Gut bacteria immune cells attack brain in autoimmune discovery
Scientists have discovered a novel mechanism by which immune cells targeting gut bacteria can infiltrate the brain and cause neuroinflammation through molecular mimicry. The research reveals how intestinal inflammation promotes the migration of microbiota-specific T cells into the central nervous system, where they mistakenly attack brain proteins.
Researchers at the University of Illinois at Chicago have uncovered a previously unknown pathway linking gut inflammation to neuroinflammation, demonstrating how T cells initially activated by gut bacteria can subsequently cause brain damage through a process called molecular mimicry. The findings, published in Nature on 18 June 2025, provide new insights into the gut-brain axis and potential therapeutic targets for neurological disorders.
Segmented filamentous bacteria drive immune response
The study focused on segmented filamentous bacteria (SFB), spore-forming commensal bacteria found in the mouse intestine. Using transgenic mice with T cell receptors specific for SFB antigens, the researchers transferred naive CD4 T cells into immunocompromised hosts lacking regulatory T cells.
“T cells that recognize gut-colonizing segmented filamentous bacteria can induce inflammation in the mouse intestine and CNS in the absence of functional regulatory T cells,” the authors reported. The transferred mice developed both intestinal inflammation and neurological symptoms including ataxia and hindlimb clasping.
Flow cytometry analysis revealed that SFB-specific T cells produced high levels of inflammatory cytokines including GM-CSF, interferon-γ, and interleukin-17A in both the gut and brain. Importantly, these pathogenic T cells were detected in the brain parenchyma rather than just blood vessels, confirming their infiltration across the blood-brain barrier.
Molecular mimicry enables cross-reactivity
The key breakthrough came when researchers discovered that one specific T cell receptor, TCR7B8, could recognise not only SFB-derived peptides but also peptides from mouse brain proteins including ERBB2, TRO1, and ANAPC2. This cross-reactivity occurred despite the SFB epitope and host protein sequences differing by only a single amino acid.
In vitro stimulation assays confirmed that TCR7B8 T cells could be activated by synthetic peptides derived from these host proteins in a major histocompatibility complex class II-dependent manner. Crucially, another SFB-specific receptor, TCR1A2, which recognises the same bacterial protein but with different fine specificity, could not cross-react with host proteins and did not cause neuroinflammation.
“TCR7B8 can thus recognize SFB-derived peptides and also has the potential to recognize at least three mouse proteins that are expressed in the CNS, which potentially contribute to the induction of immunopathological neuroinflammation in the host,” the authors explained.
Gut inflammation promotes brain infiltration
The research revealed that intestinal inflammation plays a crucial role in enabling T cell migration to the brain. When researchers used integrin β7-deficient T cells, which cannot efficiently migrate to the gut, both intestinal and brain inflammation were significantly reduced.
“The inflamed intestine could accelerate gut CD4 T cell infiltration into the CNS,” the authors noted. Supporting this hypothesis, experiments using gnotobiotic IL-10-deficient mice harbouring human microbiota showed that gut inflammation promoted T cell infiltration into the brain, even in the absence of SFB.
Dual mechanisms drive neuroinflammation
The study identified two complementary pathways by which infiltrating T cells damage the brain. The first involves IL-23 receptor-dependent production of inflammatory cytokines, whilst the second relies on IL-23 receptor-independent GM-CSF production that activates microglia.
Single-cell RNA sequencing of brain tissue revealed that T cell-derived GM-CSF activated microglia, leading to neuroinflammation. When researchers depleted microglia using CSF1 receptor inhibitors, neurological symptoms were prevented, confirming the importance of this pathway.
“TCR7B8 CD4 T cells contribute to CNS inflammation by activating microglia through an IL-23R-dependent encephalitogenic programme and IL-23R-independent GM-CSF production,” the authors concluded.
Clinical implications and therapeutic targets
The findings have important implications for understanding autoimmune neurological diseases. The researchers demonstrated that immune checkpoint blockade, commonly used in cancer treatment, exacerbated the neuroinflammation, whilst depletion of regulatory T cells also worsened symptoms.
“Our findings reveal potential mechanisms whereby perturbation of Tcomm cells can contribute to extraintestinal inflammation,” the authors stated. This suggests that maintaining healthy gut bacteria balance and regulatory T cell function could be crucial for preventing neuroinflammation.
The study also showed that TCR repertoire analysis of brain-infiltrating T cells in mice with human microbiota revealed shared clones between gut and brain tissues, indicating this mechanism may be relevant to human disease.
Future research directions
This research opens new avenues for therapeutic intervention in neuroinflammatory diseases. Potential strategies could include modulating gut microbiota composition, enhancing regulatory T cell function, or blocking specific T cell migration pathways.
The discovery that molecular mimicry between commensal bacteria and host proteins can drive neuroinflammation provides a mechanistic explanation for the gut-brain axis in disease. Future studies will need to determine whether similar pathways operate in human neurological disorders and identify specific therapeutic targets for clinical intervention.
Reference
White, Z., Cabrera, I., Mei, L., et. al. (2025). Gut inflammation promotes microbiota-specific CD4 T cell-mediated neuroinflammation. Nature, published online 18 June 2025. https://doi.org/10.1038/s41586-025-09120-w
