Investigating the potential of fish oil as a nutraceutical in an animal model of early life stress

ABSTRACT

Background: Early life stress is a key predisposing factor for depression and anxiety disorders. Selective serotonin re-uptake inhibitors (SSRI) are frequently used as the first line of pharmacology treatment for depression but have several negative qualities, i.e. a delay or absence of effectiveness and negative side-effects. Therefore, there is a growing need for new nutraceutical-based strategies to blunt the effects of adverse-life events.

Objectives: This study aimed to use the maternal separation model in rats to test the efficacy of fish oil dietary supplementation, on its own and in conjunction with the SSRI anti-depressant fluoxetine, as a treatment for depressive and anxiety-like symptoms associated with early life stress.

Methods: Behavioural tests (open field test, elevated plus maze test and forced swim test) and biochemical markers (corticosterone, BDNF, brain fatty acids and short chain fatty acids) were used to analyse the effects of the dietary treatments. Gut microbial communities and relating metabolites (SCFA) were analysed to investigate possible changes in the microbiota-gut-brain axis.

Results: Maternally separated rats showed depressive-like behaviours in the forced swim and open field tests. These behaviours were prevented significantly by fluoxetine administration and in part by fish oil supplementation. Associated biochemical changes reported include altered brain fatty acids, significantly lower plasma corticosterone levels (AUC) and reduced brain stem serotonin turnover, compared to untreated, maternally separated (MS) rats. Untreated MS animals had significantly lower ratios of SCFA producers such as Caldicoprobacteraceae, Streptococcaceae, Rothia, Lachnospiraceae_NC2004_group, and Ruminococcus_2, along with significantly reduced levels of total SCFA compared to non-separated animals. Compared to untreated MS animals, animals fed fish oil had significantly higher Bacteroidetes and Prevotellaceae and reduced levels of butyrate, while fluoxetine treatment resulted in significantly higher levels of Neochlamydia, Lachnoclostridium, Acetitomaculum and Stenotrophomonas and, acetate and propionate.

Conclusion: Despite the limitations in extrapolating from animal behavioural data and the notable differences in pharmacokinetics between rodents and humans, the results of this study provide a further advancement into the understanding of some of the complex systems within which nutraceuticals and pharmaceuticals effect the microbiota-gut-brain axis.

KEYWORDS:

• Omega 3
• DHA
• EPA
• metabolites
• gut-brain axis
• depression
• SCFA
• maternal separation model

Acknowledgements

We would like to gratefully acknowledge the funding of this work by the Department of Agriculture, Food and the Marine (DAFM), Ireland via the SMART FOOD project: ‘Science Based ‘Intelligent’/Functional and Medical Foods for Optimum Brain Health, Targeting Depression and Cognition’ project (Ref No. 13/F/411). The lead author is funded by the Irish Research Council (IRC) and Biomarine Ingredients Ireland Ltd. via the IRC Enterprise Partnership Scheme (Ref No. EPSPG/2015/57). The other authors are supported in part by Science Foundation Ireland in the form of a centre grant (APC Microbiome Ireland Grant No. SFI/12/RC/2273); and the Sea Change Strategy, NutraMara programme (Grant-Aid Agreement No. MFFRI/07/01) with the support of the Marine Institute and DAFM in Ireland. We acknowledge the Teagasc Sequencing Facility, Dr Fiona Crispie, Dr Paul Cotter and Ms. Laura Finnegan for their technical assistance with the 16S rRNA MiSeq sequencing. Furthermore, we would like to acknowledge and thank Loreto Olavarria-Ramirez for her input into sample collection and analysis.

Disclosure statement

This study was conducted under an Irish Research Council’s Enterprise Partnership funding scheme and was thereby part-funded by Biomarine Ingredients Ireland Ltd., a marine-biotech company that produces marine ingredients utilising blue whiting as raw material.

Additional information

Funding

This work was supported by Department of Agriculture, Food and the Marine: [Grant Number 13/F/411]; Department of Agriculture, Food and the Marine: [Grant Number MFFRI/07/01]; Irish Research Council for Science, Engineering and Technology: [Grant Number EPSPG/2015/57]; Science Foundation Ireland: [Grant Number SFI/12/RC/2273].

Notes on contributors

Sian Egerton

Sian Egerton graduated in Zoology with a doctorate degree in Microbiology by the University College Cork. She is currently a Research Support Project Manager at the Aquaculture & Fisheries Development Centre & Environmental Research Institute, University College Cork.

Francisco Donoso

Francisco Donoso graduated in Biochemistry with a doctorate degree in Neuroscience by the University College Cork. He is currently a Postdoctoral Researcher at APC Microbiome Ireland, University College Cork.

Patrick Fitzgerald

Patrick Fitzgerald graduated with a MSc degree in Neuropharmacology by the National University Ireland, Galway. He is currently a Research Support Officer at APC Microbiome Ireland, University College Cork.

Snehal Gite

Snehal Gite, MSc, PhD, graduated in Biochemistry with a doctorate degree in Biochemistry by the Savitribai Phule Pune University. He is currently a Senior Research & Development Technologist at Bio—marine Ingredients Ireland Ltd.

Fiona Fouhy

Fiona Fouhy, PhD, was previously a Senior Postdoctoral Researcher at Teagasc Food Research Centre Moorepark. She is currently a Lecturer at Cork Institute of Technology.

Jason Whooley

Jason Whooley, BCom, HDip, Dip, graduated in Management and Marketing. He previously held the position of CEO of Bord Iascaigh Mhara. He is currently CEO of Biomarine Ingredients Ireland Ltd.

Ted G. Dinan

Ted G. Dinan, MD, PhD, DSc, graduated with an MD and PhD in Pharmacology. He is currently a Professor of Psychiatry at University College Cork and a Principal Investigator in the APC Microbiome Ireland, University College Cork.

John F. Cryan

John F. Cryan, PhD graduated with a BSc in Biochemistry and a PhD in Pharmacology. He is currently a Professor & Chair at the Department of Anatomy & Neuroscience, University College Cork and a Principal Investigator in the APC Microbiome Ireland.

Sarah C. Culloty

Sarah C. Culloty, PhD graduated in Zoology. She is currently Head of the College of Science, Engineering and Food Science at University College Cork and Director of the Environmental Research Institute, UCC. She is also a Professor at the School of Biological. Earth and Environmental Sciences at University College Cork.

R. Paul Ross

R. Paul Ross, PhD, DSc, graduated with a B.Sc. in Biochemistry and Microbiology, a Ph.D. in Microbiology and a D.Sc. from the National University of Ireland (based on published work. He is currently Director of APC Microbiome Ireland, University College Cork where he is also a Principal Investigator focussing on antimicrobial research.

Catherine Stanton

Catherine Stanton is senior scientist at Teagasc, Moorepark Food Research Centre, Ireland for the past 25 years and Research Professor at APC Microbiome Ireland, University College Cork. She received MSc (Nutrition), PhD (Biochemistry,) and DSc in recognition of published work (2009).