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Akkermansia mono-colonization modulates microglia and astrocytes in a strain specific manner

Journal of Neuroinflammation volume 22, Article number: 94 (2025) Cite this article

This article has been updated

Abstract

Microglia and astrocytes are the primary glial cells in the central nervous system (CNS) and their function is shaped by multiple factors. Regulation of CNS glia by the microbiota have been reported, although the role of specific bacteria has not been identified. We colonized germ-free mice with the type strain Akkermansia muciniphila (AmT) and a novel A. muciniphila strain BWH-H3 (Am-H3) isolated from a subject with multiple sclerosis and compared to mice colonized with Bacteroides cellulosilyticus strain BWH-E5 (Bc) isolated from a healthy control subject. We then investigated the effect of these bacteria on microglia and astrocyte gene expression by RNA sequencing. We found altered gene expression profiles in brain microglia, with Akkermansia downregulating genes related to antigen presentation and cell migration. Furthermore, we observed strain specific effects, with Akkermansia H3 upregulating histone and protein binding associated genes and downregulating channel and ion transport genes. Astrocyte pathways that were altered by Akkermansia H3 mono-colonization included upregulation of proliferation pathways and downregulation in cytoskeletal associated genes. Furthermore, animals colonized with type strain Akkermansia and strain H3 had effects on the immune system including elevated splenic γδ-T cells and increased IFNγ production in CD4 + T cells. We also measured intestinal short chain fatty acids and found that both A. muciniphila strains produced proprionate while B. cellulosilyticus produced acetate, proprionate, and isovalerate. Taken together, our study shows that specific members of the intestinal microbiota influence both microglial and astroyctes which may be mediated by changes in short chain fatty acids and peripheral immune signaling.

Introduction

Microbes and their metabolic products are key regulators of the gut-brain axis. How gut resident bacterial species influence central nervous system glia including microglia and astrocytes is not well understood. Eluciating this relationship has important implications for developing microbiome based therapies to modulate nervous system disease. Germ free (GF) mice are a valuable tool for investigating microbes and their effect on both central and peripheral immunity. GF mice do not harbor a native microbiota and thus can be mono-colonized with individual bacterial strains [1, 2]. Mono-association studies have shown a protective capacity of microbes in inflammatory bowel disease models [3, 4] and immune effects including increased Foxp3 + Treg production in mice mono-colonized with B. fragilis [2].

In multiple sclerosis (MS), one of the most consistent findings is an elevation in Akkermansia [1, 5,6,7,8,9,10,11], which we have previously associated with improved clinical outcomes [6, 11]. These findings raise the question of whether Akkermansia has a beneficial or detrimental effect on the disease. In one study, investigators found that incubating Akkermansia with PBMCs increased IFNγ production by CD4 + T cells in vitro. However, mono-colonization with Akkermansia did not increase inflammatory cytokines in vivo [1]. In the autoimmune encephalomyelitis (EAE) model we and others have found that administering Akkermansia to specific pathogen free (SPF) mice, which harbor a full microbiome, ameliorated disease [6, 12]. There are 4 clades of Akkermansia which have differential metabolic and immunologic effects [13], and mono-colonization approachs have been used to define microbe-immune interactions in mice harboring > 50 bacterial species [14]. We identified novel MS-derived Akkermansia strains and found that Am-H3 had the greatest effect in EAE and reduced IL-17 producing γδ-T cell [15, 16]. Although it has been demonstrated that Akkermansia strains can affect immunity in mono-colonization models and CNS disease in EAE, their effect on microglia and astrocytes, the major glial cells in the CNS, is unknown.

The development of microglial and their homeostatic function is dependent on the gut microbiota [17]. Microglial in GF mice have an immature phenotype and are inefficient in clearing pathogens, which can be restored by reconstitution of the gut microbiota or treatment with several microbial metabolites including short chain fatty acids (SCFAs) [17]. In Alzheimer’s and Parkinson’s models, GF mice have showed decreased disease pathology and immature microglial. The addition of SCFAs increased microglial activation and disease pathology to the level of SPF models [18]. These data demonstrate a critical role of gut microbiota and their metabolites in maintaining CNS immune homeostasis in both health and disease.

