The study was carried out by Johannes van der Haas, Marine Mantel, Laurène Leclair-Visonneau, Pascal Derkinderen, and colleagues working at Nantes Université, the University Hospital of Nantes, and the University Hospital of Angers, within the Enteric Nervous System in Gut and Brain Disorders research group (Inserm U1235). The team set out to quantify LRRK2 expression in colon biopsies obtained from patients with Crohn’s disease, patients with established Parkinson’s disease, patients with idiopathic REM sleep behavior disorder (iRBD), and healthy controls. Idiopathic REM sleep behavior disorder, in which affected individuals physically act out their dreams because the normal muscle atonia of REM sleep is lost, is one of the strongest clinical predictors of future Parkinson’s disease or related Lewy body disorders, making it a valuable population in which to search for the earliest peripheral markers of the disease process.

LRRK2, which stands for leucine-rich repeat kinase 2, is a large, multifunctional protein with both kinase and GTPase domains. Mutations in its gene are among the most common known genetic causes of familial and sporadic Parkinson’s disease, and pharmacological inhibitors of LRRK2 kinase activity are currently being evaluated in clinical trials. At the same time, genome-wide association studies identified LRRK2 as a susceptibility gene for Crohn’s disease, and functional work has shown that the protein participates in the interferon-gamma response and in host defense against pathogens. Macrophages exposed to interferon-gamma upregulate LRRK2 through an ERK5-dependent signaling pathway, and the protein modulates cytokine production in human monocytes and macrophages. This immunological pedigree made the gut, with its dense population of immune cells and its intimate contact with the microbiota, a natural place to look for LRRK2 dysregulation in disease.

Earlier work from the same Nantes group had already produced an unexpected result along these lines. In a 2021 study published in Acta Neuropathologica, the researchers reported that LRRK2 was actually reduced, not increased, in the gut of patients with Parkinson’s disease. A follow-up study in 2023 mapped LRRK2 expression in normal and pathological human gut tissue and in rodent enteric neural cell lines, clarifying which cell types produce the protein under physiological conditions. The new correspondence extends this line of investigation in two important directions. First, it establishes a positive control: Crohn’s disease, an unambiguously inflammatory bowel condition, where the hypothesis predicts upregulation. Second, it examines idiopathic REM sleep behavior disorder, allowing the researchers to ask whether colonic LRRK2 changes emerge before the motor symptoms of Parkinson’s disease appear.

The answer to the first question was clear. In colon biopsies from patients with Crohn’s disease, LRRK2 expression was significantly increased compared with healthy controls. This result fits seamlessly with a substantial body of experimental literature. Studies in cell culture have demonstrated that the inflammatory cytokine interferon-gamma induces LRRK2 expression in macrophages, and that tumor necrosis factor-alpha and interferon-gamma cooperate to modulate cytokine signaling in human monocytic cells. Mouse experiments have reinforced the connection: animals lacking LRRK2 show attenuated colitis progression, with better resolution of inflammation and restored homeostasis of the gut microbiota, while mice carrying LRRK2 mutations develop parkinsonian features when challenged with mild chronic colitis through activation of the TNF-alpha pathway. The elevation of LRRK2 in inflamed Crohn’s tissue is exactly what one would expect if the protein is an inducible component of the mucosal immune response.

The answer to the second question was more provocative. Colonic LRRK2 expression was not increased in patients with Parkinson’s disease, and it was not increased in patients with idiopathic REM sleep behavior disorder either. In other words, even at the prodromal stage of the Lewy body disease spectrum, when alpha-synuclein pathology is thought to be spreading through the peripheral nervous system and gastrointestinal symptoms are already common, the colonic upregulation of LRRK2 that a shared gut-brain mechanism would predict is simply absent. The authors had previously shown that LRRK2 is reduced in the Parkinson’s disease gut; the new data confirm that this is not merely a medication effect or a late-stage artifact, because the same pattern of non-elevation holds in drug-naïve or early prodromal iRBD patients who have not yet developed Parkinsonism.

