Zearalenone-14-glucoside specifically promotes dysplasia of Gut-Associated Lymphoid Tissue: A natural product for constructing intestinal nodular lymphatic hyperplasia model

[Display omitted] •Zearalenone-14-Glucoside (Z14G) was found for the first time to induce intestinal nodular lymphatic hyperplasia in rats within 14 days oral administration, indicating an ideal model drug.•Z14G hydrolyzes to Zearalenone (ZEN) in the intestine exerts toxicity by altering gut microbial abundance (e.g., increased Helicobacter, and decreased Prevotella) and perturbing the gut lipid-immune axis.•Z14G is hydrolyzed to ZEN by Bifidobacterium and Bacteroides which promotes co-trophic proliferation of Bifidobacterium and Bacteroides.•Hyperproliferative Bacteroides leads to inactivation of lectins when ZEN enters the gut, resulting in abnormal homing of lymphocytes and eventually dysplasia of gut-associated lymphoid tissue. Zearalenone-14-glucoside (Z14G) is a modified mycotoxin that widely contaminates food across the world. Our preliminary experiment showed that Z14G degrades to zearalenone (ZEN) in the intestine exerting toxicity. Notably, oral administration of Z14G in rats induces intestinal nodular lymphatic hyperplasia. To investigate the mechanism of Z14G intestinal toxicity and how it differs from ZEN toxicity. We conducted a precise toxicology study on the intestine of rats exposed to Z14G and ZEN using multi-omics technology. Rats were exposed to ZEN (5 mg/kg), Z14G-L (5 mg/kg), Z14G-H (10 mg/kg), and pseudo germ free (PGF)-Z14G-H (10 mg/kg) for 14 days. Histopathological studies were performed on intestines from each group and compared. Metagenomic, metabolomic, and proteomic analyses were performed on rat feces, serum, and intestines, respectively. Histopathological studies showed that Z14G exposure resulted in dysplasia of gut-associated lymphoid tissue (GALT) compared to ZEN exposure. The elimination of gut microbes in the PGF-Z14G-H group alleviated or eliminated Z14G-induced intestinal toxicity and GALT dysplasia. Metagenomic analysis revealed that Z14G exposure significantly promoted the proliferation of Bifidobacterium and Bacteroides compared to ZEN. Metabolomic analysis showed that Z14G exposure significantly reduced bile acid, while proteomic analysis found that Z14G exposure significantly reduced the expression of C-type lectins compared to ZEN. Our experimental results and previous research suggest that Z14G is hydrolyzed to ZEN by Bifidobacterium and Bacteroides promoting their co-trophic proliferation. This leads to inactivation of lectins by hyperproliferative Bacteroides when ZEN caused intestinal involvement, resulting