In order to investigate the strain-specific role of Akkermansia on CNS glia, we mono-colonized germ free mice with type strain Akkermansia muciniphila (AmT) or a strain of Akkermansia isolated from an MS subject at Brigham and Women’s Hospital, Akkermansia strain H3 (Am-H3) [6], and analyzed their effects on microglia and astrocytes as measured by transcriptomics.

Materials and methods

Animals

All animal procedures were approved by the Brigham and Women’s Hospital IACUC. Germ-free mice on the C57BL/6 background (Jackson Laboratory, Bar Harbor, ME) were bred at the Massachusetts Host-Microbiome Center’s gnotobiotic core and were maintained under a 12 h light-dark cycle and received water and chow ad libitum.

Mono-colonization

At 8-weeks of age, mice received a single oral gavage with 200 Âµl of one of four treatments: vehicle (brain heart infusion broth; Veh), Akkermansia muciniphila type strain (AmT; ATCC BAA-835), Akkermansia muciniphila strain BWH-H3 (Am-H3), or Bacteroides cellulosyliticus strain BWH-E5 (Bc; Fig. 1A). All bacterial cultures were diluted to 1 × 108 CFU/mL in brain heart infusion broth. Mice were maintained germ-free for 2-weeks with one cage change 7 days into the experiment. Confirmation of mono-association was performed at the end of experiment via microbiological culture of cecal samples at the Host-Microbiome Center. Cecal contents were plated onto tryptic soy agar (Veh samples) and incubated in ambient oxygen air, onto Brucella blood agar with menadione (Bc samples) or brain heart infusion plates (AmT, Am-H3 samples) and incubated anaerobically. Aerobic and anaerobic microbial growth were viewed for each group as were Gram stains. Veh samples with growth or Gram stain reactivity in any oxygen condition were considered contaminated. Any aerobic growth or aerobic Gram stain reactivity in the Bc, AmT, or Am-H3 groups was considered a contaminated sample. Anaerobic growth and a Gram stain with expected structure of microbe of interest was required to be considered mono-colonized (e.g., Gram negative rods consistent with Akkermansia). A total of n = 68 animals were inoculated with one of the 4 treatments, of which n = 43 were confirmed to be mono-associated giving a success rate of 63.2%. Successful mono-colonization rates by group were as follows: Veh treated = 53.9%, AmT = 75%, Am-H3 = 47.1%, and Bc = 72.2%. Animals that were determined to not be mono-colonized were omitted from the study.

Fig. 1
figure 1

Microbial mono-colonization schematic and plots of PCA scores. Schematic showing workflow for mono-colonization through to RNAseq (A). PCA plots for four mono-colonized groups show PCA scores for microglia (B) and astrocytes (C) by treatment. PERMANOVA of PCA scores (D). Individual group PCAs are in Figure S1

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Tissue processing

After sacrifice via CO2 inhalation, mice received thoracotomy and subsequent transcardial perfusion with ice cold HBSS. Brains were removed and the whole left hemisphere was placed into 7mL glass tissue homogonizer with cold HBSS. Tissue was homogenized prior to centrifugation in 4° C at 1200 g for 7 min and subsequent aspiration of supernatant. Pellets were resuspended in 5mL of 37% Percoll before centrifugation at 4° C at 800 xg for 10 min. Percoll was washed with 5 mL FACS buffer (v: v in HBSS: 2% FBS, 2.5% HEPES, 0.4% EDTA) before centrifugation in 4° C at 1200 g for 7 min and supernatant was aspirated until ∼ 50 µl remained in the tube. Cells were stained for FACS using anti-CD45 FITC (1:400; BD, Franklin Lakes, NJ, USA), anti-CD11b PeCy7 (1:400; Biolegend), anti-ACSA-2 PE (1:200; Miltenyi Biotec, Bergisch Gladbach, Germany). Lineage negative markers were used including PerCP conjugated antibodies at 1:800 dilution to anti-CD3, anti-CD19, anti-Nk1.1, anti-B220, and anti-Ly6G (Biolegend). Cells were incubated with antibodies for 25 min at RT in the dark before being washed with 5 mL FACS buffer and subsequently centrifuged in 4° C at 1200 xg for 7 min. Supernatants were aspirated and pellets resuspended in 100 µl of FACS buffer. Cells were transferred to flow polystyrene tubes and washed with 50 µl FACS buffer. Finally, cells were transferred into clean Eppendorf tubes containing 5 µl of 7-AAD. Microglia and astrocytes were sorted on a BD FACSAria II cell sorter. After sorting, cells were spun at 3500 xg for 10 min at 4° C before being processed for RNAseq.

