Potential roles of gut microbiome and metabolites in modulating ALS in mice

Nature. 2019 Aug;572(7770):474-480. doi: 10.1038/s41586-019-1443-5. Epub 2019 Jul 22.

Abstract

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder, in which the clinical manifestations may be influenced by genetic and unknown environmental factors. Here we show that ALS-prone Sod1 transgenic (Sod1-Tg) mice have a pre-symptomatic, vivarium-dependent dysbiosis and altered metabolite configuration, coupled with an exacerbated disease under germ-free conditions or after treatment with broad-spectrum antibiotics. We correlate eleven distinct commensal bacteria at our vivarium with the severity of ALS in mice, and by their individual supplementation into antibiotic-treated Sod1-Tg mice we demonstrate that Akkermansia muciniphila (AM) ameliorates whereas Ruminococcus torques and Parabacteroides distasonis exacerbate the symptoms of ALS. Furthermore, Sod1-Tg mice that are administered AM are found to accumulate AM-associated nicotinamide in the central nervous system, and systemic supplementation of nicotinamide improves motor symptoms and gene expression patterns in the spinal cord of Sod1-Tg mice. In humans, we identify distinct microbiome and metabolite configurations-including reduced levels of nicotinamide systemically and in the cerebrospinal fluid-in a small preliminary study that compares patients with ALS with household controls. We suggest that environmentally driven microbiome-brain interactions may modulate ALS in mice, and we call for similar investigations in the human form of the disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Akkermansia
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / microbiology*
  • Amyotrophic Lateral Sclerosis / pathology
  • Amyotrophic Lateral Sclerosis / physiopathology*
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Disease Models, Animal
  • Dysbiosis
  • Female
  • Gastrointestinal Microbiome / drug effects
  • Gastrointestinal Microbiome / physiology*
  • Germ-Free Life
  • Humans
  • Longevity
  • Male
  • Mice
  • Mice, Transgenic
  • Niacinamide / biosynthesis
  • Niacinamide / metabolism*
  • Superoxide Dismutase-1 / genetics
  • Superoxide Dismutase-1 / metabolism
  • Survival Rate
  • Symbiosis / drug effects
  • Verrucomicrobia / metabolism
  • Verrucomicrobia / physiology

Substances

  • Anti-Bacterial Agents
  • Niacinamide
  • Sod1 protein, mouse
  • Superoxide Dismutase-1

Supplementary concepts

  • Akkermansia muciniphila