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C9orf72 suppresses systemic and neural inflammation induced by gut bacteria

Abstract

A hexanucleotide-repeat expansion in C9ORF72 is the most common genetic variant that contributes to amyotrophic lateral sclerosis and frontotemporal dementia1,2. The C9ORF72 mutation acts through gain- and loss-of-function mechanisms to induce pathways that are implicated in neural degeneration3,4,5,6,7,8,9. The expansion is transcribed into a long repetitive RNA, which negatively sequesters RNA-binding proteins5 before its non-canonical translation into neural-toxic dipeptide proteins3,4. The failure of RNA polymerase to read through the mutation also reduces the abundance of the endogenous C9ORF72 gene product, which functions in endolysosomal pathways and suppresses systemic and neural inflammation6,7,8,9. Notably, the effects of the repeat expansion act with incomplete penetrance in families with a high prevalence of amyotrophic lateral sclerosis or frontotemporal dementia, indicating that either genetic or environmental factors modify the risk of disease for each individual. Identifying disease modifiers is of considerable translational interest, as it could suggest strategies to diminish the risk of developing amyotrophic lateral sclerosis or frontotemporal dementia, or to slow progression. Here we report that an environment with reduced abundance of immune-stimulating bacteria10,11 protects C9orf72-mutant mice from premature mortality and significantly ameliorates their underlying systemic inflammation and autoimmunity. Consistent with C9orf72 functioning to prevent microbiota from inducing a pathological inflammatory response, we found that reducing the microbial burden in mutant mice with broad spectrum antibiotics—as well as transplanting gut microflora from a protective environment—attenuated inflammatory phenotypes, even after their onset. Our studies provide further evidence that the microbial composition of our gut has an important role in brain health and can interact in surprising ways with well-known genetic risk factors for disorders of the nervous system.

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Fig. 1: Environment governs survival, inflammation and autoimmunity in C9orf72 LOF mice.
Fig. 2: Lifelong suppression of gut microflora prevents inflammation and autoimmunity in C9orf72 LOF mice.
Fig. 3: Gut bacteria propagates inflammation and autoimmunity in C9orf72 LOF mice.
Fig. 4: Gut microflora promotes myeloid cell infiltration and microgliosis in C9orf72 LOF spinal cord.

Data availability

The 16S rDNA sequencing dataset are available through the Gene Expression Omnibus repository at GSE147325. All other data generated or analysed are included in the published Article and its Supplementary Information.

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Acknowledgements

Support to K.E. was provided by The Merkin Fund at the Broad Institute, Target ALS, NIH 5R01NS089742, Harvard Stem Cell Institute and UCB. A.B. was supported by NIH 5K99AG057808-02, M.F.W. was supported by NIH 1K99MH119327-01. We thank J. Wang for providing faeces from mice housed Johns Hopkins University.

Author information

Authors and Affiliations

Authors

Contributions

A.B., M.F.W., J.M. and K.E. conceived the study. Experiments were performed by A.B. (Figs. 1–4, Extended Data Figs. 1–9), F.L. (Fig 1, Extended Data Fig. 2), M.F.W. (Fig. 1, Extended Data Fig. 2), K.S.S. (Fig. 4, Extended Data Figs. 8, 9), A.C. (Figs. 2–4, Extended Data Figs. 3–9), J.M. (Figs. 1–3, Extended Data Figs. 2–6, 8), N.v.G. (Extended Data Fig. 2), J.-Y.W. (Fig. 4, Extended Data Fig. 8), J.K. and G.G. (Extended Data Fig. 8), and M.Q. and P.E. and C.C. (Figs. 2, 3, Extended Data Figs. 3, 4, 8). A.B., F.L., K.S.S., J.K., G.G, N.v.G., J.-Y.W., O.P., I.K., D.T.S. and K.E. interpreted results. A.B. and K.E. wrote the manuscript.

Corresponding author

Correspondence to Kevin Eggan.

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Competing interests

K.E. is a co-founder of Q-State Biosciences, Quralis and Enclear Therapies.

Additional information

Peer review information Nature thanks Michael Fischbach, Aaron D. Gitler and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

Extended Data Fig. 1 Previously published C9orf72 LOF survival studies.

a, From ref. 7. Reproduced with permission from AAAS. b, From ref. 7. Reproduced with permission from AAAS. c, Reproduced from ref. 12, licensed under a CC BY 4.0 licence. d, Reprinted from ref. 13, with permission from Elsevier. e, From ref. 6. Reproduced with permission from AAAS.

