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Acetaminophen (APAP)‐induced acute liver injury (AILI) is the most frequent cause of acute liver failure in developed countries. Trimethylamine N‐oxide (TMAO) is a metabolite derived from the gut microbiota and is relatively high in the circulation of the elderly, individuals with diabetes, and heart disease. Herein, we showed that TMAO exacerbates APAP hepatotoxicity. It is possible that delayed liver repair and regeneration that resulted from reduced macrophage accumulation was responsible for this combined hepatotoxicity. Moreover, matrix metalloproteinase 12 (Mmp12), expressed predominantly by macrophages, were reduced by TMAO in vitro and in vivo. This led to the inhibition of macrophage migration and a subsequent decrease in the recruitment of proresolving macrophages to the necrosis area. Furthermore, the administration of recombinant Mmp12 mitigated the enhanced hepatotoxicity in mice cotreated with TMAO and APAP. Overall, this study indicates that TMAO exacerbates APAP‐induced hepatotoxicity by hindering macrophage‐mediated liver repair, which might stem from the inhibition of Mmp12. These findings imply that liver damage in patients with high levels of circulating TMAO may be more severe in AILI and should exercise caution when treating with NAC. [ABSTRACT FROM AUTHOR]

Secretory immunoglobulin A (SIgA) is a non-inflammatory antibody that shields internal body surfaces, such as in the intestine to neutralize pathogens in the lumen of the intestine. As chemotherapy seriously damages the mucosal immune system, we herein demonstrated that polysaccharide from the squid ink of Ommastrephes bartrami (OBP) activated intestinal SIgA secretion to prevent chemotherapeutic injury. Using a mouse model of chemotherapy induced intestinal injury by intraperitoneal injection of 50 mg kg(-1) cyclophosphamide, our results showed an enhanced SIgA concentration in intestinal mucosa by OBP administration and the higher production of SIgA relied on the greater expression of IgA, J chain and pIgR. Furthermore, the higher expressions of IL-6, IL-10 and TNF-α increased by OBP treatment contributed to enhanced IgA and J chain synthesis in IgA(+) plasma cells, and pIgR expression in epithelial cells. It also triggered a prompt immunoglobulin secretory pathway confirmed by enhanced UPR (unfolded protein response) effectors XBP-1s and Bip expression. Our results have important implications for the mucosal immunity enhancement effects of OBP as a functional food component for chemotherapeutic patients.

Gastrointestinal mucositis and infection by chemotherapy treatment are associated with alteration of intestinal microflora and bacterial translocation due to the potential damage induced by anti-cancer drugs on the intestinal barrier and microbiota homeostasis. This study aimed to investigate the protective effect of dietary polysaccharides on chemotherapy induced intestinal microflora dysfunction. In the current contribution, with a mouse model intraperitoneally injected with 50 mg kg(-1) of cyclophosphamide (Cy) for 2 days, we revealed that polysaccharides from the ink of Ommastrephes bartrami (OBP) altered the intestinal microflora composition. OBP retarded the excessive growth of intestinal bacteria induced by cyclophosphamide, based on 16S rRNA gene (16S rDNA) quantification. The clone libraries of intestinal bacteria 16S rDNA were used to decipher the difference in bacterial community structures in different groups of mice. Followed by RFLP evaluation and OTU abundance analysis, they imply that OBP changed the intestinal microflora composition, in which the quantity of probiotic Bifidobacterium got up-regulated but Bacteroidetes decreased in mice undergoing chemotherapy. Our results may have important implications for OBP as a functional food component or nutrient against chemotherapy induced intestinal injury and potential pathogenic intestinal disorders involving inflammation and infection.