Project description:Pancreatic cancer is the 3rd most prevalent cause of cancer related deaths in United states alone, with over 55000 patients being diagnosed in 2019 alone and nearly as many succumbing to it. Late detection, lack of effective therapy and poor understanding of pancreatic cancer systemically contributes to its poor survival statistics. Obesity and high caloric intake linked co-morbidities like type 2 diabetes (T2D) have been attributed as being risk factors for a number of cancers including pancreatic cancer. Studies on gut microbiome has shown that lifestyle factors as well as diet has a huge effect on the microbial flora of the gut. Further, modulation of gut microbiome has been seen to contribute to effects of intensive insulin therapy in mice on high fat diet. In another study, abnormal gut microbiota was reported to contribute to development of diabetes in Db/Db mice. Recent studies indicate that microbiome and microbial dysbiosis plays a role in not only the onset of disease but also in its outcome. In colorectal cancer, Fusobacterium has been reported to promote therapy resistance. Certain intra-tumoral bacteria have also been shown to elicit chemo-resistance by metabolizing anti-cancerous agents. In pancreatic cancer, studies on altered gut microbiome have been relatively recent. Microbial dysbiosis has been observed to be associated with pancreatic tumor progression. Modulation of microbiome has been shown to affect response to anti-PD1 therapy in this disease as well. However, most of the studies in pancreatic cancer and microbiome have remained focused om immune modulation. In the current study, we observed that in a T2D mouse model, the microbiome changed significantly as the hyperglycemia developed in these animals. Our results further showed that, tumors implanted in the T2D mice responded poorly to Gemcitabine/Paclitaxel (Gem/Pac) standard of care compared to those in the control group. A metabolomic reconstruction of the WGS of the gut microbiota further revealed that an enrichment of bacterial population involved in drug metabolism in the T2D group.

Project description:Background: Toll-like receptor 2 (TLR2) plays a pivotal role in innate immunity and has recently emerged as a criti-cal regulator of host-microbiome interactions. However, how TLR2 influences host transcriptional responses to colonized microbiome and microbial community dynamics remains largely unclear. Germ free (GF) and conven-tionalized zebrafish (Danio rerio) model provides a valuable system to study microbiome functions. Results: RNAseq analysis revealed that transcriptomic alterations resulted from tlr2 mutation were more extensive in the presence of the microbiome than under the GF condition, indicating that tlr2 mutation has a more pro-nounced impact on host transcriptional responses when microbial signals are present. KEGG enrichment analyses showed an enhanced host response to the energy metabolism in the presence of microbial stimuli resulting from tlr2 deficiency. In addition, microbiome colonization elicited a broader transcriptional response in tlr2 wild-type larvae than in the mutants, highlighting the essential role of tlr2 in regulating host transcriptomic programs in re-sponse to microbial signals. In terms of how tlr2 influences microbial composition, 16S rRNA gene sequencing showed that tlr2 mutants exhibited higher microbial diversity during early development, whereas adult microbial diversity was highest in wild-type males, indicating a developmental stage- and sex-specific restructuring of the gut microbiome. For larvae at the genus level, tlr2 mutant larvae showed increased Chryseobacterium and Flecto-bacillus but reduced Gracilibacteria abundance relative to wild-type controls. For adult gut samples, the relative abundance of Cetobacterium was lower, while genera such as Romboutsia, Aeromonas and Pseudarthrobacter were more abundant in tlr2 wild-type male group compared to other groups. Predicted functional analyses revealed that tlr2 deficiency induced complex alterations in microbial metabolic pathways, with distinct pathway enrichments observed between larval and adult stages. Conclusions: TLR2 not only modulates host transcriptional responses to microbial colonization but also shapes gut microbial diversity, composition, and metabolic potential. Our findings highlight the critical role of TLR2 in orchestrating immunometabolic homeostasis and provide new insights into its broader function in maintaining host-microbiota symbiosis across developmental stages.

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Tonsillitis Microbiome

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