Extended Data Fig. 2 Causes of death, motor performance, levels of plasma cytokines and identification of pseudothrombocytopenia in C9orf72 LOF mice.

a, Causes of death or premature mortality of C9orf72(Harvard) mice in Fig. 1b. b, Accelerating rotarod performance of 37-week-old C9orf72(Harvard) neo-deleted mice (C9orf72(Harvard)+/+, n = 22; C9orf72(Harvard)+/−, n = 50; C9orf72(Harvard)−/−, n = 22). c, Accelerating rotarod performance of C9orf72(Broad) neo-deleted mice at 29 weeks of age (C9orf72(Broad)+/+, n = 53; C9orf72(Broad)+/−, n = 52; C9orf72(Broad)−/−, n = 48) or 42 weeks of age (C9orf72(Broad)+/+, n = 38; C9orf72(Broad)+/−, n = 48; C9orf72(Broad)−/−, n = 48). In b, c, one-way ANOVA with Dunnett’s multiple comparisons. Each point represents the average of three trials per mouse. d, Age at which mice in Fig. 1d–g were killed. One-way ANOVA with Sidak’s multiple comparisons. e, Plasma cytokines and chemokines at death from mice in Fig. 1d–g. Mean ± s.d. Two-way ANOVA with Tukey’s multiple comparisons. f, Peripheral blood smear of 18-week-old C9orf72(Harvard) neo-deleted mice. Platelets from C9orf72(Harvard)−/− mice were prone to aggregate (outlined by red dashed lines) in the presence of EDTA at 0 °C. g, Pseudothrombocytopenia could be reversed by warming the blood to room temperature. The reduced platelet count in the C9orf72(Harvard)−/− model therefore represents an indirect measure of anti-platelet auto-antibodies, rather than a reduction in platelet abundance. Two-way ANOVA with Tukey’s multiple comparisons. Each dot represents one mouse.

Source Data

Extended Data Fig. 3 Cytokines and chemokines in lifelong-antibiotic-treated C9orf72 LOF mice and sex stratification of inflammatory phenotypes.

a, PCR analysis of Helicobacter spp. and norovirus DNA in faecal pellets. Each dot represents faeces from one cage. One-way ANOVA with Dunnett’s multiple comparisons. b, Plasma cytokines and chemokines of mice in Fig. 2. Mean ± s.d. Two-way ANOVA with Tukey’s multiple comparisons. c, Representative spleen size of mice in Fig. 2. df, Total blood neutrophil count (d), platelet count (e) and spleen weight (f) from mice in Fig. 2, stratified by sex. g, h, Total blood neutrophil count (g) and platelet count (h) in 30-week-old C9orf72(Harvard) neo-deleted mice stratified by sex (C9orf72(Harvard)+/+, n = 9 male and 13 female; C9orf72(Harvard)+/−, n = 25 male and 27 female; C9orf72(Harvard)−/−, n = 13 male and 9 female). i, Spleen weight in 40-week-old C9orf72(Harvard) neo-deleted mice stratified by sex (C9orf72(Harvard)+/+, n = 8 male and 11 female; C9orf72(Harvard)+/−, n = 13 male and 7 female; C9orf72(Harvard)−/−, n = 12 male and 6 female). In di, each dot represents one mouse. One- way ANOVA with Sidak’s multiple comparisons.

Source Data

Extended Data Fig. 4 Acute antibiotic treatment improves motor function, and mitigates splenomegaly and cytokine burden, in C9orf72 LOF mice.

a, Accelerating rotarod performance of mice in Fig. 3a. Each point represents the average of three trials per mouse. Two-way ANOVA with Dunnett’s multiple comparisons. b, Plasma cytokines and chemokines of mice in Fig. 3a–d after seven weeks of treatment. c, d, Representative spleen size (c) and spleen weight (d) of mice in Fig. 3a after eight weeks of treatment. Each dot represents one mouse. One-way ANOVA with Sidak’s multiple comparisons. e, Plasma cytokines and chemokines of mice in Fig. 3e–h 10 weeks after faecal transplant. In b, e, mean ± s.d. Two-way ANOVA with Tukey’s multiple comparisons.

