Grant: Project Grant

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease in humans. The disease is caused by the degeneration of motor neurons that innervate the voluntary muscles, leading to respiratory failure and death within about 3 years from disease onset. Males are twice as likely to develop ALS than females; the age of onset is also earlier for males with ALS. Environmental and sex-specific factors are thought to play a critical role in the sex differences in disease, but the mechanisms underlying these differences remain unclear. Our recent work indicates that the sex differences observed in human ALS are recapitulated in a genetic mouse model of the disease: male ALS mice develop motor neuron disease earlier and exhibit shortened lifespan when compared to their female counterparts. We have discovered that the gut microbiota composition (i.e., the vast ensemble of bacteria that populate the gut) is also strikingly different between male and female ALS mice. We also found that the microbiota is protective in ALS mice and most importantly, its composition may account the disparate disease process in males vs females. Therefore, we hypothesize that the composition of bacteria in the gut determines ALS progression and this composition is different between males and females, thereby explaining the well-described male predominance and earlier onset of disease. To test our idea, we will perform fecal microbial transplants from mice with ALS into mice for which the intestinal microbiota has been ablated. We will then identify the gut bacteria and their products that confer preferential vulnerability to males and protection to females and determine the mechanisms by which they mediate their effects. Knowledge derived from the proposed experiments will ultimately allow us to develop therapies centred on the microbiota with the promise of slowing the progression of this debilitating disease.