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Gut-derived metabolites drive Th17 cell pathogenicity in multiple sclerosis

ABSTRACT:

The gut-brain axis is an emerging factor in promoting multiple sclerosis (MS). However, the underlying mechanisms and strategies to target this axis are not established. Here, we investigated how the gut environment influences myelin-specific Th17 cell pathogenicity. We used the adoptive Th17 cell transfer experimental autoimmune encephalomyelitis (EAE) model and antibiotic treatment to disrupt the intestinal microbiome. We observed a reduced pathogenic Th17 cell signature in the colon of antibiotic-treated mice. Treatment with fecal filtrates enhanced myelin-specific Th17 cell encephalitogenic properties both in vitro and in vivo. Fecal metabolomic profiling identified altered tryptophan-derived metabolites, including indole-3-carboxylate (I3CA). Oral I3CA supplementation accelerated EAE development. I3CA concentration in blood samples from persons with MS (PwMS) was associated with increased disease severity mirrored by increased serum neurofilament light chain levels. Altogether, our study shows that microbiota-derived metabolites play a key role in the intestine during neuroinflammation, offering potential therapeutic insights for PwMS.

INSTRUMENT(S): Liquid Chromatography MS - - - Q Exactive

PROVIDER: MTBLS980 | MetaboLights | 2025-08-15

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS980_21833__METHOD1_POS_1_metabolite_profiling_mass_spectrometry.txt	Txt
	a_MTBLS980_21833__METHOD2_POS_2_metabolite_profiling_mass_spectrometry.txt	Txt
	a_MTBLS980_21833__METHOD3_NEG_1_metabolite_profiling_mass_spectrometry.txt	Txt
	a_MTBLS980_21833__METHOD4_NEG_2_metabolite_profiling_mass_spectrometry.txt	Txt
	a_MTBLS980_25355__METHOD1_POS_1_metabolite_profiling_mass_spectrometry.txt	Txt

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Gut-derived metabolites drive Th17 cell pathogenicity in Multiple Sclerosis

Project description:The gut-brain axis is an emerging factor in promoting multiple sclerosis (MS). However, the underlying mechanisms and strategies to target this axis are not established. Here, we investigated how the gut environment influences myelin-specific Th17 cell pathogenicity. We used the adoptive Th17 cell transfer experimental autoimmune encephalomyelitis (EAE) model and antibiotic treatment to modulate the intestinal microbiome. We observed a reduced pathogenic Th17 cell signature in the colon of antibiotics-treated mice. Treatment with fecal filtrates enhanced myelin-specific Th17 cell encephalitogenic properties both in vitro and in vivo. Feces metabolomic profiling identified altered tryptophan-derived metabolites, including indole-3-carboxylate (I3CA). Oral I3CA supplementation accelerated EAE development and I3CA concentration in blood samples from persons with MS (PwMS) was associated with increased disease severity mirrored by increased serum neurofilament light chain levels. Altogether, our study shows that microbiota-derived metabolites play a key role in the intestine during neuroinflammation, offering potential therapeutic insights for PwMS.

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Gut-derived metabolites drive Th17 cell pathogenicity in Multiple Sclerosis

Project description:Gut-derived metabolites drive Th17 cell pathogenicity in Multiple Sclerosis

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Notch3+ Regulatory T cells Drive Autoimmune Neuroinflammation in Multiple Sclerosis

Project description:The immune regulatory defects that promote neuroinflammation in multiple sclerosis (MS) remain unclear. We show that a specific regulatory T (Treg) cell subpopulation expressing Notch3 is increased in individuals with MS and in mice with experimental autoimmune encephalomyelitis (EAE). Notch3 is induced by the gut microbiota by toll-like receptor (TLR)-dependent mechanisms to promote EAE severity. Notch3 interacts with delta-like ligand 1 (DLL1) on microglia to subvert Treg cells into T helper 17 (Th17) cells. Notch3 Treg-specific deletion inhibits EAE by preventing Treg cell destabilization while simultaneously promoting the expansion of a novel tissue-resident neuropeptide receptor 1 (NPY1R)+ Treg cell population that suppressed pathogenic IFNg+ and GM-CSF+ T cells. Our studies thus identify altered Treg cell population dynamics as a fundamental pathogenic mechanism in autoimmune neuroinflammation.

