Gut- and oral-dysbiosis differentially impact spinal- and bulbar-onset ALS, predicting ALS severity and potentially determining the location of disease onset

Background Prior studies on the role of gut-microbiome in Amyotrophic Lateral Sclerosis (ALS) pathogenesis have yielded conflicting results.

We hypothesized that gut- and oral-microbiome may differentially impact two clinically-distinct ALS subtypes (spinal-onset ALS (sALS) vs. bulbar-onset ALS (bALS), driving disagreement in the field.

Methods ALS patients diagnosed within 12 months and their spouses as healthy controls ( n  = 150 couples) were screened.

For eligible sALS and bALS patients ( n  = 36) and healthy controls ( n  = 20), 16S rRNA next-generation sequencing was done in fecal and saliva samples after DNA extractions to examine gut- and oral-microbiome differences.

Microbial translocation to blood was measured by blood lipopolysaccharide-binding protein (LBP) and 16S rDNA levels.

ALS severity was assessed by Revised ALS Functional Rating Scale (ALSFRS-R).

Results sALS patients manifested significant gut-dysbiosis, primarily driven by increased fecal Firmicutes/Bacteroidetes- ratio ( F/B- ratio).

In contrast, bALS patients displayed significant oral-dysbiosis, primarily driven by decreased oral  F/B- ratio.

For sALS patients, gut-dysbiosis (a shift in fecal  F/B- ratio), but not oral-dysbiosis, was strongly associated with greater microbial translocation to blood ( r  = 0.8006,  P  < 0.0001) and more severe symptoms ( r  = 0.9470,  P  < 0.0001).

In contrast, for bALS patients, oral-dysbiosis (a shift in oral  F/B- ratio), but not gut-dysbiosis, was strongly associated with greater microbial translocation to blood ( r  = 0.9860,  P  < 0.0001) and greater disease severity ( r  = 0.9842,  P  < 0.0001).

For both ALS subtypes, greater microbial translocation was associated with more severe symptoms (sALS: r  = 0.7924, P  < 0.0001; bALS: r  = 0.7496, P  = 0.0067).

Importantly, both sALS and bALS patients displayed comparable oral-motor deficits with associations between oral-dysbiosis and severity of oral-motor deficits in bALS but not sALS.

This suggests that oral-dysbiosis is not simply caused by oral/bulbar/respiratory symptoms but represents a pathological driver of bALS.

Conclusions We found increasing gut-dysbiosis with worsening symptoms in sALS patients and increasing oral-dysbiosis with worsening symptoms in bALS patients.

Our findings support distinct microbial mechanisms underlying two ALS subtypes, which have been previously grouped together as a single disease.

Our study suggests correcting gut-dysbiosis as a therapeutic strategy for sALS patients and correcting oral-dysbiosis as a therapeutic strategy for bALS patients.