Reshaping the gut microbiota affects pain and anxiety-like behaviors in a transgenic model of sickle cell disease

Sickle cell disease (SCD) patients experience recurrent episodes of excruciating acute pain and persistent chronic ongoing pain which negatively impacts their quality of life and is the main cause for hospitalizations. Although major progress has been made in understanding the complex SCD pathophysiology, marked deficiencies in the knowledge regarding SCD pain, the factors underlying the transition from acute to chronic pain, pain comorbidities and effective pain management have been realized. Several studies have reported a crucial role of gut microbiota in the pathophysiological features of SCD; however, its role in pain has not been explored. Our study aimed at evaluating the compositional differences in the gut microbiota of SCD transgenic mice and non-sickle control mice and differences in the gut-derived metabolites. We further investigated the role of gut microbiota in SCD pain by utilizing antibiotic-mediated gut microbiota depletion and fecal microbiota transplantation (FMT). We report significant differences in the alpha and beta diversity between the two cohorts. The antibiotic mediated gut microbiota depletion did not affect evoked pain but significantly attenuated ongoing spontaneous pain in SCD mice. FMT from sickle to non-sickle mice resulted in reduced pain threshold for von Frey (0.95±0.17g vs 0.08±0.02g, p<0.001), reduced withdrawal latency for heat hyperalgesia and cold allodynia (15.10±0.79s vs 8.68±1.17s, p<0.01and 2.75±0.26s vs 1.68±0.08s, p<0.01) along with an increase in anxiety-like behaviors tested using elevated-plus maze (EPM) and open field test (OFT). The transfer of gut microbiota from SCD mice to non-sickle control mice was sufficient to evoke anxiety-like behaviors in the recipient mice as evidenced by decreased time spent in the open arm of the EPM and decreased time spent in the central compartment of the open field (76.18±13.18s vs 36.15±7.34s, p<0.05 for EPM and 126.4±35.3s vs 53.98±19.33s for OFT). Additionally, reshaping the gut microbiota of SCD mice with FMT resulted in reduced mechanical allodynia (0.05±0.01g vs 0.25±0.03g, p<0.001) and heat hyperalgesia (5.89±0.67s vs 12.25±0.76s, p<0.001) and reduced anxiety-like behaviors as evidenced by increased amount of time spent in open arms of the elevated plus maze (20.2±6.3s vs 42.1±15.03s) and increased amount of time spent in the central chamber of the open field (44.03±14.49s vs 104.4±[WJ1] 32.79s). These findings provide novel insights into the relationship between gut microbiota and pain in SCD, highlighting the different gut microbial communities which may serve as potential targets for pain management. Funding: This study was supported in part by a grant from the National Heart, Lung, and Blood Institute (NHLBI) R35 HL140021 (Z.W.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NHLBI or NIH. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.