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Role of the Intestinal Microbiota in ALS

Award Number: R01NS115951
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Role of the Intestinal Microbiota in ALS - PROJECT SUMMARY ALS is a neurodegenerative disease affecting motor neurons with limited treatment options and a median survival of 3-5 years. We submit a significantly revised proposal that addresses the comments of the reviewers and provides new preliminary data. Our hypothesis is that the intestinal microbiome and its metabolites play an important role in in ALS by modulating peripheral and CNS immunity and by affecting ALS disease pathways. Our hypothesis is strengthened by a recent paper in Nature by Blacher showing an important role of the gut microbiome and metabolites in ALS. In new preliminary data we show: 1) Antibiotics that worsen survival also downregulate microglia homeostatic genes while upregulating inflammatory genes. 2) Changes in the microbiome in 68 ALS patients vs. 61 healthy controls (largest microbiome study to date), including a decrease in butyrate producing bacteria E. rectale and R. intestinalis, are robust when controlled for ALS clinical confounders. 3) Administering these bacteria or Akkermansia reverses SOD1-disease associated transcriptional changes in the spinal cord; including Fus, Oxr1, and Smn1, and protein degradation (Ubqln1). 4) Transferring SOD1 microbiota to WT mice modulates microglia pathways involved in ALS related to RNA processing (Fus), protein degradation (HSPa1b and USP2) and lysosomal transport (CD68 and Lyz2). We believe there is compelling evidence to support the investigation of the microbiome in ALS. We will address these aims: AIM 1. Which microbial components are associated with protection in SOD1 and TDP-43 models? We will deplete the microbiota with specific low-dose antibiotics, orally administer Akkermansia components and a unique micro-RNA and identify brain, serum, and stool metabolites associated with disease protection. AIM 2. Which human microbiota components contribute to disease pathogenesis? It is unknown whether the ALS microbiota can also drive disease pathogenesis. We will transfer microbiota from patients with ALS to the SOD1 and TDP-43 models and measure motor function and survival time. We will identify microbial populations, functions, and metabolites that are associated with protection or worsening of disease. We will also confirm and expand our findings in the ALS microbiome in a newly recruited cohort. AIM 3. Investigate the immune mechanisms by which the gut microbiota modulates disease progression in ALS animal models. We will sort microglia, monocytes, and T cells from mice treated with individual antibiotics, colonized with ALS microbiota, or specific bacterial strains and characterize transcriptional signatures by RNAseq. Utilizing WT mice to investigate how the microbiota affect microglia, we will transfer specific microbes identified associated with ALS and screen for changes in genes involved in ALS pathogenesis.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $621,167 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/17/2024	NON-COMPETING CONTINUATION	$621,167
														Subtotal = $621,167

Issue Date FY: 2024 ( Subtotal = $669,479 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/24/2024	NON-COMPETING CONTINUATION	$621,167
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/10/2024	NON-COMPETING CONTINUATION	$48,312
														Subtotal = $669,479

Issue Date FY: 2023 ( Subtotal = $797,842 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	1/30/2023	NON-COMPETING CONTINUATION	$69,017
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	1/31/2023	SUPPLEMENT FOR EXPANSION	$107,658
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/19/2022	NON-COMPETING CONTINUATION	$621,167
														Subtotal = $797,842

Issue Date FY: 2022 ( Subtotal = $797,154 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	2	3/24/2022	NON-COMPETING CONTINUATION	$69,017
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	2/7/2022	SUPPLEMENT FOR EXPANSION	$106,970
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/24/2022	NON-COMPETING CONTINUATION	$621,167
2022	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/22/2021	NEW	$0
														Subtotal = $797,154

Issue Date FY: 2021 ( Subtotal = $709,934 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/14/2021	NEW	$709,934
														Subtotal = $709,934

Grand Total All Awards = $3,595,576

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Role of the Intestinal Microbiota in ALS

Award Number: R01NS115951

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/15/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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