Oh my gut! Is the microbial origin of neurodegenerative diseases real?

Abstract

There is no cure or effective treatment for neurodegenerative protein conformational diseases (PCDs), such as Alzheimer’s or Parkinson’s diseases, mainly because the etiology of these diseases remains elusive. Recent data suggest that unique changes in the gut microbial composition are associated with these ailments; however, our current understanding of the bacterial role in the pathogenesis of PCDs is hindered by the complexity of the microbial communities associated with specific microbiomes, such as the gut, oral, or vaginal microbiota. The composition of these specific microbiomes is regarded as a unique fingerprint affected by factors such as infections, diet, lifestyle, and antibiotics. All of these factors also affect the severity of neurodegenerative diseases. The majority of studies that reveal microbial contribution are correlational, and various models, including worm, fly, and mouse, are being utilized to decipher the role of individual microbes that may affect disease onset and progression. Recent evidence from across model organisms and humans shows a positive correlation between the presence of gram-negative enteropathogenic bacteria and the pathogenesis of PCDs. While these correlational studies do not provide a mechanistic explanation, they do reveal contributing bacterial species and provide an important basis for further investigation. One of the lurking concerns related to the microbial contribution to PCDs is the increasing prevalence of antibiotic resistance and poor antibiotic stewardship, which ultimately select for proteotoxic bacteria, especially the gram-negative species that are known for intrinsic resistance. In this review, we summarize what is known about individual microbial contribution to PCDs and the potential impact of increasing antimicrobial resistance.

Identification of proteotoxic and proteoprotective bacteria that non-specifically affect proteins associated with neurodegenerative diseases

“…This mechanism is likely mediated by the interplay between host proteostasis and immune responses to bacteria. 27,28…”

“…This mechanism is likely mediated by the interplay between host proteostasis and immune responses to bacteria. 27,28 Many of the studies aiming to identify neurodegenerative PCD etiology or treat the disease have centered on host-targeted therapeutics, primarily focused on targeting the aggregating proteins or the affected cell types. However, this approach has not been successful in pre-clinical or clinical trials.…”