Everyone does surely remember the “spider-sense” warning Peter Parker of an approaching danger. No explanations about how it came out, though “DNA recombination” could have worked as an “antenna” to let “the friendly neighborhood” have this power. In a breakthrough that reimagines the way the gut and brain communicate very fast, researchers have uncovered what they call a “neurobiotic sense”, a newly identified system that lets the brain respond in real time to signals from our “inner neighborhood”. The new research, led by Duke University School of Medicine neuroscientists Diego Bohórquez and Maya Kaelberer, and published in Nature, centers on neuropods, tiny sensor cells lining the colon’s epithelium. These cells detect a common microbial protein and send rapid messages to the brain that help curb appetite.
But this is just the beginning. The team believes this neurobiotic sense may be a broader platform for understanding how gut detects microbes, influencing everything from eating habits to mood – and even how the brain might shape the microbiome in return. The key player is flagellin, an ancient protein found in bacterial flagella, a tail-like structure that bacteria use to move. When we eat, some gut bacteria release flagellin. Neuropods detect it, with help from a receptor called TLR5, and fire off a message through the vagus nerve – a major line of communication between the gut and the brain. The team, supported by the National Institutes of Health, proposed a bold idea: that bacterial flagellin in the colon could trigger neuropods to send an appetite-suppressing signal to the brain – a direct microbial influence on behavior.
Scientists tested this by fasting mice overnight, then giving them a small dose of flagellin directly to the colon: those mice ate less. When researchers tried the same experiment in mice missing the TLR5 receptor, nothing changed: mice kept eating and gained weight, a clue that the pathway helps regulate appetite. The findings suggest that flagellin sends a “we’ve had enough” signal through TLR5, allowing the gut to tell the brain it’s time to stop eating. Without that receptor, the message doesn’t get through. The experiments overall reveal that disrupting the pathway altered eating habits in mice pointed to a deeper link between gut microbes and behavior. But another research team, thought differently or directly, if we would, by developing a neuron-bacteria interface revealing that the gut bacterial community can directly interact with brain neurons.
Alterations in gut microbiota composition and functionality, referred to as dysbiosis, have been linked to several neurological diseases, including Alzheimer’s disease, ADHD, autism spectrum disorders and depression. It is already well-established in the literature that the gut microbial communities and their metabolites directly influence the gut-brain axis. However, information on direct communications and bidirectional information exchange between bacteria and brain neurons is not widely available. In the current study, researchers developed a neuro-bacterial interface model using the foodborne probiotic bacterium Lactiplantibacillus plantarum and rat cortical neural cultures to explore how nerve cells respond to the bacterial presence at the morphological, functional and transcriptional levels.
The study model is based on a two-dimensional culture of rat-derived cortical neurons, which lacks the structural and cellular complexity of a physiological neural environment. The cortical neurons were selected as an experimental cell type to explore whether brain neurons can respond directly to bacterial presence instead of enteric or sensory neurons. However, these cortical neurons may not reflect a biologically plausible scenario, as there is currently no evidence for direct interactions between gut microbiota and cortical neurons under normal conditions. It is important to note that the study was conducted entirely in vitro using rat embryonic cortical neurons, which do not directly encounter gut bacteria in vivo. The use of these neurons was intended to test whether brain neurons can respond to bacterial contact, rather than to model a real-life gut-brain scenario.
The assessment of physical interaction between the bacteria and nerve cells revealed that the bacteria adhere to the surface of nerve cells without entering the neuronal cytoplasm. Regarding functional response of neurons following bacterial exposure, it was found a significant increase in calcium signaling when cells encounter the bacteria. This increased signaling was dependent on bacterial concentrations and active metabolism. Neurons exposed to a high concentration of metabolically active bacteria exhibited the highest calcium signaling. Similarly, neurons exposed to heat-killed bacteria (normal cellular integrity but no metabolic activity) showed the second highest calcium signaling at the same concentration. However, neuronal cells exposed to a very low concentration of active bacteria exhibited similar intensity signaling as unexposed cells.
These observations indicate that bacterial load and membrane-to-membrane contact are essential for inducing a neuronal response, and neuronal activation is significantly greater when nerve cells interact with live bacteria, rather than metabolically inactive bacteria. Regarding altering of neural activity, the study found significant changes in the expression of key proteins involved in neuroplasticity, including phosphorylated CREB (a marker of early neural activity) and Synapsin I (a cytoplasmic marker related to synaptic connections). Specifically, the study found a significant reduction in pCREB expression and a significant increase in SYN I expression in nerve cells exposed to bacteria. These findings indicate bacteria-mediated functional changes in nerve cells. The study also verified that these functional changes are not due to cytotoxic effects, since no reduction of neuronal viability or induction of cell death were observed at all.
Transcriptional changes associated with the neuro-bacterial interactions revealed significant restructuring of the transcriptional landscape of nerve cells in response to bacteria, affecting vital biological processes related to neuroplasticity, gene expression regulation, signaling pathways, and stress response.A detailed transcriptional analysis identified a prominent role for several bioelectricity-related genes in underlying neuro-bacterial interactions. This investigation, therefore, provides valuable experimental evidence on direct interactions between brain and bacterial cells, leading to multiple downstream changes at the structural, functional and transcriptional levels. Indeed, RNA sequencing identified 384 differentially expressed genes after bacterial contact, with shifts in gene networks linked to brain conditions such as cognition and mood disorders.
A set of potential bioelectricity-related genes involved in neural responses has also been identified, including the brain-derived neurotrophic factor gene Bdnf, the adrenomedullin gene, Adm, and the potassium and chloride ion channel genes Kcna1 and Clcn1, respectively. The bioelectrical profile is increasingly considered a functional property of bacterial cells, as it correlates with relevant physiological events regardless of causality. Overall, the study provides a promising platform to decode the direct effects of bacteria on brain cells and generate new knowledge on the biological–biophysical interaction between highly divergent cells. Despite some limitations, the study provides a fundamental framework for developing novel neuroactive therapeutics interventions targeting brain–microbiota interactions. Future studies will use more physiologically relevant systems, including co-cultures with enteric neurons and organ-on-chip platforms.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Liu WW, Reicher N et al. Nature 2025 Jul 23; in press.
Yang Z, Zhou SH et al. Cell Res. 2025; 35(4):243-264.
Lombardo-Hernandez J et al. Sci Rep. 2025; 15(1):25535.
Toledo M et al. Nature Metabolism 2025; 7:1123–1135.
Bourqqia-Ramzi M et al. Int J Mol Sci. 2024; 25(11):6233.