SCFA quantification

Cecal contents were removed and placed into a sterile Eppendorf tube prior to analysis of SCFAs via gas chromatography-mass spectrometry at the Massachusetts Host-Microbiome Center. Samples were analyzed for the following short-chain acids: acetate, propionate, isobutyrate, butyrate, isovalerate, valerate, isocaproate, caproate, and heptanoate. Detectable levels were observed in a majority of samples for 4 SCFAs: acetate, propionate, isobutyrate, and isovalerate which were quantified and analyzed via one-way ANOVA across mono-colonization groups.

RNAseq

Microglia and astrocytes were processed on the same plate at the Broad Institute using their mRNA SMART-Seq2 Cell Population v1 sequencing pipeline. Transcriptome alignments were conducted using the Salmon tool with its standard parameters [19]. The R software (version 4.2.1) and DESeq2 package (version 1.36.0) [20] were employed to analyze differential gene expression. After transcript alignment with Salmon, genes were filtered based on adjusted p value < 0.1 and p value < 0.05 to yield a significant DEGene table. The genes used to generate heatmaps were further filtered and selected based on an adjusted p value < 0.05, a baseMean greater than 20, and a log2 fold change exceeding 1.5. We then used Ingenuity Pathway Analysis (IPA; Qiagen, Hilden, Germany) to identify pathways based on 626 and 909 input genes for microglia and astrocytes, respectively. Genes included in pathway analysis were chosen in IPA based on the number of genes remaining after filtering on unadjusted p < 0.05 [21,22,23] and fold change between − 1.5 and 1.5. Pathway outputs are presented based on p value < 0.05 across mono-colonization groups and presented according to biological relevance.

