Abstract
BackgroundPrior 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.MethodsALS 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).ResultssALS 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.ConclusionsWe 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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a phenotypically heterogeneous neurodegenerative disorder with survival ranging from a few months to over 20 years [1]
Our study suggests correcting gut-dysbiosis as a therapeutic strategy for spinal-onset ALS (sALS) patients and correcting oral-dysbiosis as a therapeutic strategy for Bulbar-onset ALS (bALS) patients
To examine if gut- and oralmicrobiome can differentiate between spinal-onset ALS and bulbar-onset ALS, fecal and saliva samples were collected from 24 sALS patients and 12 bALS patients
Summary
Amyotrophic lateral sclerosis (ALS) is a phenotypically heterogeneous neurodegenerative disorder with survival ranging from a few months to over 20 years [1]. This substantial heterogeneity has contributed to poor clinical trial outcomes and a lack of effective treatments [1]. Consistent with distinct clinical features, these two ALS subtypes manifest different pathological signatures [5], impact different brain regions [6], and are associated with different sets of genetic risk factors [1]. We hypothesized that gut- and oral-microbiome may differentially impact two clinicallydistinct ALS subtypes (spinal-onset ALS (sALS) vs bulbar-onset ALS (bALS), driving disagreement in the field
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