Impact of Microbial Metabolites on Microbiota-Gut-Brain Axis in Inflammatory Bowel Disease

Abstract

The complex bidirectional communication system existing between the gastrointestinal tract and the brain initially termed the "gut-brain axis" and renamed the "microbiota-gut-brain axis", considering the pivotal role of gut microbiota in sustaining local and systemic homeostasis, has a fundamental role in the pathogenesis of Inflammatory Bowel Disease (IBD). The integration of signals deriving from the host neuronal, immune, and endocrine systems with signals deriving from the microbiota may influence the development of the local inflammatory injury and impacts also more distal brain regions, underlying the psychophysiological vulnerability of IBD patients. Mood disorders and increased response to stress are frequently associated with IBD and may affect the disease recurrence and severity, thus requiring an appropriate therapeutic approach in addition to conventional anti-inflammatory treatments. This review highlights the more recent evidence suggesting that alterations of the microbiota-gut-brain bidirectional communication axis may concur to IBD pathogenesis and sustain the development of both local and CNS symptoms. The participation of the main microbial-derived metabolites, also defined as "postbiotics", such as bile acids, short-chain fatty acids, and tryptophan metabolites in the development of IBD-associated gut and brain dysfunction will be discussed. The last section covers a critical evaluation of the main clinical evidence pointing to the microbiome-based therapeutic approaches for the treatment of IBD-related gastrointestinal and neuropsychiatric symptoms.

Keywords: IBD; antibiotics; dysbiosis; fecal transplant therapy; microbiota targeting therapies; microbiota–gut–brain axis; prebiotics; probiotics.

Figure 1

Schematic representation of the microbiota–gut–brain axis. Signals from the gut saprophytic microflora reach the central nervous system (CNS) and the enteric nervous system (ENS) via different pathways, including endocrine, immune, metabolic, and neuronal pathways as described in the text. In normal conditions, the blood–brain barrier allows the access of tryptophan, kynurenines, SCFAs, and bile acids. Abbreviations: NTS, the nucleus of the solitary tract; NVG, nodose vagal ganglion; DRG, dorsal root ganglion; MP, myenteric plexus; IPAN, intrinsic primary afferent neurons; SMP, submucosal plexus; ECC, enteroendocrine cell; EC, enterochromaffin cells; SCFAs, short-chain fatty acids (adapted from Baj et al., 2019 [26]).

Figure 2

Potential role of microbial metabolites in the modulation of symptoms associated with IBD. Environmental changes, stress, diet, previous infection, and dysbiosis may alter the homeostasis of the gut–brain axis underlying the development of motor dysfunction, visceral pain, and stress-related responses, such as anxiety and depression, in IBD patients. Tryptophan metabolites, SCFAs, and secondary bile acids by influencing the epithelial barrier and the immune function and KYN by modulating the ENS peripherally influence symptom development, as described in the text. Furthermore, changes in KYN and SCFAs brain levels may underlay the development of mood disorders and anxiety, while KYN may be involved in visceral hypersensitivity by modulating visceral pain along the gut–brain axis. Abbreviations: DRG, dorsal root ganglion; KYN, kynurenine; IBD, Inflammatory Bowel Disease; NGV, nodose vagal ganglion; NTS, the nucleus of the solitary tract; ENS, enteric nervous system, HPA, hypothalamic–pituitary axis, SCFAs, short-chain fatty acids (with modifications from Baj et al., 2019 [26]).