A Novel Gut-Brain Interaction Underlies Reduced Appetite in Parasitic Infection
Parasitic infections are often associated with fatigue, nausea, and reduced appetite. However, the mechanisms through which parasites that infect the gastrointestinal tract contribute to such symptoms are incompletely understood. Understanding this process would help clarify the relationship between infection and the body’s response, ultimately laying an important foundation for future therapeutic approaches.
Magnified image of mammalian gut epithelium.
Image Source: Unsplash
Recent research by Touhara et al. (2026) elucidates the mechanism of a novel gut-brain interaction that contributes to the understanding of this relationship. The pathway involves communication between tuft cells, rare intestinal cells that detect chemical changes, and enterochromaffin cells, gut cells that produce the majority of the body’s serotonin. Overall, the researchers proposed a pathway in which tuft cells release acetylcholine in response to parasitic immune activity, triggering enterochromaffin cells to release serotonin, thereby activating vagal nerves to reduce appetite.
The researchers first demonstrated that acetylcholine can activate enterochromaffin cells, causing serotonin release. They used organoids: simplified, lab-grown models of organs. This model of the gut’s intestinal lining contained enterochromaffin cells engineered to glow when activated. As expected, the addition of acetylcholine resulted in a strong glow. To confirm that the cells were releasing serotonin, the researchers placed cells that generate an electrical signal in response to serotonin near the enterochromaffin cells. Thus, the produced current demonstrated serotonin secretion.
After establishing the response of enterochromaffin cells, the researchers examined acetylcholine release by tuft cells. Importantly, tuft cells lack the machinery exhibited by cell types that typically release signalling molecules such as acetylcholine. The researchers used organoids to model type 2 inflammation, a chronic immune response associated with parasitic infection. Testing the fluid surrounding the organoids showed that organoids containing tuft cells produced significantly more acetylcholine than organoids without. The researchers also found that acetylcholine release was persistent rather than transient by intermittently washing away acetylcholine, finding that new acetylcholine was continuously produced. It is important to note that findings derived from organoids are limited to some extent: while organoids are a widely accepted model of the intestinal epithelium, they represent a simplified model of the living gut that lacks its full neuro-immune complexity. Limitations of this kind are often addressed through in vivo validation, in which findings are tested in live animal models.
To perform in vivo validation, the researchers induced type 2 inflammation in mice. They also infected mice with Nippostrongylus brasiliensis, a parasite that models hookworm infection in mice. Mice showed increased serotonin in the intestinal lining in both treatment types. This increase was abolished in mice lacking tuft cells or mice in which acetylcholine production was disrupted, further supporting the proposed acetylcholine-serotonin pathway. The researchers then explored how this pathway reached the brain to affect behavior. Imaging revealed that type 2 inflammation increased the activation of vagal neurons from signals originating in the gut. In mice where serotonin release was blocked, the activation of vagal neurons was reduced, suggesting that serotonin contributes to gut-brain signalling associated with parasitic infection.
Finally, the researchers linked the mechanistic pathway to behavior. During type 2 inflammation, mice showed decreased feeding. The expression of this behavior was delayed and decreased when serotonin release from enterochromaffin cells was blocked, suggesting that the pathway proposed by the researchers contributed to decreased feeding. Similar results were observed in response to infection with N. brasiliensis. While this data does establish a relationship between the proposed pathway and behavior during parasitic infection, the implications are not definitive: reduced food intake can point toward a variety of internal states, including nausea, abdominal discomfort, and others.
Overall, the researchers present a pathway that helps build the understanding of how parasitic infection affects behavior via the gut-brain axis. However, the study is limited with regard to the interpretation of reduced feeding behavior and reliance on ex vivo models. While clinical relevance remains somewhat distant, the pathway outlined by Touhara et al. represents an important contribution to understanding parasitic infections.
The researchers first demonstrated that acetylcholine can activate enterochromaffin cells, causing serotonin release. They used organoids: simplified, lab-grown models of organs. This model of the gut’s intestinal lining contained enterochromaffin cells engineered to glow when activated. As expected, the addition of acetylcholine resulted in a strong glow. To confirm that the cells were releasing serotonin, the researchers placed cells that generate an electrical signal in response to serotonin near the enterochromaffin cells. Thus, the produced current demonstrated serotonin secretion.
After establishing the response of enterochromaffin cells, the researchers examined acetylcholine release by tuft cells. Importantly, tuft cells lack the machinery exhibited by cell types that typically release signalling molecules such as acetylcholine. The researchers used organoids to model type 2 inflammation, a chronic immune response associated with parasitic infection. Testing the fluid surrounding the organoids showed that organoids containing tuft cells produced significantly more acetylcholine than organoids without. The researchers also found that acetylcholine release was persistent rather than transient by intermittently washing away acetylcholine, finding that new acetylcholine was continuously produced. It is important to note that findings derived from organoids are limited to some extent: while organoids are a widely accepted model of the intestinal epithelium, they represent a simplified model of the living gut that lacks its full neuro-immune complexity. Limitations of this kind are often addressed through in vivo validation, in which findings are tested in live animal models.
To perform in vivo validation, the researchers induced type 2 inflammation in mice. They also infected mice with Nippostrongylus brasiliensis, a parasite that models hookworm infection in mice. Mice showed increased serotonin in the intestinal lining in both treatment types. This increase was abolished in mice lacking tuft cells or mice in which acetylcholine production was disrupted, further supporting the proposed acetylcholine-serotonin pathway. The researchers then explored how this pathway reached the brain to affect behavior. Imaging revealed that type 2 inflammation increased the activation of vagal neurons from signals originating in the gut. In mice where serotonin release was blocked, the activation of vagal neurons was reduced, suggesting that serotonin contributes to gut-brain signalling associated with parasitic infection.
Finally, the researchers linked the mechanistic pathway to behavior. During type 2 inflammation, mice showed decreased feeding. The expression of this behavior was delayed and decreased when serotonin release from enterochromaffin cells was blocked, suggesting that the pathway proposed by the researchers contributed to decreased feeding. Similar results were observed in response to infection with N. brasiliensis. While this data does establish a relationship between the proposed pathway and behavior during parasitic infection, the implications are not definitive: reduced food intake can point toward a variety of internal states, including nausea, abdominal discomfort, and others.
Overall, the researchers present a pathway that helps build the understanding of how parasitic infection affects behavior via the gut-brain axis. However, the study is limited with regard to the interpretation of reduced feeding behavior and reliance on ex vivo models. While clinical relevance remains somewhat distant, the pathway outlined by Touhara et al. represents an important contribution to understanding parasitic infections.
Featured Image Source: Unsplash
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