This dissociation carries real conceptual weight for the field. The idea that Parkinson’s disease begins in the gut was propelled by landmark neuropathological studies showing that phosphorylated alpha-synuclein, the hallmark protein aggregate of Lewy body disorders, is distributed across multiple organs, including the gastrointestinal tract, in affected individuals. The presence of enteric alpha-synuclein pathology early in the disease course, together with the well-documented burden of gastrointestinal dysfunction in Parkinson’s patients, some studies showing that objective colonic dysfunction is far more prevalent than subjective constipation, gave rise to the notion that environmental or immunological insults in the gut might trigger or accelerate the neurodegenerative process. If colonic inflammation were a common initiating factor, one might expect inflammatory response genes such as LRRK2 to be activated in the Parkinson’s colon. The new findings argue against that simple model: the colonic biology of Parkinson’s disease, at least as reflected in LRRK2 expression, is distinct from the colonic biology of overt inflammatory bowel disease.

The study also speaks to an epidemiological puzzle. Meta-analyses encompassing more than 13.4 million individuals have reported that inflammatory bowel disease is associated with an increased risk of subsequently developing Parkinson’s disease, and experimental work suggests that mild chronic colitis can exacerbate intracerebral inflammation in mouse models of the disease through LRRK2-mediated regulation of NF-kappaB activation and inhibition of the antioxidant regulator Nrf2. How can inflammatory bowel disease raise Parkinson’s risk if the Parkinson’s colon does not show LRRK2 upregulation? One possibility is that the relevant inflammatory signal is transient or occurs in a specific window, or that only a subset of inflammatory bowel disease patients, perhaps those with particular genetic backgrounds or microbiome configurations, experience the gut-to-brain propagation that animal models simulate. Another possibility, highlighted by the Nantes group’s related work, is that subtler immune changes are present in the prodromal gut. Indeed, the same consortium recently reported elevated levels of the inflammatory cytokines interleukin-1beta and interleukin-8 in the colon of patients with isolated REM sleep behavior disorder, even in the absence of measurable changes in intestinal permeability. Cytokine elevation without LRRK2 induction suggests that prodromal Parkinson’s involves a distinctive, low-grade inflammatory signature rather than a full-throttle interferon-driven response of the kind seen in Crohn’s disease.

From a methodological standpoint, the study benefits from a carefully assembled clinical cohort. Sigmoid biopsies from the iRBD, Parkinson’s disease, and control groups were collected under a protocol approved by the local Committee for the Protection of Persons (Comité de Protection des Personnes Ouest VI) and registered on ClinicalTrials.gov under identifier NCT04652843. Colonic biopsies from Crohn’s disease patients were obtained through the biobank federation of the University Hospital of Nantes under approval number DC-2008-402. The work was supported by grants from Nantes University Hospital, France Parkinson, SFN/Novartis, and the Fondation de France, with PhD and fellowship support for several of the young investigators involved. The authors declare no competing interests, and the data supporting the findings are available from the corresponding author upon reasonable request.

For the broader research community, the message is one of disciplined specificity. LRRK2 appears to be a sensitive readout of mucosal inflammation, a marker that lights up robustly in Crohn’s disease where interferon-gamma and related cytokine cascades are active, but it is not a universal marker of the gut involvement that characterizes Parkinsonian disorders. Therapeutic strategies that target LRRK2 kinase activity, currently in development for Parkinson’s disease, will therefore need to reckon with the possibility that the protein’s expression and function in the Parkinson’s gut follow rules different from those governing it in inflammatory bowel disease. Conversely, for Crohn’s disease researchers, the confirmed upregulation of LRRK2 in inflamed colon tissue strengthens the case for exploring LRRK2-targeted anti-inflammatory approaches, an idea already supported by the mitigating effects of LRRK2 deficiency in experimental colitis. As the search for peripheral biomarkers of prodromal Parkinson’s disease intensifies, this study provides a sober and valuable data point: the inflammatory fingerprint of Crohn’s disease is real and measurable in the colon, but it does not stamp itself onto the prodromal Parkinsonian gut, at least not through LRRK2. Untangling what does change in that tissue, cytokine by cytokine and cell type by cell type, remains the next great challenge for the gut-brain axis in neurodegeneration.

