Antibiotic-induced gut dysbiosis elicits gut-brain axis relevant multi-omic signatures and behavioral and neuroendocrine changes in a nonhuman primate model

ABSTRACT

Emerging evidence indicates that antibiotic-induced dysbiosis can play an etiological role in the pathogenesis of neuropsychiatric disorders. However, most of this evidence comes from rodent models. The objective of this study was to evaluate if antibiotic-induced gut dysbiosis can elicit changes in gut metabolites and behavior indicative of gut-brain axis disruption in common marmosets (Callithrix jacchus) – a nonhuman primate model often used to study sociability and stress. We were able to successfully induce dysbiosis in marmosets using a custom antibiotic cocktail (vancomycin, enrofloxacin and neomycin) administered orally for 28 days. This gut dysbiosis altered gut metabolite profiles, behavior, and stress reactivity. Increase in gut Fusobacterium spp. post-antibiotic administration was a novel dysbiotic response and has not been observed in any rodent or human studies to date. There were significant changes in concentrations of several gut metabolites which are either neurotransmitters (e.g., GABA and serotonin) or have been found to be moderators of gut-brain axis communication in rodent models (e.g., short-chain fatty acids and bile acids). There was an increase in affiliative behavior and sociability in antibiotic-administered marmosets, which might be a coping mechanism in response to gut dysbiosis-induced stress. Increase in urinary cortisol levels after multiple stressors provides more definitive proof that this model of dysbiosis may cause disrupted communication between gut and brain in common marmosets. This study is a first attempt to establish common marmosets as a novel model to study the impact of severe gut dysbiosis on gut-brain axis cross-talk and behavior.

KEYWORDS:

• Gut–microbiota–brain axis
• psychiatry
• metabolome
• stress reactivity
• microbiome-metabolome-correlation
• cortisol
• antimicrobials

Acknowledgments

This work was completed using the Holland Computing Center of the University of Nebraska, supported by the Nebraska Research Initiative. This work was also completed using the University of Nebraska DNA Sequencing Core, which receives partial support from the National Institute for General Medical Science (NIGMS) INBRE-P20GM103427-19 grant and the Fred & Pamela Buffett Cancer Center Support Grant-P30 CA036727. The Proteomics & Metabolomics Facility (RRID:SCR_021314), Nebraska Center for Biotechnology at the University of Nebraska-Lincoln and instrumentation, supported by the Nebraska Research Initiative, were used to complete this work. We thank the staff from the Callitrichid Research Center for outstanding animal husbandry.

Disclosure statement

The authors declare that the research was conducted in the absence of any financial relationships that could be viewed as potential conflicts of interest.

Authors’ contributions

SSH: conceptualization, methodology, formal analysis, investigation, writing – original draft, writing – review & editing. MC: methodology, investigation, writing – review & editing. JAF: conceptualization, methodology, investigation, writing – review & editing. AKB: formal analysis, writing – review & editing. SAl: investigation. AF: investigation. KC: formal analysis. ZWA: formal analysis. WG: formal analysis. MVH: investigation. HRH: investigation. SAz: investigation. MB: investigation. SG: investigation. AJ: investigation. JLT: investigation. JBC: conceptualization, methodology, investigation, writing – original draft, writing – review & editing, resources, supervision, funding acquisition. All authors approve of the final draft of the manuscript.

Availability of data and materials

The 16S rRNA gene amplicon sequence data reported in this paper have been deposited in the European Nucleotide Archive (ENA) at EMBL-EBI under accession number PRJEB61190.

Ethical approval

All procedures conformed to guidelines established by the U.S. National Institutes of Health and have been approved by the University of Nebraska at Omaha’s Institutional Animal Care and Use Committee (protocol #21-001-08-FC).

Supplemental material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2305476

Additional information

Funding

This research was supported by startup funds provided by the University of Nebraska at Omaha and the Nebraska Food for Health Center to J.B.C. Research reported in this publication was supported by the Office Of The Director, National Institutes Of Health of the National Institutes of Health under Award Number K01OD030514 awarded to J.B.C. and was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under Award Number R25GM141506 awarded to K.C. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.