Poster Presentation 2025 Joint Meeting of the COSA ASM and IPOS Congress

Interrogating the role of the gut microbiota in bortezomib-induced peripheral neuropathy through human-to-mouse faecal microbiota transfer (126538)

Jacqui S Scott 1 2 , Sadia Munir 1 2 , Miriam Lynn 2 3 , Feargal Ryan 3 , Courtney B Cross 1 2 , Susanna Park 4 , Kate Vandyke 1 2 , Jo Gardiner 5 6 , Cindy Lee 1 6 , Angie Yong 1 6 , Andrew CW Zannettino 1 2 , David J Lynn 2 3 , Krzysztof M Mrozik 1 2 , Hannah R Wardill 1 2
  1. School of Biomedicine, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
  2. Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
  3. Flinders Health and Medical Research Institute, Flinders University, Adelaide, South Australia, Australia
  4. Brain and Mind Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
  5. Myeloma Australia, Melbourne, Victoria, Australia
  6. Department of Haematology, Central Adelaide Local Health Network, Adelaide, South Australia, Australia

We have previously observed a potential role for the gut microbiota (GM) in peripheral neuropathy (PN) caused by the anti-myeloma drug, bortezomib, with faecal microbiota transplantation (FMT) altering symptom profiles in germ-free mice. Here, we aimed to extend these findings to determine: i) if people with bortezomib-induced PN have distinct a GM composition compared with those without symptoms, and ii) if PN symptoms could be transferred from humans to mice via FMT.

Myeloma patients treated with bortezomib were recruited (August 2023-May 2024) in South Australia (n=29; 66.9±2.07 years; 55% female). PN severity was determined using the validated tool, CIPN8, and faecal samples collected for shotgun metagenomic analysis. Participants were classified as low-PN or moderate/high-PN (CIPN8 score≤/>cohort median, respectively). Faecal samples from two moderate/high-PN participants (hD1=low GM diversity; hD2=high PN severity) were transferred to germ-free mice (N=12/donor) via oral gavage. Mice were treated with vehicle or bortezomib (0.5mg/kg) intravenously for two weeks. PN-associated symptoms were assessed using behavioural phenotyping and von Frey mechanical sensitivity testing in paws.

People with moderate/high-PN (N=14) had reduced microbial diversity (Shannon index; 3.55±0.137) compared with the low-PN group (2.94±0.132, P=0.0038). The GM of moderate/high-PN participants were enriched for taxa associated with rheumatoid arthritis (FDR=0.01), and depleted for taxa producing isovaleric acid (FDR=0.08). Transfer of a human PN-GM to germ-free mice did not induce overt symptoms of PN; however, the combination of a GM transfer from hD2 and bortezomib treatment increased time spent still compared with treatment-naïve germ-free mice (P=0.0211).

These data reinforce the emerging role of the GM in PN, however underscore the complexity of GM-drug-neural interactions and PN aetiology. Although subtle, the induction of behavioural deficits consistent with bortezomib treatment following human-to-mouse GM transfer warrants further investigation with increased numbers of donors and recipient mice to determine whether these effects are statistically and clinically meaningful.