Abstract
Worldwide the incidence of cancer has been continuing increasing. Mucositis of the gastrointestinal tract is a common side effect in patients under chemotherapy. Anticancer drug busulfan, used for treating chronic myeloid leukemia especially in pediatric patients, causes mucositis of the gastrointestinal tract. Alginate oligosaccharides (AOS) are natural products with attractive pharmaceutical potentials. We aimed to investigate, at the single-cell level, AOS preventing small intestine mucositis induced by busulfan. We found that busulfan disturbed the endoplasmic reticulum and mitochondria of cells in the small intestine, damaged cell membranes especially cell junctions, and disrupted microvilli; all of which were rescued by AOS. Single-cell RNA sequencing analysis and functional enrichment analysis showed that AOS could recover small intestinal function. Deep analysis found that AOS improved the expression of transcriptional factors which explained AOS regulating gene expression to improve small intestine function. Further investigation in IPEC-J2 cells found that AOS acts its function through mannose receptor signaling pathway. Moreover, the improved blood metabolome confirmed small intestinal function was recovered by AOS. As a natural product with many advantages, AOS could be developed to assist in the recovery of intestinal functions in patients undergoing anticancer chemotherapy or other treatments.
Highlights
The incidence of cancer has been continuing increasing worldwide.[1,2,3,4] Many investigations have reported that mucositis of the gastrointestinal (GI) tract is a common side effect and occurs in ~40% of cancer patients under chemotherapy.[1,2,3,4] Intestinal mucositis is characterized by decreased villi length, and disruption of crypt cell homeostasis and tight junction proteins in the small intestinal mucosa.[2,4] The epithelium of the mammalian small intestine is a highly ordered and structured tissue with repeated crypt-villus units along the axis
We found that some transcription factors such as GATA4 and HMGB1 were decreased by busulfan, while they were increased by Alginate oligosaccharides (AOS) (B + A 10)
Our findings showed that busulfan increased some of the metabolites while they were decreased by AOS (B + A 10) (Fig. 8c); alternately, some metabolites were decreased by busulfan while they were increased by AOS (B + A 10; Fig. 8c)
Summary
The incidence of cancer has been continuing increasing worldwide.[1,2,3,4] Many investigations have reported that mucositis of the gastrointestinal (GI) tract is a common side effect and occurs in ~40% of cancer patients under chemotherapy.[1,2,3,4] Intestinal mucositis is characterized by decreased villi length, and disruption of crypt cell homeostasis and tight junction proteins in the small intestinal mucosa.[2,4] The epithelium of the mammalian small intestine is a highly ordered and structured tissue with repeated crypt-villus units along the axis. Tuft cells are chemosensory cells expressing taste receptors like α-gustducin and TRPM5.11 All these five types of cells are tightly structured in the crypt-villus.[5,6,11] Mucositis may lead to morbidity and even mortality, because the GI tract is a barrier that protects the body from pathogenic microbes,[6,9,10,12,13,14] and it plays vital roles in the digestion and absorption of nutrients, the secretion of mucus and hormones, and interaction with commensal microbiota.[6,10]
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