Flow cytometry

Spleens were homogeized and passed through a 70 Î¼m mesh filter on a 96-well culture plate containing complete media composed of: v:v; Iscove’s modified dulbecco’s medium (Gibco, Grand Island, NY, USA) supplemented with 10% fetal bovine serum (FBS; Thermo Fisher Scientific, Waltham, MA, USA), 1% penicillin/streptomycin (Thermo Fisher Scientific, Waltham, MA, USA), 1% Non-essential amino acid solution (Millipore-sigma, St. Louis, MO, USA), and 0.1% 2-Mercaptoethanol (Gibco, Grand Island, NY, USA). Splenocytes were centrifuged at 2000 rcf for 3 min. Supernatant was aspirated and cells were incubated for 2 min at RT in 1 mL ACK lysing buffer (Gibco, Grand Island, NY, USA). Cell pellet then received 10 mL of FACS buffer before being centrifuged at 2000 rcf for 3 min. Supernant was then aspirated prior to resuspension in 1 mL of complete media. Cells were filtered a second time before being plated at 50 µL per well and subsequently centrifuged at 2000 rcf for 3 min and decanted to remove remaining FACS buffer. Cells were treated with Fc blocking antibody (BD) at 1:200 dilution in FACS buffer and incubated at 4 C for 5 min. Next, 50 µL of zombie fixable viability stain (BioLegend, San Diego, CA, USA) was added prior to incubation at 4 C for 20 min. Cells were then centrifuged and decanted prior to washing 1x in 150 µL FACS buffer before addition of 50 µL extracellular antibody solution or fluorescence minus one (FMO) controls. Antibodies for extracellular staining were as follows: BUV395-anti-CD62L (1:800; BD), BUV496-anti-CD4 (1:800; BD), BV785-anti-CD8 (1:800; Biolegend), AF700-anti-CD44 (1:400; Biolegend), APC-Cy7-anti-CD3 (1:400; Biolegend), BV605-anti-PD-1 (1:400; Biolegend), PE-anti-LAP (1:400; Biolegend), PE-Dazzle-594-anti-CXCR3 (1:400; Biolegend), APC-anti-γδTCR (1:400; Carlsbad, CA, USA), BV650-anti-CXCR5 (1:200; Biolegend), Per-Cp-anti-CD107 (1:100; Biolegend). Cells were incubated in antibody solution for 20 min at 4 C before washing with 150 µL FACS buffer, centrifugation, and decanting. Intracellular staining was performed by resuspending splenocytes in 100 µL of fixation and permeabilization solution from a Foxp3 / transcription factor staining buffer set (eBioscience, San Diego, CA, USA) for 20 min at 4 C. Cells were washed with 200 µL permeabilization buffer and centrifuged at 2000 rcf for 3 min. After decanting, 50 µL of intracellular antibody solution or FMO controls was added to appropriate wells. Splenocytes for cytokine analysis were stimulated at 37 Â°C for 4 h with PMA/ionomycin and GolgiStop containing monensin (1:1000; BD) prior to being centrifuged at 1500 rcf for 5 min and decanted. Cells were washed with 200 µL FACS buffer before centrifugation at 2000 rcf for 3 min and subsequently decanted. Antibodies for cytokine staining were as follows: APC-Cy7-anti-CD3, BUV496-anti-CD4, BV785-anti-CD8, and BV421-anti-IFNγ (1:400, Biolegend). Cells were incubated in antibody solution for 30 min at RT before being washed with 200 µL of permeabilization buffer, centrifuged, and decanted. Splenocytes were resuspended in 400 µL of FACS buffer and transferred to flow tubes. Cells were processed for flow cytometric acquisition on a Fortessa using DIVA software (BD Biosciences). Data was analyzed in FlowJo (v10.1, TreeStar Inc, Ashland, OR, USA).

Goblet cell analysis

Lectin labelling was performed on 50 Î¼m sections of proximal colon from mono-colonized animals. Protocols were similar to those previously described [24]. Sections received 1.25 Âµg / mL of the lectin Ulex europus agglutinin– 1 (UEA-1; Vector Laboratories, Newark, CA) conjugated to fluorescein and diluted in PBS with 1% BSA, 5% CaCl2, 2% polyvinylpyrolodine-40, and 0.125% Tween-20 to incubation for 72 h. After incubation with UEA-1, sections were washed in PBS before mounting (Aqua-Poly/Mount; Polysciences, Inc., Warrington, PA) and imaged on a Leica DMi8 Widefield microscope. Quantification of goblet cell counts and size was performed as previously described [25], with z-stack images being acquired at 1 Î¼m intervarls from 3 crypts / section, from 3 sections for each animal being averaged and reported with the n = 3 animals / group. Image analysis was performed on max intensity Z-projections using FIJI (v2.14, 1.54f; NIH).

Data and code availability

All raw sequencing data is accessible at the NCBI Sequence Read Archive: SUB14686820 and BioProject PRJNA1152580. We used standard bioinformatic workflows throughout this study which are available on a GitHub repository (https://github.com/tobylanser/akk_monocolonization).

