Scheithauer, T. P. M. | bioRxiv Science

bioRxiv2021

Gut-derived bacterial flagellin induces beta-cell inflammation and dysfunction

ObjectiveHyperglycemia and type 2 diabetes (T2D) are caused by failure of pancreatic beta cells. The role of the gut microbiota in T2D has been studied but causal links remain enigmatic. DesignObese individuals with or without T2D were included from two independent Dutch cohorts. Human data was translated in vitro and in vivo by using pancreatic islets from C57BL6/J mice and by injecting flagellin into obese mice. ResultsFlagellin is part of the bacterial locomotor appendage flagellum, present on gut bacteria including Enterobacteriaceae, which we show to be more abundant in the gut of individuals with T2D. Subsequently, flagellin induces a pro-inflammatory response in pancreatic islets mediated by the Toll-like receptor (TLR)-5 expressed on resident islet macrophages. This inflammatory response associated with beta-cell dysfunction, characterized by reduced insulin gene expression, impaired proinsulin processing and stress-induced insulin hypersecretion in vitro and in vivo in mice. ConclusionWe postulate that increased systemically disseminated flagellin in T2D is a contributing factor to beta cell failure in time and represents a novel therapeutic target. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/463317v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@b719aeorg.highwire.dtl.DTLVardef@f72958org.highwire.dtl.DTLVardef@bb7af5org.highwire.dtl.DTLVardef@859c70_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2021

Members of a highly widespread bacteriophage family are hallmarks of metabolic syndrome gut microbiomes

There is significant interest in altering the course of cardiometabolic disease development via the gut microbiome. Nevertheless, the highly abundant phage members -which impact gut bacteria- of the complex gut ecosystem remain understudied. Here, we characterized gut phageome changes associated with metabolic syndrome (MetS), a highly prevalent clinical condition preceding cardiometabolic disease. MetS gut phageome populations exhibited decreased richness and diversity, but larger inter-individual variation. These populations were enriched in phages infecting Bacteroidaceae and depleted in those infecting Ruminococcaeae. Differential abundance analysis identified eighteen viral clusters (VCs) as significantly associated with either MetS or healthy phageomes. Among these are a MetS-associated Roseburia VC that is related to healthy control-associated Faecalibacterium and Oscillibacter VCs. Further analysis of these VCs revealed the Candidatus Heliusviridae, a highly widespread gut phage lineage found in 90+% of the participants. The identification of the temperate Ca. Heliusviridae provides a novel starting point to a better understanding of the effect that phages have on their bacterial hosts and the role that this plays in MetS.

microbiology↗