Abstract Background Fatigue is an impactful psychological comorbidity among patients with inflammatory bowel disease (IBD) that often persists during disease remission. Interestingly, we previously demonstrated that mice also exhibit fatigue-like behaviour post-colitis, which coincides with persistent neuroinflammation1. Complement component 1q (C1q) was identified as a hub mediator underlying the inflammatory signature. The aim of this study was to uncover a mechanistic link explaining this persistent neuroinflammation, and to translate these findings to fatigue in patients with IBD in remission. Methods Extinguished chronic colitis (cDSS) was induced in female C57BL/6J mice by cyclic administration of 2% dextran sodium sulphate, followed by a four-week recovery period. C1q serum levels were measured using ELISA, and neuroinflammation was assessed by qPCR. A blood-cerebrospinal fluid barrier was set up in vitro using human choroid plexus endothelial cells (iHCPEnC) and choroid plexus epithelial cells (HIBCPP) grown on opposite sides of a Transwell® filter membrane, and placed over human microglia cells (HMC3) (Figure 1A). Barrier strength was measured via transepithelial electrical resistance (TEER), and HMC3 activation was assessed by qPCR. The serum C1q concentration of patients with IBD in remission included in a previous clinical trial2 was measured using ELISA. Results Serum C1q levels were numerically higher in cDSS mice compared to controls (Figure 1B) and correlated positively with the expression of Lcn2 (r = 0. 50, P=0. 03), S100a8 (r = 0. 56, P=0. 01), and S100a9 (r = 0. 51, P=0. 02) in the prefrontal cortex. The administration of C1q to the endothelial side of the in vitro choroid plexus model induced a drop in the TEER after 24h (P=0. 009, control: 110. 8%±12. 6, 250 µg/mL C1q: 69. 5%±11. 3), indicating compromised barrier integrity. Moreover, the expression of microglia activation markers (TNFa, P2RY12) was disturbed (Figure 1C). In a retrospective analysis of patients with quiescent IBD2, serum C1q levels correlated significantly with fatigue severity, as measured by the fatigue visual analogue scale (fVAS) (Figure 1D). Conclusion We demonstrated that C1q may play a key role in the persistence of neuroinflammation during asymptomatic chronic colitis and could represent a promising therapeutic target for alleviating fatigue in IBD patients. References: 1. M Truyens, H Lernout, C Vandendriessche, A Bruggeman, J Xie, M De Vos, V Vermeirssen, R Vandenbroucke, D Laukens, P014 Behaviour in mice with chronic DSS colitis mimics fatigue in IBD and is associated with neuroinflammation, Journal of Crohn’s and Colitis, Volume 17, Issue Supplement₁, February 2023, Page i184, https: //doi. org/10. 1093/ecco-jcc/jjac190. 0144 2. Truyens M, Lobatón T, Ferrante M, Bossuyt P, Vermeire S, Pouillon L, Dewint P, Cremer A, Peeters H, Lambrecht G, Louis E, Rahier JF, Dewit O, Muls V, Holvoet T, Vandermeulen L, Peeters A, Gonzales GB, Bos S, Laukens D, De Vos M. Effect of 5-Hydroxytryptophan on Fatigue in Quiescent Inflammatory Bowel Disease: A Randomized Controlled Trial. Gastroenterology. 2022 Nov;163 (5): 1294-1305. e3. doi: 10. 1053/j. gastro. 2022. 07. 052. Epub 2022 Aug 6. PMID: 35940251. Conflict of interest: Ms. Lernout, Hannah: No conflict of interest Truyens, Marie: No conflict of interest De Nolf, Clint: No conflict of interest Vandendriessche, Charysse: No conflict of interest Bruggeman, Arnout: No conflict of interest Xie, Junhua: No conflict of interest Van Welden, Sophie: No conflict of interest Lobatón Ortega, Triana: Grant: Abbvie, Ferring, Viatris, MSD, EG, Mundipharma, Biogen, Janssen, Pfizer, Takeda, Galapagos, Afasigma and Sandoz. Personal Fees: Speaker fees from MSD, Abbvie, Janssen, Amgen, Fresenius Kabi, Galapagos, Viatris, Ferring, Celltrion, Alfasigma, Lilly and Takeda. Consultancy fee from Janssen, Galapagos, Alfasigma, Amgen, Bristol Myers, Squibb Fresenius Kabi, Takeda and Abbvie De Vos, Martine: No conflict of interest Vermeirssen, Vanessa: No conflict of interest Vandenbroucke, Roosmarijn: No conflict of interest Laukens, Debby: Personal Fees: RedX Pharmaceuticals
Lernout et al. (Thu,) studied this question.