Results

Mono-colonization with Akkermansia modulates microglia gene expression

We previously found a differential effect of Akkermansia strains and B. cellulosyliticus on CNS inflammation in the experimental autoimmune encephalomyelitis (EAE) model [6]. In order to identify strain-specific effects on glia, we mono-colonized mice with these strains and investigated transcriptional profiles of microglia and astrocytes. Principal component analysis (PCA) plots based on the mono-colonization group vs. vehicle controls (Fig. 1B-C, Figure S1A). Results of PERMANOVA on PCAs show R2 and p values for microglia and astrocytes with Veh vs. Am-H3, Veh vs. Bc, and Am-H3 vs. Bc being significantly different for astrocytes, while only Veh vs. Am-H3 trended towards significant (p = 0.06) in microglia (Fig. 1D). Microglia gene expression demonstrated a downregulation of Ndufaf7, Mmgt2, and Lpar6 in AmT treated mice vs. vehicle GF animals and an upregulation of Dgkq and Nhsl2 among others (Fig. 2A-B). Furthermore, Am-H3 mono-colonized mice had 18 downregulated and 14 upregulated genes vs. Veh (Fig. 2C-D). When we compared AmT treated mice vs. Am-H3, we found 1 significantly altered gene, Tbc1d24, and when comparing Veh vs. a gram negative control bacteria, Bc, we found 3 genes significantly altered, Pcdh17, Dennd1a, and Gprin2. In microglia from mice mono-colonized with Am-H3 vs. Bc, 8 genes were downregulated and 4 upregulated (Fig. 2E-F). Analysis of all significant (p < 0.05) DEGs (Additional file 1) using IPA showed that mono-colonization with any microbe altered pathways involved in cellular immunity, extracellular matrix organization, and nervous system signaling (Fig. 2G). When comparing AmT vs. Am-H3 mono-colonized animals we found altered pathways involved in cellular immune response, nervous system signaling, and extracellular matrix related alterations (Fig. 2H). Genes contributing to identified IPA pathways are available in Additional file 3.

Fig. 2
figure 2

Mono-colonization with Akkermansia alters microglia gene expression. Altered gene expression in AmT mono-colonized animal microglia compared to Veh (A) and representative DEGene count graphs (B). Genes altered between Am-H3 vs. Veh (C) and representative bar graphs of DEGene counts (D). Significantly altered genes between Bc and Am-H3 (E) and representative graphs of up and downregulated DEGene counts (F). Ingenuity Pathway Analysis (IPA) top pathways altered in animals mono-colonized with microbes vs. vehicle treated for relevant pathway families (G). Pathways identified in IPA significantly (-log(p-val) > 1.3) for AmT vs. Am-H3 groups (H). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. n = 6 Veh, Am-H3, n = 7 for AmT and Bc

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Akkermansia mono-colonization modulates astrocyte gene expression

We then investigated the impact of mono-colonization with MS associated microbes on astrocyte gene expression and found altered gene expressions profiles in both AmT and Am-H3 treated mice vs. Veh controls, and plotted PCA scores (Fig. 1C, Figure S1B). Tmpo, Ppp1r7, Foxg1, and Ccdc22 were upregulated and Sec24a, Gpt, and B3galt5 were downregulated in AmT vs. Veh treated mice (Fig. 3A-B). When comparing Am-H3 astrocytes vs. Veh mono-colonized, we found 10 genes downregulated and 21 upregulated (Fig. 3C-D) including Top2a and Ermn (Fig. 3D). Analysis of astrocytes isolated from mice mono-colonized with Am-H3 vs. Bc, identified 14 downregulated and 60 upregulated genes (Fig. 3E-F). Pathway analysis on all significant (p < 0.05) DEGs (Additional file 2) using IPA and found differential pathways across mono-colonization groups for patwhays related to cellular immune response, myelination related signaling, and nervous system signaling (Fig. 3G). When comparing AmT vs. Am-H3, numerous pathways associated with myelination were upregulated in Am-H3, as were multiple cellular immune and nervous system signaling related pathways (Fig. 3H). Genes contributing to identified IPA pathways are available in Additional file 3.

