Thread by @OmarMglia

Does #gut #microbiota interact with #microglia in the #aging #brain? Are microglia metabolically affected (#mitochondria)? Does #diet take part? any #translational data?
Our paper made it last week in @NatureNeuro
so it's about time for a 🧵!
nature.com/articles/s4159…

1. Microglia from aged and young-adult #male & #female mice, under SPF or #germ_free conditions were profiled by bulk #RNAseq. We identified a gene-set, which depended on the housing condition regardless of #age & regulate central processes in microglia. "Microglial GF signature"

2. Utilizing #WGCNA, we found major differences between microglia of SPF and GF mice in the aged groups. But do we see any functional difference on a cellular level?

3. Yes, in the absence of the microbiota, microglia produce less #ROS and potentially less NO.

4. Microbiota is also associated with microglia accumulating more mitochondria of defect morphology (red arrowheads) and lower mitochondrial activity. But how?

5. Based on the rich literature, our first suspects were #SCFAs. There, #acetate and #propionate showed an increase in sera of aged mice.

6. Unbiased metabolomics on serum and brain in aging SPF mice gave us many hits.

7. So, to filter these metabolites before going in vivo, we did a targeted analysis in GF mice and examined available human datasets (@TwinsUKres). #CML and #TMAO were the top hits.

8. The next logical step was to see if any of the top hits recapitulates the age-related microglia phenotype in young-adult mice. There, CML started to shine!

9. CML accumulation in microglia with age is microbiota-dependent. We could also show the age-related accumulation in the human brain. So is CML produced by the microbiota? where does it come from?

10. We obviously hoped it was, so we checked its levels in feces of aged SPF and GF mice. To our surprise, it was much higher in GF! how come?!
gut microbiota mediates age-related changes in intestinal permeability..... allowing CML to accumulate systematically.

11. CML is an advanced glycation end product (AGE), which is majorly diet-derived and is formed via various routes in food processing such as #Maillard reaction (high-temperature #cooking). Other AGEs will be interesting to examine since our analysis was restricted to CML.

12. Is AGEs-low diet the next #trend for healthy #longevity? still early to say!
For now, enjoy the graphical summary ;)
and read the full text on @ResearchGate
bit.ly/3MvCmb0