Single-cell RNA sequencing analysis reveals alginate oligosaccharides preventing chemotherapy-induced mucositis

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.

Microbiota from alginate oligosaccharide-dosed mice successfully mitigated small intestinal mucositis

“…Regular FMT involves the transplantation of fecal material from a healthy donor into a diseased recipient [8]. However, we found that AOS also rescues busulfan-impaired gut microbiota in the small intestine [23]. We hypothesize that FMT from AOS-dosed mice might alleviate small intestine disruption following recipient chemotherapy to a greater extent than FMT from control animals.…”

“…In a recent report, we revealed that AOS mitigated small intestine cell membranes damage especially cell junctions and microvilli by the anticancer drug busulfan; simultaneously, AOS supported the blood metabolome to assist small intestinal recovery [23]. This is because gut microbiota can metabolize nutrients and also regulate intestinal metabolites to affect the blood metabolome [35,36].…”

“…They have been found to be anti-inflammatory [17], anti-apoptotic [19], antiproliferation [20], and to have antioxidant [16,19,21] and even anti-cancer activities [22]. Very recently, we showed that AOS rescues busulfan disrupted murine small intestinal cell endoplasmic reticulum and mitochondria [23]. Furthermore, AOS improves busulfan disturbed intestinal cell membranes through the enhancement of cell junctions, recovery of small intestinal functions (as shown by the single-cell RNA-seq analysis), and improvement of transcriptional factors which may contribute to the gene expression [23].…”

“…Furthermore, AOS improves busulfan disturbed intestinal cell membranes through the enhancement of cell junctions, recovery of small intestinal functions (as shown by the single-cell RNA-seq analysis), and improvement of transcriptional factors which may contribute to the gene expression [23]. Furthermore, AOS improves the blood metabolome to support the recovery of small intestine function [23]. Subsequently, we also found that AOS may benefit gut microbiota through an increase in "beneficial" gut microbes and a decrease in "harmful" gut microbes (unpublished data).…”

“…Very recently, we showed that AOS rescues busulfan disrupted murine small intestinal cell endoplasmic reticulum and mitochondria [23]. Furthermore, AOS improves busulfan disturbed intestinal cell membranes through the enhancement of cell junctions, recovery of small intestinal functions (as shown by the single-cell RNA-seq analysis), and improvement of transcriptional factors which may contribute to the gene expression [23]. Furthermore, AOS improves the blood metabolome to support the recovery of small intestine function [23].…”