Fig. 3
figure 3

Akkermansia mono-colonization alters astrocyte gene expression. Mono-colonization with AmT altered gene expression compared to Veh (A) with DEGene counts showing genes highly altered (B). Am-H3 treatment altered gene expression profiles compared to Veh treated animals (C) with DEGene counts (D) showing important genes significantly altered by Am-H3 mono-colonization. In mice mono-colonized with Bc vs. Am-H3, gene expression alterations are heatmapped (E) and DEGene counts of interest plotted (F). Ingenuity Pathway Analysis (IPA) top pathways altered across groups for relevant pathway families (G). Pathways identified in IPA with cellular immunology relevance in AmT vs. Am-H3 mono-colonized animals (H). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. n = 6 Veh and Bc, n = 7 for AmT and Am-H3

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Am T and Am-H3 modulate T cells

Because the microbiome may also influence glia by modulating peripheral immunity, we investigated with effect of mono-colonization of AmT and Am-H3 on splenic T cells. Total CD3 + T cells were increased in AmT (p < 0.01) and Am-H3 (p < 0.05) mono-colonized compared to Veh treated animals (Fig. 4A). Effector CD4 + T cells (p < 0.01) and CD44(Hi) CD62L(lo) activated T cells (p < 0.05) were increased in AmT compared to Veh (Fig. 4B-C). We observed an increase in γδ-TCR T cells in AmT (p < 0.05) and Am-H3 (p < 0.001) vs. vehicle, whereas Am-H3 was also increased compared to Bc (p < 0.05; Fig. 4D, E). Total CD4 + and CD8 + frequency were not altered (Figure S2A, C, E). However, we did find increased IFNγ production by CD4 + T cells in mice colonized with Am-H3 and Bc (Figure S2B) an effect not observed in CD8 + T cells (Figure S2D).

Fig. 4
figure 4

Effect of AmT and Am-H3 on T cells. (A) Total CD3 + T cells, (B) CXCR3 + CD44 + Effector T cells, (C) CD44(Hi) CD62(lo) activated T cells, and (D) γδ-TCG T cells in mice colonized with Akkermansia and Bacteroides strains. Representative dot plot of CD3 by γδ-TCR across mono-colonization groups. *p < 0.05, **p < 0.01, ***p < 0.001. n = 4 per group

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Differential production of SCFAs in mono-colonized mice and gut mucosal integrity

Studies have shown that SCFAs modulate microglia [18]. We found that specific SCFAs were elevated in the cecum from mono-colonized animals vs. Veh treated GF mice. Bc mono-colonized animals had increased acetate (p < 0.0001) propionate (p < 0.0001) and isovalerate (p < 0.0001) compared to Veh, AmT, and Am-H3 mono-colonized animals (Fig. 5A-C). Both AmT and Am-H3 produced propionate as the primary SCFA (p < 0.001; Fig. 5B). Since Akkermansia and Bc are known to degrade mucus [26, 27], we investigated the gut mucus barrier and epithelial integrity by measuring goblet cells labelled for UEA-1 + and analyzed cell quantity and size. Colonic goblet cells were labeled with UEA-1 lectin and we found similar quantities (Figure S3A-B) and sizes (Figure S3C) in Veh, Bc, AmT, and Am-H3 mono-colonized mice.

Fig. 5
figure 5

Mono-colonization promotes SCFA production. Acetate (A), propionate (B), and isovalerate (C) were significantly elevated in Bc mono-colonized mice while AmT and Am-H3 increased propionate levels. Isobutyrate was not detected in any group besides Bc mono-colonized mice (D). **p < 0.01, ***p < 0.001, and ****p < 0.0001. n = 8–13 per group

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Discussion

The gut microbiota influences peripheral and central immune function in health and disease [28,29,30]. It is not known whether strain-specific effects of single bacteria or their metabolites can augment protective pathways involved in CNS homeostasis, or conversely promote pathogenic processes in the CNS. To address these questions, we colonized GF mice with MS associated microbes [6] and investigated their effects on gene expression in brain microglia and astrocytes and linked these effects to changes in peripheral immunity and intestinal microbial metabolites.

