Host tp53 mutation induces gut dysbiosis eliciting inflammation through disturbed sialic acid metabolism

Abstract

Background Host tp53 mutations are frequently found during the early stages of colitis-associated colorectal cancer (CAC), but whether such mutations induce gut microbiota dysbiosis and chronic intestinal inflammation that contributes to the development of CAC, remains unknown. Results We found that zebrafish tp53 mutant larvae exhibited elevated intestinal inflammation, by monitoring the NFκB activity in the mid-distal intestines of zebrafish larvae using an NFκB:EGFP transgenic reporter line in vivo as well as neutrophil infiltration into the intestine. This inflammation was due to dysbiotic gut microbiota with reduced diversity, revealed using both 16S rRNA amplicon sequencing and a germfree larva model. In this dysbiosis, Aeromonas spp. were aberrantly enriched as major pathobionts and exhibited the capacity for aggressive colonization in tp53 mutants. Importantly, the ex-germfree experiments supported the causality of the host tp53 mutation for inducing the inflammation. Transcriptome and high-performance liquid chromatography analyses of the host gastrointestinal tracts identified dysregulated sialic acid (SA) metabolism concomitant with increased host Neu5Gc levels as the key determinant of aberrant inflammation, which was reversed by the sialidase inhibitors oseltamivir and Philippin A. Conclusions These results demonstrate a crucial role for host tp53 in maintaining symbiosis and immune homeostasis via SA metabolism. Disturbed SA metabolism via a tp53 mutation may be exploited by specific elements of the gut microbiome, eliciting both dysbiosis and inflammation. Manipulating sialometabolism may therefore provide an efficacious therapeutic strategy for tp53 mutation-induced dysbiosis, inflammation, and ultimately, related cancers.

Sialic acid exacerbates gut dysbiosis-associated mastitis through the microbiota-gut-mammary axis by fueling gut microbiota disruption

“…We showed that FMT from the A or AN group induced mastitis in recipient mice, suggesting that gut dysbiosis is attributed to the development of mastitis [ 19 , 21 , 22 ]. Our results agree with previous findings that microbiota-liberated host SA facilitates enteric pathogen invasion and promotes host gene mutant-induced opportunistic pathogen expansion [ 34 , 65 , 66 ]. Similar findings have also been reported in other microbiota-liberated host sugars, including succinate and fucose [ 45 , 67 ], indicating that changed carbon metabolism may confer an expansion advantage for pathogens.…”

“…However, the origin of microbial sialidase and how it is elevated are unclear in the present study. We confirmed that inhibition of SA release alleviated SARA-induced mastitis by zanamivir, which could be extended to previous studies showing that inhibition of sialidase is a potential strategy to improve gut dysbiosis and subsequent inflammatory responses [ 66 , 69 ]. Another potential reason for the increased SA is mucosal inflammation, in which LPS triggered host neuraminidase release through TLR4 and treatment with sialidase inhibitor attenuated inflammation caused by LPS or pathogen invasion [ 33 , 82 ].…”

Exploring the synergistic pharmacological mechanism of Huoxiang Drink against irritable bowel syndrome by integrated data mining and network pharmacology

“…[55] A study published in 2022 revealed that TP53 mutation mediated sialic acid metabolism imbalance and severed gut microflora dysbiosis closely related to abnormally inflammatory response. [56] Further research on the pathological mechanism of glioblastoma has shown that TP53 overexpression was accompanied by the activation of TNF-α, which led to the continuous deterioration of glioblastoma and seriously affected the quality of patient prognosis. [57] Due to extensive anti-inflammatory effects of HD, we inferred that the pharmacological mechanism of HD against IBS was significantly associated with HIF-1 signaling pathway and TNF signaling pathway.…”

Application of zebrafish in the study of the gut microbiome

“… 10 , 11 Accordingly, it is possible to directly determine causality between the gut microbiome and disease‐associated alterations in functional and mechanistic studies. 12 Studies on gut microbiome using the zebrafish model have been considered a pioneering and vital field of research in recent years.…”

“…Last but not least, germ‐free (GF) zebrafish provide a robust system for dissecting or manipulating microbial signals owing to its cost‐effectiveness and the convenience of the techniques for constructing sterile zebrafish 10,11 . Accordingly, it is possible to directly determine causality between the gut microbiome and disease‐associated alterations in functional and mechanistic studies 12 . Studies on gut microbiome using the zebrafish model have been considered a pioneering and vital field of research in recent years.…”