Source Data

Extended Data Fig. 5 Bacteria and protozoa diversity across environments.

a, b, Phylum-level (a) and species-level (b) relative abundance of bacteria from 16S rDNA sequencing in Fig. 3i. Each bar represents sequencing from one pellet per cage. c, d, Relative abundance (c) and Gram-stain classification (d) of bacterial species, the abundance of which was significantly different between pro-inflammatory environments (Harvard BRI and Johns Hopkins University) and pro-survival environments (Broad Institute and Jackson Laboratory). t-test with Bonferroni multiple comparisons; 62/301 detected species had significance P < 0.0002. n = 5 faecal pellets per environment. Mean ± s.d. e, Quantitative PCR with reverse transcription analysis of T. muris 28S rDNA relative to total Eubacteria 16S rDNA in faeces. f, Simpson index of faecal α-diversity. g, Relative abundance of ε proteobacteria (Helicobacter). In eg, each dot represents a faecal pellet from one cage. One-way ANOVA with Tukey’s multiple comparisons. h, PCR analysis of Helicobacter spp.16S rDNA and total Eubacteria 16S rDNA in faeces. i, PCR analysis of Helicobacter spp.16S rDNA and total Eubacteria 16S rDNA in faeces (six weeks after transplant) from Fig. 3e.

Source Data

Extended Data Fig. 6 Environment-enriched bacteria engraft faecal-transplant recipients.

af, Analysis of bacteria in faeces at 10 weeks after transplant (from mice in Fig. 3e) by 16S rDNA sequencing. Each bar represents a faecal sample from an individual cage. a, b, Phylum-level (a) and species-level (b) relative abundance. c, Relative abundance of bacterial species grouped as those only observed in cages from Harvard BRI (Harvard-only), those only observed in cages from the Broad Institute (Broad-only), those observed in cages from Harvard BRI and the Broad Institute (Harvard/Broad-shared) or those not observed in Harvard BRI or Broad Institute cages but detectable in transplant recipient cages (emergent). d, Bray–Curtis dissimilarity matrix of faeces β-diversity. e, Relative abundance of ε proteobacteria (Helicobacter). f, Putative pro-inflammatory species (n = 27) enriched in pro-inflammatory environments (Harvard BRI and Johns Hopkins University) that were also enriched in Harvard-to-Harvard recipients, and putative pro-survival species (n = 12) enriched in pro-survival environments (Broad Institute and Jackson Laboratory) and enriched in Broad-to-Harvard recipients.

Source Data

Extended Data Fig. 7 C9orf72 restricts myeloid cytokine release in response to foreign stimuli.

ad, Analysis of cytokines and chemokines in supernatant 24 h after stimulation of bone-marrow-derived macrophages (BMDM) with activators of Toll-like receptor (Tlr) or NOD-like receptor (Nlr) agonists (ac) or filtered Eubacteria-normalized faecal preparations (d). c, The abundance of cytokine and chemokine in the supernatant was normalized and colour-coded (blue, low; red, high) relative to the average level of each molecule in unstimulated C9orf72+/+ bone-marrow-derived macrophage wells. Levels of each analyte were measured by Luminex in multiplex. d, The abundance of total Eubacteria in each faecal sample was measured by qPCR for 16S rDNA and this value was used to normalize faecal Eubacteria bacteria concentration before generation of the dilution curve. Each dot represents one well. Panels are representative of n = 2 replicate experiments (a); n = 5 replicate experiments (b); one representative experiment with average of n = 3 technical replicates per condition (c); n = 2 replicate experiments (d). In a, two-way ANOVA with Sidak’s multiple comparison. In b, two-way ANOVA with Dunnett’s multiple comparisons. In c, two-way ANOVA with Sidak’s multiple comparison for each analyte tested. In d, one-way ANOVA with Sidak’s multiple comparisons.