Multiple studies have reported microbiota alterations in neurologic diseases [1, 5,6,7,8,9, 31,32,33,34,35]. Akkermansia has been shown to ameliorate disease in animal models of MS, AD, ALS, and epilepsy [6, 36,37,38,39], whereas disease related pathways are worsened when Akkermansia is cultured with PBMCs from MS subjects [1] and when cultured with an enteroendocrine cell line [40]. There are 4 clades of Akkermansia with distinct metabolic and immunologic properties [13]. We previously found that treatment of SPF mice with Akkermansia strain BWH-H3 had a greater protective effect in EAE than the 3 other Akkermansia strains [6]. In addition, strain specific asssociations of Akkermansia with MS and MS clinical measures have been described [5, 6], and increased abundance of Akkermansia is associated with lower measures of neuroinflammation in mice with a complex microbiome [41].

To investigate the properties of these Akkermansia strains, we mono-colonized mice with either Akkermansia muciniphila type strain, or our recently isolated Akkermansia BWH-H3 strain [6]. We observed strain specific effects on microglial gene expression after mono-colonization. Minimal effects were observed with the AmT strain compared to vehicle treated animals. We found that Am-H3 had a greater effect on microglia gene expression including those involved in cell adhesion (e.g., Nid2), none of which were altered by AmT mono-colonization. Srsf1, a nuclear export adapter whose depletion prevents neurodegeneration in the drosophila model of C9ORF72 related diseases [42, 43] was downregulated in Am-H3 treated animals. Eif2s3y, a Y-chromosomal gene that causes autism-like behaviors in male mice [44] was also downregulated in Am-H3 mono-colonized microglia. Bc, a Gram-negative anaerobic microbe that we used as a non-Akkermansia control elevated Eif2s3y compared to Am-H3, supporting Am-H3’s beneficial influence on brain microglia. Our study used germ free, non-immunized mice, as opposed to other studies that have shown Akkermansia to lower inflammation in EAE [6]. Due to the mostly absent inflammatory microglial signatures in these mice, the changes we observed in our non-immunized mice were not dramatic. This was compounded by use of commensal bacteria which we would not expect to result in overt inflammation. These methodological considerations make it possible that the effect of Akkermansia on microglia may differ during inflammatory states (e.g., in MS) compared to homeostasis. Taken together, our data provide evidence of strain specific effects on microglial gene expression, however, future investigations with multi-strain and multi-species colonizations would provide further evidence of Akkermansia’s role in MS.

Microbial mono-colonization also influenced astrocyte gene expression in a strain specific manner. We observed an increase in Tmpo in mice mono-colonized with AmT. Tmpo codes for thymopoietin which downregulates inflammatory responses in EAE [45]. Am-H3 altered astrocyte gene expression pathways involved in extracellular matrix organization, myelination, and cellular immune regulation, and our observed downregulation of Ermn in Am-H3 mono-colonized animals is consistent with the altered astrocyte cytoskeletal rearrangement we observed in our pathway analysis. Ermn is downregulated in RRMS [46], and knocking-out Ermn leads to inflammation, microgliosis and increased astrocyte numbers [47]. This suggests that downregulation of Ermn in Am-H3 treated animals is associated with astrocyte restructuring. We also observed elevation of actin and cytoskeletal associated genes in Am-H3 vs. vehicle mono-colonized animals, including Fam107a, an actin associated gene that’s protein product functions to maintain astrocytes in a quisescent, nonproliferative state [48]. Together our findings identify the structural and functional regulation of astrocytes by Akkermansia strain Am-H3.

Alterations in immune function during mono-colonization are likely driven by a combination of factors. We observed strain specific alterations in peripheral immune populations from mono-colonized mice, with Am-H3 being associated with elevated splenic γδ-T cells. In MS, γδ-T cells have two distinct phenotypes, one characterized by IL-17 production and one driven by IFNγ producing cells [16]. We previously found that Am-H3 reduces IL-17 producing γδ-T cells in EAE [6]. We found an elevation in γδ-T cells in Am-H3 mono-colonized animals, and an elevation of IFNγ producing T cells in our Am-H3 and Bc mono-colonized animals but not type strain AmT. Our data point towards Akkermansia mono-colonization, and specifically Am-H3, shifting peripheral T populations towards a more protective phenotype. How this T cell phenotypic shift relates to central immunity still needs to be investigated.