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Transcription factor EGR2 controls homing and pathogenicity of TH17 cells in the central nervous system.

Project description:CD4+ T helper 17 (TH17) cells protect barrier tissues but also trigger autoimmunity. The mechanisms behind these opposing processes remain unclear. Here, we found that the transcription factor EGR2 controlled the transcriptional program of pathogenic TH17 cells in the central nervous system (CNS) but not that of protective TH17 cells at barrier sites. EGR2 was significantly elevated in myelin-reactive CD4+ T cells from patients with multiple sclerosis and mice with autoimmune neuroinflammation. The EGR2 transcriptional program was intricately woven within the TH17 cell transcriptional regulatory network and showed high interconnectivity with core TH17 cell-specific transcription factors. Mechanistically, EGR2 enhanced TH17 cell differentiation and myeloid cell recruitment to the CNS by upregulating pathogenesis-associated genes and myelomonocytic chemokines. T cell-specific deletion of Egr2 attenuated neuroinflammation without compromising the host’s ability to control infections. Our study shows that EGR2 regulates tissue-specific and disease-specific functions in pathogenic TH17 cells in the CNS.

2023-06-28 | GSE226795 | GEO

Transcription factor EGR2 controls homing and pathogenicity of TH17 cells in the central nervous system.

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Transcription factor EGR2 controls homing and pathogenicity of TH17 cells in the central nervous system.

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Id2 acts as a metabolic checkpoint underpinning Th17 cell fate decision [scRNA-seq]

Project description:T helper 17 (Th17) cells protect barrier tissues but also trigger autoimmunity. The precise mechanisms control these opposing processes remain unclear. We identify Id2 as a key factor for pathogenic Th17 cells. Id2 expression is markedly elevated in Myelin-reactive T cells from multiple sclerosis (MS) patients and autoimmune mice. Mice lacking Id2 in Th17 cells completely fail to develop neuroinflammation and do not generate neuron-pathogenic Th17 subset.

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Id2 acts as a metabolic checkpoint underpinning Th17 cell fate decision [CUT&Tag]

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Id2 acts as a metabolic checkpoint underpinning Th17 cell fate decision [RNA-seq]

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Myelin oligodendrocyte glycoprotein reactive Th17 cells drive Janus Kinase 1 dependent transcriptional reprogramming in astrocytes and alter cell surface cytokine receptor profiles during experimental autoimmune encephalomyelitis.

Project description:Multiple sclerosis (MS) is an autoimmune demyelinating disease affecting the central nervous system (CNS). T helper (Th) 17 cells are involved in the pathogenesis of MS and its animal model of experimental autoimmune encephalomyelitis (EAE) by infiltrating the CNS and producing effector molecules that engage resident glial cells. Among these glial cells, astrocytes have a central role in coordinating inflammatory processes by responding to cytokines and chemokines released by Th17 cells. In this study, we examined the impact of pathogenic Th17 cells on astrocytes in vitro and in vivo. We identified that Th17 cells reprogram astrocytes by driving transcriptomic changes partly through a Janus Kinase (JAK)1-dependent mechanism, which included increased chemokines, interferon-inducible genes, and cytokine receptors. In vivo, we observed a region-specific heterogeneity in the expression of cell surface cytokine receptors on astrocytes, including those for TGFβ, IL-10, IL-1, IL-17, IFN-γ, and TNF-α. Additionally, these receptors were dynamically regulated during EAE induced by adoptive transfer of myelin-reactive Th17 cells. This study overall provides evidence of Th17 cell reprogramming of astrocytes, which may drive changes in the astrocytic responsiveness to cytokines during autoimmune neuroinflammation.

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