Subject of Research: Colonic expression of the LRRK2 protein in Crohn's disease, Parkinson's disease and idiopathic REM sleep behavior disorder

Article Title: Colonic LRRK2 expression is increased in Crohn’s disease but not in Parkinson’s disease and idiopathic RBD

Article References: van der Haas, J., Mantel, M., Sellier-Montaigne, L., de Guilhem de Lataillade, A., Durand, T., Oullier, T., Le Berre, C., Letournel, F., Rolli-Derkinderen, M., Leclair-Visonneau, L., & Derkinderen, P. (2026). Colonic LRRK2 expression is increased in Crohn’s disease but not in Parkinson’s disease and idiopathic RBD. Acta Neuropathologica, 152(1), Article 38. https://doi.org/10.1007/s00401-026-03087-2

Image Credits: AI Generated

DOI: 10.1007/s00401-026-03087-2

Keywords: LRRK2, Crohn's disease, Parkinson's disease, REM sleep behavior disorder, colon, inflammation, alpha-synuclein, gut-brain axis, enteric nervous system, interferon-gamma, biomarkers, neurodegeneration

New research led by Scott Kanoski at the USC Dornsife College of Letters, Arts and Sciences suggests the gut contributes to memory encoding, particularly when food is involved. The work centers on the vagus nerve, a major communication pathway linking the gut to the brain and known to regulate digestion, appetite, and satiety.

In the study, rats that consumed nutrient-rich foods showed increased acetylcholine-related signaling in circuits involving the hippocampus, a region critical for learning and memory. Acetylcholine is a neurotransmitter that supports synaptic plasticity and helps the brain translate experience into durable memory traces.

The effect depended on gut-to-brain signaling. When researchers experimentally disrupted communication along the vagus nerve, the nutrient-driven increase in acetylcholine disappeared, and rats performed worse on tasks requiring them to remember where they had recently found food.

Crucially, the brain’s response reflected nutritional content rather than mere palatability. Rats exposed to sugar or fat displayed strong memory-associated brain activity, while sweet-tasting but low-calorie or non-caloric solutions failed to trigger comparable hippocampal effects.

The researchers propose an evolved mechanism: by broadcasting nutrient value from the gut, vagus-mediated signals help animals remember which food sources are worth seeking. Remembering where key nutrients are located would improve survival when resources are scarce.

While the same nutrient classes activated memory pathways, chronic exposure to high-fat and high-sugar diets also impaired memory over time. Early-life consumption weakened later gut–hippocampus communication, and even after switching to healthier diets, the animals showed reduced memory-related brain responses.

These findings may help explain why obesity, poor diet, and metabolic disorders are associated with cognitive decline. They also raise the possibility of new avenues for neurodegenerative disease research, including Alzheimer’s, where acetylcholine signaling disruptions emerge early.

Although the results come from animal experiments and human relevance remains to be tested, the study adds weight to a growing view: the gut and brain are not just connected—they may actively cooperate to store what matters.

Subject of Research: Animals
Article Title: The vagus nerve promotes memory in rats via nutrient-induced septo-hippocampal acetylcholine signaling
News Publication Date: 4-Jun-2026
Web References: https://www.nature.com/articles/s41467-026-73896-2
References: 10.1038/s41467-026-73896-2
Image Credits:
Keywords: vagus nerve, acetylcholine, hippocampus, memory, gut-brain axis, nutrients, Alzheimer’s disease, metabolism

Recent trends have seen an alarming rise in the incidence of mental health disorders globally, with anxiety being a significant contributor. In Singapore, a nationwide study revealed that one in seven individuals has experienced some form of mental health disorder, encompassing both anxiety and depressive disorders. The situation has escalated to the extent that mental health issues were identified as one of the leading causes of disease burden in the country as of 2019.

In an effort to further understand the role of gut microbes on anxiety, the researchers conducted pre-clinical studies focusing on germ-free environments. The findings were striking: animals devoid of live microbes exhibited significantly higher levels of anxiety-related behavior compared to those that carried typical microbial populations. This stark contrast highlights the potential influence that gut microbiota exerts on emotional regulation and mental health.

