Modulating the microbiome: a revolution in the making?

The idea that altering the intestinal microbiome might modulate neuroinflammation and so amyloid-beta (Aβ) deposition came in part from the work of Marco Prinz and colleagues suggesting that the microbiota control the maturation and function of microglia in the CNS,¹ Professor Sisodia told the AAIC virtual meeting. 

Following this lead, his group treated male APP_swe/PS1_DE9 mice through their lifespan with a cocktail of high-dose antibiotics.² Cecal and fecal contents showed that the abundance of bacteria was unchanged – but the composition was radically different. And, in this transgenic mouse model of Alzheimer’s disease (AD), plaque burden was reduced by around 60%.

Altering intestinal flora reduced amyloid by around 60% and changed microglial phenotype

The morphology of the microglia that surrounded plaque was also radically altered, as was their transcriptome. Microglia in the cortex of antibiotic-treated male mice returned to their homeostatic signature. TGF-β signaling, in particular, was restored.

Role of the microbiome truly causal

Subsequent work in a different mouse model found that using antibiotics to alter the microbiome also reduced amyloid pathology and changed microglial morphology but – importantly – only in male animals.³ Transplanting fecal microbiota from age-matched male mice into antibiotic-treated animals partially reversed these changes, suggesting the effects of an altered microbiome are truly causal.

The sex-specific modulation of innate immunity may relate to the influence of the maternal microbiome on microglial differentiation extending back into early postnatal development and possibly even the prenatal environment.⁴

Experiments have been repeated using an acute, early-post natal course of antibiotics. Findings were essentially the same. Modulating the microbiome produced long-term change in the gut flora accompanied by reduced brain Aβ deposition, changes in populations of T cells and an altered inflammatory picture revealed in the CSF. 

The gut microbiome regulates brain function by influencing host immunity

 A paradigm shift?

And it is not just in AD that such effects may prove clinically relevant. Lloyd Kasper and colleagues from Dartmouth College have shown that a Bacteroides fragilis polysaccharide can protect the brain in a mouse model of MS.⁵ And there is evidence this year that antibiotics in mice can alter the gut microbiome in a way that protects against the consequences of ischemic stroke.⁶

Our new understanding of the importance of the microbiome to the brain may be one of Thomas Kuhn’s revolutions in science whereby one worldview is replaced by another,⁷ Professor Sisodia suggested.