysuckle decoction or honeysuckle decoction supplemented with MIR168a, these mice showed measurable levels of dietary miRNAs in their sera and urine, whereas untreated mice gavage-fed with the same cocktail did not display measurable levels of exogenous miRNAs (Figure 1E). Using a glycerol-induced model for ARF7, we obtained similar BUN levels, but were unable to detect exogenous dietary miRNAs in the sera of gavage-fed mice (Figure 1E and Supplementary information, Figure S1F). This suggests that kidney damage alone did not lead to enhanced miRNA retention in the mouse circulation. Microscopic investigation of the intestinal villi stained with hematoxylin and eosin (H&E) showed that cisplatin treatment, but not glycerol treatment or honeysuckle feeding, disrupted the organization of small intestine epithelial cells (Figure 1F). This suggests that, first, cisplatin promotes the elevation of blood dietary miRNA levels by modulating gut function and architecture, and second, long-term honeysuckle feeding potentiates absorption of dietary miRNA through a mechanism that likely differs from cisplatin treatment.

In summary, our work suggests that consumers of particular diets and/or with alterations in intestinal permeability have an improved capacity to absorb dietary small RNAs (Figure 1G). We hypothesize that the cisplatin experiments exemplify phenotypes that may occur during various disease states that cause “leaky gut”-type symptoms. Cisplatin does not exclusively damage cancer cells and has diverse side effects, including changes in the organization of the GI tract9. Our results suggest that altered or damaged guts resulting from illness and/or therapeutic treatments could enhance dietary RNA uptake.

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