Investigating deeper into this connection, the researchers identified the basolateral amygdala (BLA) in the brain, which plays a pivotal role in processing emotions such as fear and anxiety. Their studies suggested that heightened activity in the BLA was closely linked to the absence of beneficial microbes. This phenomenon was attributable to calcium-dependent SK2 channels within brain cells, which are implicated in modulating anxiety-related behavior. Under normal conditions where the system is exposed to live microbial metabolites, these SK2 channels function effectively to prevent neurons from excessive excitation, stabilizing emotional responses.

The research team, led by Associate Professor Shawn Je, delved further into the impact of reintroducing live microbes into germ-free mice. The results were compelling: the introduction of microbial populations resulted in a substantial decrease in neuronal hyperactivity in the BLA. Consequently, these mice exhibited much lower levels of anxiety-related behavior, aligning their emotional responses with those of mice that had an established microbial community.

Additionally, the team explored the therapeutic potential of indoles, the specific metabolites produced by certain gut microbes. Germ-free mice that received indole treatment showed a marked reduction in BLA activity and exhibited less anxiety-related behavior. This crucial observation reinforces the hypothesis that our indigenous microbiota could significantly influence our emotional well-being through the production of beneficial metabolites.

Professor Sven Pettersson elaborated on the implications of these findings, positing that the biological basis of hunger signals as an evolutionary defense mechanism plays a significant role in our understanding of anxiety. At birth, an infant’s innate perception of hunger can be viewed as an initial wave of anxiety exposure, linked to the vital necessity of sustenance. The exposure to breast milk, rich in beneficial microbes capable of producing indoles, further highlights the link between nutrition, gut microbiota, and mental health.

The research findings beckon the exploration of how different levels of microbial metabolites, particularly indoles, may reflect individual variability in stress sensitivity and the corresponding risk of experiencing anxiety. This novel understanding presents promising avenues for therapeutic interventions targeting the gut-brain axis, suggesting that restoring microbial composition through dietary strategies or the administration of indole-producing probiotics could provide effective relief for anxiety disorders.

In the context of modern medicine, these insights could lead to personalized treatment regimens aimed at treating anxiety by rebuilding the gut microbiome. As the research suggests, such strategies could align with the principles of precision medicine, potentially enhancing the efficacy of treatment for anxiety-related conditions.

Concurrently, the findings catalyze important discussions around the broader implications of microbial health on overall mental wellness. The relationship between microbes, nutrition, and brain function explores uncharted territories in understanding stress-related conditions, emphasizing that mental health challenges are not merely confined to the brain. Instead, they originate from a complex interplay between gut microbiota and brain activities.

As the research team prepares to embark on clinical trials, there is a growing anticipation around the potential for indole-based probiotics or dietary supplements to emerge as viable natural treatments for anxiety in humans. If substantiated through future studies, this research could herald a significant shift in mental health care, showcasing the pivotal role that our gut microbiome may play in not just managing anxiety but perhaps also in maintaining overall psychological equilibrium.

The intricate biochemical dialogue between gut microbes and our brains underscores the need for a holistic approach to mental health, one that considers the gut as an essential element of our emotional landscape. As scientists continue to unearth the mysteries of this gut-brain connection, we stand on the brink of a new frontier where our understanding of anxiety—and effective responses to it—can be radically improved.

This research not only ignites hope for individuals grappling with anxiety disorders seeking alternative therapies but also reinforces the need for continued inquiry into the biological foundations of mental health. The journey into understanding how our microbiota influences our emotions is poised to unveil deeper insights that could forever change the landscape of mental health treatment.

Subject of Research: Gut microbiota and its impact on anxiety-related behavior.

Article Title: Microbial metabolites tune amygdala neuronal hyperexcitability and anxiety-linked behaviors.

News Publication Date: February 5, 2025.

Web References: EMBO Molecular Medicine.

References: Institute of Mental Health, Ministry of Health Singapore.

Image Credits: Image credits not specified.

Keywords: Anxiety, Gut microbiota, Indoles, Mental health, Probiotics, Neurobiology, Emotional regulation, Precision medicine.