Ulcerative colitis, a chronic inflammatory condition of the colon, is far more than a digestive disorder. Clinicians have long observed that people with the disease experience anxiety at strikingly higher rates than the general population, yet the biological basis of this comorbidity has remained murky. A team led by Yaojiang Liu and Shengjie Huang of The Second Affiliated Hospital of Chongqing Medical University, together with colleagues and corresponding author Song He, set out to determine whether a specific molecular player in the gut lining could determine how vulnerable the brain becomes when the gut is inflamed.

The focus of their investigation was GPR35, a G-protein-coupled receptor expressed on intestinal epithelial cells. G-protein-coupled receptors are among the most druggable protein families in biology, sitting in cell membranes where they relay signals from the outside environment into the cell. GPR35 in particular has attracted attention because it can sense small metabolites produced by the body and by microbes, placing it at a natural crossroads between diet, bacteria, and host physiology. The researchers hypothesized that this receptor might serve as a gatekeeper for messages traveling along the microbiome-gut-brain axis, the bidirectional communication network linking gut microbes and their chemical products to brain function and behavior.

To test the idea, the team generated mice in which GPR35 was deleted specifically from intestinal epithelial cells while the rest of the animal remained genetically intact. These animals, known as GPR35ΔIEC mice, were then subjected to chemically induced colitis, a standard laboratory model that reproduces key features of ulcerative colitis, including inflammation of the colon and disruption of the gut lining. When the researchers compared the colitic knockout animals with colitic controls carrying normal GPR35, a clear behavioral difference emerged. The mice lacking the gut receptor showed markedly greater susceptibility to anxiety-like behaviors, spending less time exploring open, elevated spaces and less time in brightly lit zones, classic signs of heightened fearfulness in rodents.

Crucially, the anxiety was not explained by the severity of gut inflammation alone. Something beyond the inflamed colon was amplifying the behavioral response, and the trail led back to the gut’s microbial residents. Sequencing of the gut microbiota revealed that loss of epithelial GPR35 triggered a significant disturbance in the composition of the bacterial community. Among the casualties was Limosilactobacillus reuteri, a lactic acid-producing bacterium widely regarded as beneficial and frequently associated with gut and mental health. The abundance of L. reuteri dropped in the GPR35-deficient animals, and with it fell the levels of one of the bacterium’s signature metabolic products: indole-3-lactic acid, or ILA.

ILA belongs to a family of compounds derived from tryptophan, the amino acid best known as the precursor of serotonin. Gut bacteria convert dietary tryptophan into indole derivatives, including ILA, which can act as signaling molecules in the host. The Chongqing team found that when colitic mice lacking gut GPR35 received ILA, their anxiety-like behaviors eased. The molecule, in other words, was not merely a passive marker of a healthy microbiome but an active messenger capable of calming the anxious brain.

How could a bacterial metabolite produced in the gut lumen influence behavior? The answer, the researchers discovered, lies in the hippocampus, the brain region central to emotion regulation, learning, and the stress response. In anxious animals, the hippocampus showed signs of astrocyte activation. Astrocytes are star-shaped glial cells that support neurons and, when activated during inflammation, can release inflammatory mediators that disrupt normal neuronal function. ILA treatment suppressed this activation. The pathway the team traced runs through the aryl hydrocarbon receptor, or AhR, a transcription factor found in many cell types and a well-known sensor of microbial and dietary indoles. By engaging AhR and downstream interleukin-22 signaling, ILA restrained the inflammatory activation of hippocampal astrocytes, allowing the brain’s emotional circuitry to function more normally despite the ongoing disease.

The researchers then turned to humans to see whether the same signature exists in patients. They recruited individuals with ulcerative colitis, some of whom also suffered from comorbid anxiety, and analyzed their blood and gut tissue. The results were strikingly consistent with the animal data. Peripheral ILA concentrations were significantly lower in UC patients with anxiety than in those without, and the abundance of mucosa-associated L. reuteri, bacteria clinging to the gut lining rather than simply floating in the lumen, was similarly diminished. The convergence of the mouse and human findings strengthens the case that the GPR35-microbiome-ILA axis is not a laboratory artifact but a feature of human disease.

Taken together, the study sketches a coherent mechanistic chain. Gut epithelial GPR35 supports a healthy microbial community, including L. reuteri, which in turn produces ILA from tryptophan. ILA travels along the gut-brain axis, engages AhR-IL-22 signaling in the hippocampus, and restrains astrocyte activation there, protecting the brain from the anxiety-promoting effects of inflammation. Remove GPR35 from the picture, as the knockout mice demonstrate, and the entire cascade unravels: the microbiome becomes disturbed, ILA falls, astrocytes activate, and anxiety-like behavior intensifies. The receptor, in the authors’ framing, acts as an intermediate player and messenger along the gut-brain axis, quietly shaping how vulnerable the brain is to the inflammatory storm generated by colitis.

The implications are considerable. Because GPR35 is a cell-surface receptor, it is the kind of molecule that medicinal chemists know how to target, and agonists of GPR35 have already been explored in other contexts. The study suggests that boosting GPR35 signaling in the gut, restoring L. reuteri through probiotics, or supplementing ILA directly could each represent strategies to prevent or treat anxiety in ulcerative colitis patients. More broadly, the work adds to a growing body of evidence that metabolites derived from bacterial tryptophan metabolism are key chemical intermediaries between the gut and the brain, with consequences that extend from digestion to mood.

The authors caution that much remains to be worked out, including the precise cellular targets of ILA within the brain, whether the findings generalize to anxiety in other inflammatory conditions, and how such interventions might translate into safe and effective therapies. The research was conducted with appropriate ethical oversight, approved by the institutional review board of The Second Affiliated Hospital of Chongqing Medical University for the human study and by the laboratory animal welfare committee of Chongqing Medical University for the animal work, with informed consent obtained from all human participants. Still, with anxiety among inflammatory bowel disease patients remaining underdiagnosed and poorly treated, the identification of a gut-derived molecular switch that influences anxiety susceptibility offers a genuinely new target, one that sits at the intersection of gastroenterology, microbiology, and neuroscience. If the pathway holds up in further studies, the era of treating a psychiatric symptom with a molecule made by gut bacteria may be drawing closer.