Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn's disease, characterized by intestinal structure destruction and chronic relapsing intestinal inflammation [1]. Genetic, environmental and microbiome factors cause an unbalanced immune system, which ultimately leads to IBD [2], [3], [4]. IBD not only results in gastrointestinal symptoms such as diarrhea and rectal bleeding but also many extraintestinal organ disorders [5].

In recent years, accumulative studies have shown that IBD can cause pathological changes in the central nervous system (CNS). When compared with the general population, depression and anxiety are more frequent in people with IBD [6]. Dextran sulfate sodium (DSS)-induced colitis mice showed depression/anxiety-like behavior by affecting inflammation (cytokines, NLRP3/ASC/caspase-1 inflammasome), oxidative stress (SOD, MDA), apoptosis (TUNEL staining, caspase-3) and nerve tissue (synaptic density and plasticity) [7, 8]. Chronic colitis (1% DSS for 4 weeks) impaired spatial and cognitive memory and exacerbated age-related neuropathology in aged wild-type mice but not age-paired NLRP3 KO mice [9]. Another study demonstrated that acute and chronic colitis had quite different effects on hippocampal neurogenesis and innate immune cell response [10]. In addition, aggravated locomotor defects and dopaminergic neuron loss were observed in LRRK2 G2019S mutation mice after induction of mild chronic colitis [11]. However, the link between the gut and brain in IBD remains to be explored.

The kynurenine (Kyn) pathway, major degradation route of tryptophan (Trp), is involved in multiple pathologies of CNS [12]. In hippocampal sections of Alzheimer's disease (AD) patients, elevated expression of IDO-1/TDO (rate-limiting enzyme of Kyn metabolism) was co-located with neurofibrillary tangles (pathological hallmarks of AD) [13, 14], indicated the involvement of activated Kyn pathway in AD pathology. In 6-OHDA induced mice of Parkinson's disease, the treatment of 1-Methyltryptophan (1-MT, an IDO-1 inhibitor) improved behavioral parameters and neurotransmitter levels, which might through the reduction of neuroinflammation (TNF-α, IFN-γ, IL-6), neuronal apoptosis (caspase-3) and oxidative stress [15]. Besides, researchers observed significant improvement of disease severity in experimental allergic encephalomyelitis mouse model after the treatment of 1-MT and Ro 61-8048 (KMO inhibitor) [16]. All these clues indicate that the Kyn pathway of Trp metabolism is an important mechanism of neuropathology and it is necessary to clarify the changes of Trp metabolism in disease states. Until now, the effect and mechanism of IBD on brain Trp metabolism has not been explored.

Accumulative studies have focused on the bidirectional communication pathways between gut and the CNS, in which the gut microbiota is one of the most important mediators [17, 18]. Dysregulation of the microbiota-gut-brain axis has been increasingly involved in the pathophysiology of CNS diseases such as Alzheimer's disease, autism spectrum disorder, brain injury, multiple sclerosis, Parkinson's disease, and stroke [19]. In addition, previous studies have demonstrated major shifts in microbial diversity and relative abundance between IBD patients and healthy individuals [20], [21], [22], [23]. Intestinal flora can also affect Trp metabolism in the intestinal tract. Intestinal microbiome derived Trp decarboxylases converted dietary Trp to tryptamine and other molecules, which not only changed host physiology by reducing available Trp, but also activated aryl hydrocarbon receptors by producing indole derivatives [24, 25]. Moreover, studies have shown that Akkermansia muciniphila and Parabacteroides distasonis directly regulated Trp metabolism in serum and hippocampus respectively [26, 27]. However, the relationship between gut flora dysbiosis (caused by DSS treatment) and Trp metabolism in the brain has not been discussed.

In this study, we used DSS-induced colitis models (acute and sub-chronic colitis) to explore the effects of IBD on Trp metabolism (both in peripheral circulation and the CNS), as well as the role of intestinal flora in Trp metabolism.