LPA3 agonist-producing Bacillus velezensis ADS024 is efficacious in multiple neuroinflammatory disease models

•A selective agonist of GPCR LPA3 is produced by Bacillus velezensis ADS024.•Oleoyl-LPA and an extract of ADS024 promote LPA3 recruitment of 14–3-3 proteins.•ADS024 modifies cell-surface expression of LPA3 on immune cells in a MOG-EAE model.•ADS024 is efficacious in neuroinflammatory disease models...

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Published in:Brain, behavior, and immunity behavior, and immunity, 2024-10, Vol.121, p.384-402
Main Authors: Acton, Susan, O’Donnell, Michelle M., Periyasamy, Kalaichitra, Dixit, Bharat, Eishingdrelo, Haifeng, Hill, Colin, Paul Ross, R., Chesnel, Laurent
Format: Article
Language:English
Subjects:
14–3-3 proteins
Amyotrophic Lateral Sclerosis
Bacillus velezensis
Bacteria
Chemotherapy-Induced Peripheral Neuropathy
GPCR
Gut-brain-immune axis
Huntington’s Disease
LPA3
Multiple Sclerosis
Neuroinflammation
Parkinson’s Disease
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Summary:•A selective agonist of GPCR LPA3 is produced by Bacillus velezensis ADS024.•Oleoyl-LPA and an extract of ADS024 promote LPA3 recruitment of 14–3-3 proteins.•ADS024 modifies cell-surface expression of LPA3 on immune cells in a MOG-EAE model.•ADS024 is efficacious in neuroinflammatory disease models of PD, HD, MS, ALS, CIPN.•Broad efficacy of ADS024 suggests a common anti-neuroinflammatory mechanism. Neuroinflammation is a common component of neurological disorders. In the gut-brain-immune axis, bacteria and their metabolites are now thought to play a role in the modulation of the nervous and immune systems which may impact neuroinflammation. In this respect, commensal bacteria of humans have recently been shown to produce metabolites that mimic endogenous G-protein coupled receptor (GPCR) ligands. To date, it has not been established whether plant commensal bacteria, which may be ingested by animals including humans, can impact the gut-brain-immune axis via GPCR agonism. We screened an isopropanol (IPA) extract of the plant commensal Bacillus velezensis ADS024, a non-engrafting live biotherapeutic product (LBP) with anti-inflammatory properties isolated from human feces, against a panel of 168 GPCRs and identified strong agonism of the lysophosphatidic acid (LPA) receptor LPA3. The ADS024 IPA extracted material (ADS024-IPA) did not agonize LPA2, and only very weakly agonized LPA1. The agonism of LPA3 was inhibited by the reversible LPA1/3 antagonist Ki16425. ADS024-IPA signaled downstream of LPA3 through G-protein-induced calcium release, recruitment of β-arrestin, and recruitment of the neurodegeneration-associated proteins 14–3-3γ, ε and ζ but did not recruit the β isoform. Since LPA3 agonism was previously indirectly implicated in the reduction of pathology in models of Parkinson’s disease (PD) and multiple sclerosis (MS) by use of the nonselective antagonist Ki16425, and since we identified an LPA3-specific agonist within ADS024, we sought to examine whether LPA3 might indeed be part of a broad underlying mechanism to control neuroinflammation. We tested oral treatment of ADS024 in multiple models of neuroinflammatory diseases using three models of PD, two models of MS, and a model each of amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and chemo-induced peripheral neuropathy (CIPN). ADS024 treatment improved model-specific functional effects including improvements in motor movement, breathing and swallowing, and allodynia suggesting th
ISSN:0889-1591
1090-2139
1090-2139
DOI:10.1016/j.bbi.2024.08.024