Translocation of gut commensal bacteria to the brain
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Abstract
The gut-brain axis, a bidirectional signaling network between the intestine and the central nervous system, is crucial to the regulation of host physiology and inflammation. Recent advances suggest a strong correlation between gut dysbiosis and neurological diseases, however, relatively little is known about how gut bacteria impact the brain. Here, we reveal that gut commensal bacteria can translocate directly to the brain when mice are fed an altered diet that causes dysbiosis and intestinal permeability, and that this also occurs without diet alteration in distinct murine models of neurological disease. The bacteria were not found in other systemic sites or the blood, but were detected in the vagus nerve. Unilateral cervical vagotomy significantly reduced the number of bacteria in the brain, implicating the vagus nerve as a conduit for translocation. The presence of bacteria in the brain correlated with microglial activation, a marker of neuroinflammation, and with neural protein aggregation, a hallmark of several neurodegenerative diseases. In at least one model, the presence of bacteria in the brain was reversible as a switch from high-fat to standard diet resulted in amelioration of intestinal permeability, led to a gradual loss of detectable bacteria in the brain, and reduced the number of neural protein aggregates. Further, in murine models of Alzheimer’s disease, Parkinson’s disease, and autism spectrum disorder, we observed gut dysbiosis, gut leakiness, bacterial translocation to the brain, and microglial activation. These data reveal a commensal bacterial translocation axis to the brain in models of diverse neurological diseases.
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Having this information paired with making the 16S data publicly available will give readers confidence that the taxonomic assignments for bacteria found in the brain are accurate given the implications. I believe that there was a Twitter comment that S. xylosus is usually a skin commensal and it was surprising to see it in the gut or brain, so I think this could be a reasonable issue to address making sure OTUs were classified correctly. Particularly the more accurate way to do this would be shotgun metagenomic sequencing to better confirm taxonomic classification and similarity of populations between the intestine and brain.
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and primers specific to the 16S (V3-V4) region
What primers? Overall this section is missing a lot of methodology, details, and references for how the library prep, sequencing, and analysis was carried out. I don't see any supplementary attached with the preprint so I assume all the methods done and details that are provided should be in the main text unless I missed something.
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All data, code, and materials used in the analysis will be available to any researcher for purposes of reproducing or extending the analysis.
I think at the bare minimum code and raw data files should be uploaded somewhere that is publicly accessible, given the probably high interest in this piece of work. I can only speak for microbial data since that is my background, but 16S amplicons should be uploaded to the NCBI SRA, and the commands or code used for 16S analysis can easiliy be put on github.
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Taxonomic Units for analyses including diversity, taxonomy, and differential analyses
What database was used to assign taxonomy to reads? I also don't see methods for the results claim that sequences from the intestine vs brain were 100% matched. Were they matched by just taxonomy, OTU grouping?
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Divisive Amplicon Denoising Algorithm
This sounds like either QIIME or DADA2 was used?
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Sequence analyses were performed using the NovaSeq platform
I don't think you analyzed the sequences using NovaSeq since that's just a different type of Illumina instrument for sequencing. Did you use a program like QIIME, Mothur, or DADA2 for example?
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We found that the culture can detect as low as 5 CFU bacteria.
Were similar limits of detection calculated for the other organs? Also there is a range in the discussion listed as detecting 1-300 CFUs, is this possible with this limit of detection?
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Further, we observed these phenotypes in young mice (∼8-15 weeks old), long before the characteristic disease-related changes that occur in some of the mouse models employed here. Therefore, the data suggest that commensal bacterial translocation to the brain is an early event and could even be an initiating trigger for microglial changes associated with neuroinflammation and neural protein aggregate formation, leading to certain neurodegenerative and neurodevelopmental diseases
Could this instead be explained that in young mice the intestinal barrier isn't as strong? I guess that isn't the case since the same level of permeability wasn't seen in the wildtype background. What might happen in mice that are a little older that have induced intestinal permeability? This also relates to my question about how quick this seems to happen …
Further, we observed these phenotypes in young mice (∼8-15 weeks old), long before the characteristic disease-related changes that occur in some of the mouse models employed here. Therefore, the data suggest that commensal bacterial translocation to the brain is an early event and could even be an initiating trigger for microglial changes associated with neuroinflammation and neural protein aggregate formation, leading to certain neurodegenerative and neurodevelopmental diseases
Could this instead be explained that in young mice the intestinal barrier isn't as strong? I guess that isn't the case since the same level of permeability wasn't seen in the wildtype background. What might happen in mice that are a little older that have induced intestinal permeability? This also relates to my question about how quick this seems to happen from intestinal permeability to bacterial translocation/neuroinflammation. I wonder how quickly this leads to observed disease phenotype?
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that is distinct from an acute, fulminant brain infection.
Could you provide context to the reader approximate CFU levels that are associated with brain infections?
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Further, the bacteria detected in the brain and the vagus nerve in these strains were 100% matched with those that were detected in the feces and ileum.
I think this answers my question above, but how were they 100% matched? By 16S rRNA gene sequence identity since I only see description for 16S sequencing? They could be the same at the species/genus resolution but since the 16S rRNA gene has poor resolution sometimes even at genus level there could be a lot of species or strain differences
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We subsequently reversed their diet back to normal rodent chow and tested their phenotypes at days 14
Throughout the results I'm surprised at the short timelines that bacteria are either translocated to the brain or effects are reversed. Do you think that perhaps the deterioration of the gut lining leading to gut leakiness is a slow process but then the subsequent translocation and neuroinflammatory effects are quite quick? I know this isn't a direct hypothesis in this paper, but still surprising to me that these effects are seen so quickly once gut leakiness is established
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Taken together, these data show that bacteria can translocate to the brain of multiple genetic types of mice including wild-type mice, that numerous types of bacteria can translocate to the brain even simultaneously, and that in all cases studied thus far, the bacteria detected in the brain are also found in the intestine.
Very interesting! Same question as above - could you perform shotgun sequencing of the bacteria retrieved from either the intestine/ileum vs the brain and compare if they are the same populations for these different bacterial species that are translocating to the brain, not just S. xylosus?
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Figure 2.
Similar to my small comment above about colors, it would be great if throughout the figures the colors for control and Paigen-diet were consistent to help the reader, and using color-blind friendly colors
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the composition of the microbiome (i.e., diet and antibiotic use) analogously changes the bacteria that localize to the brain
Very interesting!
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It was unclear how S. xylosus translocated to the brain and why this localization was specific and not also observed in systemic organs
This is interesting that there are more CFUs of S. xylosus in both the feces, illeum, vagus, and brain of paigen-fed mice vs the control. Was whole-genome sequencing done to compare the populations of S. xylosus in feces vs the brain to see if there are strain differences contributing to success in brain translocation?
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Figure 1.
A small nitpick, but the contrasting colors of green and red won't be color-blind friendly
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