Tracing the immune dialogue between the gut and brain

Parkinson’s disease is a devastating brain disorder, marked by tremors, stiffness, and slowness. But long before these symptoms appear, many patients experience gastrointestinal issues like constipation, nausea, and abdominal discomfort that can emerge years, even decades, earlier. Mounting evidence suggests these aren’t just incidental precursors, they may be part of the cause.

Seppe is tackling the crucial question of how this might happen. His research is advancing a bold hypothesis that dysfunction in gut immune cells may trigger a cascade culminating in neurodegeneration. “We’re speculating that Parkinson's, in some cases, might not be purely neurological, but also an immune-mediated disorder that might start outside the brain,” he says. “And the gut, being constantly exposed to stressors, might be ground zero.”

From gut immunology to neurodegeneration

Seppe’s journey to this intersection of gut, brain, and immunology began at KU Leuven, where he uncovered that specialized immune cells called macrophages play a crucial role in maintaining normal gut function. During his PhD work, he discovered that gut macrophages are not just passive scavengers but actively support the gut’s enteric nervous system, the complex network of neurons that controls digestive function. His research, published in the journal Cell in 2018, showed that macrophages and neurons form an intimate partnership, with immune signals helping to maintain neuronal health and gut motility. Intrigued by emerging evidence linking the immune system to Parkinson's and Alzheimer’s disease, and encouraged by Bart De Strooper, then Director of the UK Dementia Research Institute (UK DRI), Seppe moved to London in 2019. He joined the lab of Soyon Hong at the UK DRI based at University College London, where he expanded his research focus to the brain’s immune environment. 

Hong, a rising star in neuroimmunology, has gained recognition for her work dissecting the role of microglia, the brain's resident immune cells, in Alzheimer's disease. Her research investigates how these normally protective cells become dysfunctional in diseases like Alzheimer's, shifting from maintaining brain health to instead engulfing and eliminating synapses. 

For Seppe, this focus on immune cell function and dysfunction in the context of neurodegeneration offered a perfect environment to apply his immunology expertise to challenging neuroscience questions. Seppe’s efforts in the lab led to the identification of a novel signaling pathway that drives microglia-mediated synapse loss in Alzheimer’s models. His research revealed that a protein called SPP1 (osteopontin), secreted mainly by immune cells near the blood-brain barrier, acts as a key signal for microglia to upregulate phagocytic machinery and engulf synapses. 

“It was a risky move,” he reflects. “But it gave me an immersive crash course in neuroscience, and I got to help shape a new lab and research program from the ground up.” 

One eye on the brain, the other on the gut

All the while, the gut-brain axis fascinated him. This curiosity led to a collaboration with UCL/UK DRI alpha-synuclein expert, and lab neighbor Tim Bartels to investigate whether alpha-synuclein, the misfolded protein associated with Parkinson's disease, might initially target gut immune cells.

"We discovered that gut macrophages start to malfunction when they encounter alpha-synuclein," Seppe explains. "They enter a reactive state, recruiting T-cells and possibly initiating the spread of pathology to the brain." What started as a curiosity about gut immune cells had by now evolved into a bold scientific vision: to understand how the body's peripheral immune system can shape the brain's fate.

The immunologist returns with a neurologist's vision

Armed with these findings in hand and vision in mind, Seppe returned to Belgium to launch his own lab at the VIB Center for Molecular Neurology in Antwerp. His research vision and its bold implications earned him the prestigious Odysseus grant from the Research Foundation Flanders (FWO). 

Seppe’s scientific journey has mirrored his geographical one. It began with gut immunology in Belgium, ventured into brain research abroad, and now culminates in his return home to integrate these worlds. Like his own path back to Belgium, his research has come full circle: from studying gut macrophages as an immunologist to investigating brain microglia, and now back to those same gut immune cells but with a neurologist's perspective on how they might influence the brain.

Now, equipped with funding and freedom, Seppe is digging deeper into the immune pathology he helped uncover. His lab blends immunology, neuroscience, and cutting-edge tools from spatial transcriptomics to high-dimensional immunophenotyping and advanced mouse models to dissect how gut immune cells interact with neurons and what happens when those interactions go wrong.

His approach is firmly translational. “Imagine being able to delay the onset of Parkinson's symptoms,” he says. “Just by modulating the immune response in the gut.” One of his key interests lies in patients with REM Sleep Behavior Disorder, a condition where people physically enact their dreams. Crucially, this disorder is known to be a powerful early indicator of Parkinson's disease, often appearing years before the classic symptoms are seen. Because a high percentage of people with REM Sleep Behavior Disorder eventually receive a Parkinson's diagnosis, studying their gut could potentially offer a unique window to the onset and progression of the disease. Seppe hopes to leverage this to identify immune-based biomarkers in these individuals that could forecast disease progression years in advance.

Mapping new terrain, together

Parkinson's disease is only the beginning. Seppe is already setting his sights on other conditions where the gut-immune-brain axis may play a role, for example, in stroke or food allergy. He embraces a guiding philosophy from former VIB group leader and immunologist Adrian Liston: “Every disease is immunological unless proven otherwise.” Seppe laughs as he repeats the line, but he takes its implications seriously.

He draws energy from those who inspired and mentored him, from his professors in immunology at the Rega Institute in Leuven who first sparked his fascination with immunology, to his PhD adviser and former colleagues at the UK DRI, to his colleagues now at CMN. 

“We have an incredible and highly inspiring team here, with Rosa Rademakers as center director, Renzo Mancuso and Emanuela Pasciuto pushing groundbreaking ideas in neuroimmunology. The center's expertise in Alzheimer's, FTD, epilepsy, and other neurological conditions creates the perfect environment for my Parkinson's research. Together, we're expanding the center's impact across neurodegenerative disorders.”

The player becomes the coach

Reflecting on his path, Seppe speaks most passionately about mentorship and scientific growth. He compares leading a lab to coaching a football team, a sport he loves. “Now I’m the coach, helping my team develop their vision. But ultimately, they’re the ones on the field, making it happen.”

For Seppe, science is about forging connections: between disciplines, between immune cells and neurons, and between trainees and mentors. In his new Antwerp lab, he is just beginning to weave those threads together, hopeful they will lead to breakthroughs in diseases that have resisted understanding for decades.

“Ultimately,” he says, “it all comes down to curiosity and creativity. That’s what makes science exciting. And that’s what brought me home.”