Excited to see that our review is out for Thanksgiving 🥳 @ScienceMagazine @pipethero

Excited to share this work by @cao_bio and colleagues @PingFan78765311 @geoffpronovost -- a fascinating example of how environmental factors interact synergistically to alter the gut microbiome and impair hippocampal function and cognitive behavior in mice. Short 🧵:

The ketogenic diet is widely used to treat refractory epilepsy and is increasingly being explored for other neurological and neurodegenerative disorders as well. But the results for other conditions seem to vary widely.

We previously found that changes in the gut microbiome mediate the anti-seizure effects of the diet in mouse models of epilepsy, which led us to think about the context-specificity of our findings.

For example, if the ketogenic diet (+ associated microbiome) can be beneficial for treating seizures in epilepsy, how would they impact cognitive ability in people that don’t have epilepsy? 🤔

To test this, Dr. Christine Olson + colleagues induced cognitive impairment in mice by subjecting them to acute intermittent hypoxia, and tested the effects of keto vs. control diet on their learning & memory behavior.

The first really interesting finding was that the ketogenic diet alone had no impact on cognitive behavior, but when combined with the hypoxic stressor, it actually worsened behavior in the learning and memory task.

If mice were first depleted of the microbiome or raised with no microbiome, the ketogenic diet no longer worsened the effects of hypoxia on behavior. In contrast, transplanting the microbiota into new mice made them perform more poorly in the learning and memory task.

Mice with poor behavior & mice transplanted with their microbiomes had >1000X higher Bilophila, with sequences best matching Bilophila wadsworthia. Colonizing mice with B. wadsworthia alone impaired their cognitive behavior.

Big thanks to @Suzanne_Devkota and @ConnieWYHa for teaching us almost everything we know about B. wadsworthia. @Suzanne_Devkota's prior work showed that high fat diets increase B. wadsworthia via taurocholic acid & that B. wadsworthia induces Th1 cells.

Following this, @cao_bio @geoffpronovost @PingFan78765311 saw that mice with poor cognitive behavior had higher levels of gut IFNg+ Th1 cells. Raising mice with no Th1 cells prevented the negative effects of B. wadsworthia (& keto diet + hypoxia) on behavior.

@cao_bio saw that poor behavior in mice exposed to keto diet + hypoxia or colonized with B. wadsworthia alone tracked with decreased hippocampal LTP (+ altered gene expression). So, we think that keto+hypoxia -> Bilophila -> Th1 cells -> IFNg -> hippocampus -> behavior.

Thrilled to see Elena Coley's labor of love shared with the community! Her review addresses a potential role of the gut microbiome in mediating effects of early life nutrition on neurodevelopment, especially in the context of the global prevalence of malnutrition.