Mutant and curli‑producing E. coli enhance the disease phenotype in a hSOD1‑G93A mouse model of ALS

Scientific Reports, 2023 · DOI: 10.1038/s41598-023-32594-5 · Published: April 3, 2023

Simple Explanation

The gut microbiome, specifically an increase in E. coli, may contribute to ALS. E. coli produces curli proteins, which are bacterial amyloids. This study examines if long-term curli overexposure can worsen ALS development. The study used hSOD1-G93A mice, a model for ALS, and fed them curli-producing or non-producing E. coli for six months. The study found that male mice exposed to curli-producing E. coli showed changes in gut bacteria and immune responses, as well as increased inflammation in skeletal muscle. Both types of E. coli exposure led to distant organ pathology in the mouse model, including astrogliosis in the brainstem and demyelination in the lumbar spinal cord. This suggests a connection between gut bacteria and distant organ health.

Study Duration

7 Months

Participants

91 male and female hSOD1-G93A mice and C57BL/6J WT littermate controls

Evidence Level

Level II; Animal study

Key Findings

1
Chronic gut exposure to curli-producing E. coli led to significant shifts in the diversity of gut bacteria in male hSOD1 mice.
2
Curli-fed hSOD1 males showed significant maximum lateral deviation of hind feet and variations in rotation compared to vehicle and mutant-fed hSOD1 males.
3
Chronic feeding of E. coli, both mutant and curli-producing, increased several markers of muscle atrophy and inflammation in male hSOD1 mice.

Research Summary

This study investigated the impact of chronic gut dysbiosis induced by E. coli on the progression of ALS in a mouse model. The researchers found that introducing curli-producing E. coli shifted the gut microbial composition, inducing bacterial and viral dysbiosis. The study revealed sex-specific effects, with male hSOD1 mice showing poorer microbial species diversity and suppressed peripheral immune activation in response to E. coli curli. Both mutant and curli-producing E. coli exposure led to skeletal muscle pathology. The researchers conclude that chronic exposure to both curli-producing and non-producing E. coli can exacerbate certain features of ALS. They also suggest that increased peripheral blood frequency of CD19+ B cells may contribute to earlier motor impairment in males.

Practical Implications

Therapeutic Targets

The study suggests potential therapeutic targets related to gut dysbiosis and immune modulation for managing ALS.

Personalized Medicine

The sex-specific effects highlight the need for personalized medicine approaches in ALS treatment, considering the gut microbiome and immune responses.

Early Detection

Increased peripheral blood frequency of CD19+ B cells may serve as a biomarker for early detection or risk assessment of ALS, particularly in males.

Study Limitations

1
The study could not assess the influence of E. coli-induced gut dysbiosis on full-blown hindlimb paralysis and survival.
2
The researchers lacked the tools and techniques to potentially detect curli protein in distant organs.
3
The study did not detect a breach in the gastrointestinal barrier in mice at 6 months.

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