The human microbiota is believed to influence health. Microbiome dysbiosis may be linked to neurological conditions like Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). We report the ability of a probiotic bacterial strain in reversing neurodegeneration phenotypes. We show that Lacticaseibacillus rhamnosus HA-114 is neuroprotective in C. elegans models of ALS and HD. Our results show that neuroprotection from L. rhamnosus HA-114 is unique from other L. rhamnosus strains, and resides in its fatty acid content. Neuroprotection by L. rhamnosus HA-114 requires acdh-1/ACADSB, kat-1/ACAT1 and elo-6/ELOVL3/6, which are key fatty acid metabolism and mitochondrial β-oxidation genes. Moreover, L. rhamnosus HA-114 delayed disease onset and suppressed motor neuron degeneration in an aggressive mouse model of ALS. Our data suggest that disrupted lipid metabolism contributes to neurodegeneration and that dietary intervention with L. rhamnosus HA-114 restores lipid homeostasis and energy balance through mitochondrial β-oxidation. L. rhamnosus HA-114 is suitable for human consumption opening the possibility of modifying disease progression by dietary intervention.
Article
Probiotic Lacticaseibacillus rhamnosus HA-114 suppresses age-dependent neurodegeneration via mitochondrial beta-oxidation
https://doi.org/10.21203/rs.3.rs-59192/v1
This work is licensed under a CC BY 4.0 License
Journal Publication
published 07 Dec, 2022
Version 1
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There is NO Competing Interest.
- FigS1.png
Lacticaseibacillus rhamnosus HA-114 prevents damage from chronic oxidative stress but does not extend lifespan. Transgenics were monitored from the adult stage, scored daily for paralysis. (A) FUSDS57 worms fed with L. rhamnosus strains R0011, R0343 and HA-111 have the same paralysis rate as the worms fed with OP50. (B) Worms fed with HA-114 from day 6 (onset of paralysis) showed less paralysis compared to transgenics expressing mutant FUS fed with OP50. (C) Chronic treatment of 250 μM paraquat increased paralysis in FUSDS57 animals. HA-114 supplementation prevents increase of paralysis from paraquat treatment. (D) Transgenics were monitored from the adult stage, scored every two days for mortality and fed with control OP50 or HA-114. Mutant FUS worms fed with HA-114 do not show any lifespan extension when compared to transgenics expressing mutant FUS fed with OP50. **: p< 0.01.
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HA-114 does not require classic stress and metabolic pathways in FUSDS57 worms for neuroprotection. Transgenics were monitored from the adult stage, scored daily for paralysis. Neuroprotection provided by L. rhamnosus HA-114 was unaffected by daf-16(mu86) deletion, nor by hsf-1(sy441) point mutation. Both sir-2.1 and aak-2 genes are not required for neuroprotection granted by HA-114 probiotics.
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kat-1 and elo-6 are essential for neuroprotection provided by HA- 114 in TDP-43A315T ALS model. Transgenics were monitored from the adult stage, scored daily for paralysis. Deletion of kat-1 (A) and elo-6 (B) altered the beneficial effect of HA-114. *: p< 0.05.
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Simplified pathway of fatty acids metabolism and b-oxidation in C. elegans and H. sapiens. Enzymes names are enclosed in rounded rectangles. acdh-1/ACADSB: Acyl CoA dehydrogenase; cpt-1/CPT1: carnitine palmitoyl transferase 1; cpt-2/CPT2 : carnitine palmitoyl transferase 2; elo-6/ELOVL3/6: fatty acid elongase 3/6; kat-1/ACAT1: 3-Ketoacyl-coA thiolase.
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Genes associated with b-oxidation are differentially expressed in the cerebellum and the frontal cortex of c9ALS patients. (A) Differentially expressed genes associated with the b-oxidation pathway between C9orf72 ALS patients and healthy individuals were plotted as heatmap. Red indicates low relative expression and blue indicates high relative expression. (B) Log2 Fold change of differentially expressed genes associated with the b-oxidation pathway between C9orf72 ALS patients and healthy individuals. (C) ACADL expression is upregulated in the cerebellum of c9ALS and ACADVL is downregulated in c9ALS and sALS cerebellum. Interestingly, ACSL5 expression is upregulated in the cerebellum and the frontal cortex of c9ALS. Data: GEO accession: GSM1642314; SRA study: SRP056477.
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HA-114 does not extend lifespan in a SOD1G93A mouse model. Kaplan-Meier plot showing lifespan (A) Probiotics had no effect on body weight (B) hangwire assay (C) nor neurological score (D). 20 mice per group were used.