Gut epithelial and mucus barrier integrity are important components of intestinal homeostasis and SCFAs have an important physiologic role including modulating barrier function [49]. SCFAs have also been shown to promote microglial homestasis and contribute to microglial maturation in germ free animals [17]. Bc produced multiple SCFAs [50] and both strains of Akkermansia we investigated produced propionate, which has been shown to be beneficial in MS [51]. It is well recognized that the microbiota is responsible for SCFAs in the gut and as expected we did not detect SCFA in vehicle treated mice. While SCFAs are potentially influencing our observed gene alterations in CNS glia, they are likely only one of many microbial metabolites involved. Akkermansia is a mucin degrader [52] raising the question of whether mono-colonization would impair gut barrier function. We found no differences in gut wall mucus in goblet cells in mono-colonized groups.

In this study, we present important data on the impact of mono-colonization with MS derived microbes on microglia and astrocyte gene expression profiles, however, there are limitations. Mono-colonization studies in germ-free animals are inherently limited due to physiologic and developmental issues of germ-free mice [53]. Furthermore, the differences in gene and immune profiles between Akkermansia strains in our study were subtle, likely due to our study being conducted in wild-type, non-immunized mice as opposed to immunized / challenged models like EAE, in which we have previously shown that Akkermansia lowers inflammation [6]. While protein level validation for our gene expression alterations would be valuable, we were limited by tissue availability for these investigations. Influence of multi-species and multi-strain colonizations on microglia and astrocytes in homeostatic vs. immunized (e.g., EAE) models at the gene and protein level should be further investigated.

In conclusion, we found that Akkermansia mono-colonization modulates microglia and astrocyte gene expression, which may be mediated by changes in short chain fatty acids and peripheral immune signaling.

Data availability

All raw sequencing data is accessible at the NCBI Sequence Read Archive: SUB14686820 and BioProject PRJNA1152580. We used standard bioinformatic workflows throughout this study which are available on a GitHub repository (https://github.com/tobylanser/akk_monocolonization).

Change history

  • 09 April 2025

    The missing Funding information was added.

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Acknowledgements

The authors wish to express their gratitude to Dr. Lynn Bry and her exceptional team at the Massachusetts Host-Microbiome Center, including Vladimir Yeliseyev for overseeing and performing mono-colonization gavages, and Mary Delaney for processing cecal SCFAs.

Funding

LAS– National Multiple Sclerosis Society, Grant #FG-2207-40162; LMC - National Institute of Health/NINDS, 1R21NS126866.

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Authors and Affiliations

  1. Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, 60 Fenwood Road, Boston, MA, 02115, USA

    Luke A. Schwerdtfeger, Toby B. Lanser, Federico Montini, Thais Moreira, Danielle S. LeServe, Laura M. Cox & Howard L. Weiner

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  1. Luke A. Schwerdtfeger
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  7. Howard L. Weiner
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Contributions

LAS conceived the study, performed the experiments, analyzed and interpreted the data and wrote the manuscript. TBL and FM, analyzed RNAseq data and edited the manuscript. DSL performed experiments and edited the manuscript. TM analyzed and interpreted immunology data and edited the manuscript. LMC and HLW conceived the study and oversaw the entirety of the project. All authors reviewed the manuscript.

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Correspondence to Howard L. Weiner.

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All animal procedures were approved by the Brigham and Women’s Hospital IACUC under protocol# 2016N000230.

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Schwerdtfeger, L.A., Lanser, T.B., Montini, F. et al. Akkermansia mono-colonization modulates microglia and astrocytes in a strain specific manner. J Neuroinflammation 22, 94 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12974-025-03417-3

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Keywords

Journal of Neuroinflammation

ISSN: 1742-2094