Source Data

Extended Data Fig. 8 Neutrophils and T cells infiltrate spinal cord of C9orf72 LOF mice.

af, Mass cytometry investigation of single-cell-dissociated forebrain or spinal cord from 36-week-old C9orf72(Harvard) neo-deleted male and female mice (C9orf72(Harvard)+/+, n = 7; C9orf72(Harvard)+/−, n = 7; C9orf72(Harvard)−/−, n = 8). One C9orf72 +/+ forebrain sample failed, and was excluded from analysis. Representative gating scheme can be found in Supplementary Information. Populations were defined as CD45mid CX3CR1+CD39+ microglia (a), CD45highLy6C+Ly6Ghigh neutrophils (b), CD45highLy6C+Ly6Glow monocytes (c), CD45highCD3e+CD4+ T cells (d), CD45highCD3e+CD4 T cells (e) and CD45highCD19+ B cells (f). Quantification of total cells per tissue was obtained by multiplying the percentage of each gated population by the total cells recovered from the tissue of that mouse. Each dot represents one mouse. Two-way ANOVA with Dunnett’s multiple comparisons. g, Quantitative PCR with reverse transcription of Ly6c expression in total cortex tissue of 47-week-old C9orf72(Harvard) neo-deleted mice (C9orf72(Harvard)+/+, n = 8; C9orf72(Harvard)−/−, n = 9) or C9orf72(Broad) neo-deleted mice (C9orf72(Broad)+/+, n = 10; C9orf72(Broad)−/−, n = 9). Each dot represents one mouse. One-way ANOVA with Sidak’s multiple comparisons. h, Orthogonal projection of confocal imaging of CD11b and mouse immunoglobulin IgG in lumbar spinal cord of a 43-week-old C9orf72(Harvard) mouse.

Source Data

Extended Data Fig. 9 Elevated lysosomal proteins and microgliosis in spinal cords of C9orf72 LOF mice.

a, b, eg, Orthogonal projection and quantification of confocal imaging of LAMP1 (a), cathepsin B (b), CCR9 (e), dectin 1 (CLEC7A) (f) and LPL (g) in IBA1+ microglia in spinal cord of a 55-week-old C9orf72(Harvard) mouse. One-way ANOVA with Sidak’s multiple comparisons. Each dot represents the average mean fluorescent intensity (MFI) of the antigen within microglia on a given spinal cord section. Over 100 microglia were surveyed per section. Sections from n = 3 C9orf72+/+ and n = 3 C9orf72−/− mice were surveyed. c, d, Flow cytometry quantification of LAMP1 (c) or cathepsin B (d) in CD45midCD11b+CD39+ microglia from spinal cord of C9orf72(Harvard) neo-deleted mice in Fig. 2. One-way ANOVA with Sidak’s multiple comparisons. h, Graphical illustration of C9orf72 functioning within the haematopoietic system to restrict the development of inflammation, autoimmunity, peripheral immune infiltration into the central nervous system (CNS) and microgliosis in response to hyper-stimulatory communities of gut microflora. The microglia image was modified from Servier Medical Art (https://smart.servier.com/smart_image/microglia-2/) under a CC BY 3.0 licence.

Source Data

Supplementary information

Supplementary Table

SI Table 1 | Difference in microbiota between vivaria and SI Mass cytometry gating | Forebrain and spinal cord population gating.

Reporting Summary

Supplementary Figures

SI Un-cropped gel images | Un-cropped gel images for Extended Data Fig 5h-i.

Video 1

SI Video. 1 | CD45 (Green) and mouse IgG (Red) staining of C9orf72 +/+ spinal cord (mp4).

Video 2

SI Video. 2 | CD45 (Green) and mouse IgG (Red) staining of C9orf72 -/- spinal cord (mp4).

Video 3

SI Video. 3 | Iba1 (Green) and Lamp1 (Magenta) staining of C9orf72 +/+ spinal cord (mp4).

Video 4

SI Video. 4 | Iba1 (Green) and Lamp1 (Magenta) staining of C9orf72 -/- spinal cord (mp4).

Video 5

SI Video. 5 | CD11b (Green) and Cathepsin B (Magenta) staining of C9orf72 +/+ spinal cord (mp4).

Video 6

SI Video. 6 | CD11b (Green) and Cathepsin B (Magenta) staining of C9orf72 -/- spinal cord (mp4).

Video 7

SI Video. 7 | Iba1 (Green) and Dectin1 (Magenta) staining of C9orf72 +/+ spinal cord (mp4).

Video 8

SI Video. 8 | Iba1 (Green) and Dectin1 (Magenta) staining of C9orf72 -/- spinal cord (mp4).

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Burberry, A., Wells, M.F., Limone, F. et al. C9orf72 suppresses systemic and neural inflammation induced by gut bacteria. Nature 582, 89–94 (2020). https://doi.org/10.1038/s41586-020-2288-7

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