Curli-producing E. coli enhances the disease phenotype in an hSOD1 G93A mouse model of ALS

Abstract Amyotrophic Lateral Sclerosis (ALS) is a rapid and fatal neuromuscular degenerative disease which has no known genetic cause in ~ 90% of cases. We explored the microbiome as a potential non-genetic contributing factor for the disease. Microbial dysbiosis in the gut can occur due to diet, lifestyle and environmental factors and differences in gut microbial communities have been detected between ALS subjects and healthy controls, including an increase in E. coli in ALS subjects. E. coli and other physiological gram-negative bacteria produce curli proteins which are functional bacterial amyloid fibrils. Curli fibrils form biomatrices and interact with several proteins in the extracellular matrix, such as CD14, Toll-like receptors and MHC1 molecules expressed on the surfaces of all nucleated cells. Over-exposure to curli in the gut enhanced neuroinflammation and alpha synuclein misfolding in the brain in a rodent model of Parkinson’s disease. In this study, we examined whether curli exposure can exacerbate the development and progression of ALS. We utilized the hSOD1 G93A mouse model of slow developing ALS, with their inherent microbiome on a normal chow diet. These mice were fed curli-producing or curli-nonproducing (mutant) E. coli in applesauce 3 times/week from 4 weeks of age to 6 months. Chronic consumption of E. coli was well-tolerated by all mice, measured regularly by signatures of general wellness. Male hSOD1 mice demonstrated faster ALS progression compared to female hSOD1 mice. Chronic exposure to E. coli significantly shifted bacterial and viral alpha and beta diversities in the gut of all mice. Curli-fed mice showed significant decrease in relative abundance of Proteobacteria phyla. Within the male hSOD1 cohort, curli-fed mice exhibited locomotive signs of faster ALS progression, increased markers of skeletal muscle atrophy, increased inflammation in the muscle and spinal cord, and suppressed peripheral immune responses compared to mutant-fed and vehicle mice. Within the female cohort, exposure to both curli-producing and mutant E. coli suppressed peripheral immune responses. In conclusion, over-exposure to curli-producing E. coli in the gut worsened the pathological, immunological and motor features of ALS, in the absence of overt signs of illness. These results suggest that opportunities for manipulation of the gut microbiome in ALS need to be explored.