Microbiologist Elies Bik is well-known for applying a close eye to studies, and has spent years anonymously submitting reports on plagiarism and image duplication to journal editors. Last year, she published an analysis of work, with troubling results – that 1 in 25 biomedical papers contains inappropriate duplications in images. She’s never stopped reading papers closely, and recently flagged one on Twitter for concerns about its methodology. Although Bik is not against animal research, she said the treatments rats faced in the paper made her queasy – and didn’t seem justified. She explains her reasoning below.
For the past three years, I have been reporting about new papers in the microbiome field through my blog Microbiome Digest. The stream of microbiome publications appears to get bigger every week — as research has tied intestinal microbiota to a range of health conditions such as atopic dermatitis, periodontitis, and even neurological conditions — so since last month the blog is now being run with the help of an amazing team of young microbiology researchers and science communicators.
Earlier in February, a paper by Yu et al. was published in the Journal of Pharmaceutical and Biomedical Analysis with the interesting title “Variations in gut microbiota and fecal metabolic phenotype associated with depression by 16S rRNA gene sequencing and LC/MS-based metabolomics.” The title suggested that stool samples from patients diagnosed with depression were different from that of controls, which sounded very interesting. However, when I read the abstract, it became clear that the study was performed in animals, by using the “chronic variable stress (CVS)-induced depression rat model”.
At that moment, I recognized the study; I had been asked to peer review the manuscript for a different journal in September 2016. The methods section of that manuscript described the treatments that were used to induce stress in these rats in great detail — and they were horrible.
The rats were treated with several different “stimuli” such as multiple electrical shocks within a minute, forced swimming in ice cold or hot water, withholding food or water for 48 hours, immobilization for five hours, and exposure to loud sounds or stroboscopic lights. Each animal received at least one or two of these treatments every day for 28 days. That’s nearly a month of torture.
I found these methods so appalling and inhumane that I refused to peer review the manuscript. I contacted the Editor, who agreed that this manuscript should be rejected. But apparently, the authors got it accepted for publication in JPBA.
In its published form, the methods section describing the rat treatments has been taken out completely, and instead the authors refer to an older, 2011, paper by the same group. The awfulness of the experimental setup in the current paper is therefore not very obvious, and might have not been noticed during peer review.
This paper has several very concerning issues.
Firstly and most obviously, the treatment of these rats was horrendous and out of proportion. Just reading the methods section made me feel nauseous, and I felt sorry for what these poor animals must have gone through. The paper states that the experimental procedures were approved by the Ethics Committee of the Beijing Institute of Medicinal Plant Development and the CAMS and PUMC (Chinese Academy of Medical Sciences Peking Union Medical College), but I cannot imagine that any institutional animal research board elsewhere would have approved this study.
I’d like to make clear here that I am not against animal experiments. In the microbiome field, animal studies have proven to be very valuable. For example, germ-free mice, which are born and raised in sterility, allowed researchers to study the effect of microbial colonization or lack thereof on the development of organs, tissues and the immune system, the in vivo interactions of different individual microbiome members, or the effects of inoculations with the stool from obese or lean humans. Such carefully designed and executed animal studies have greatly advanced the field. However, the experiments performed on the rats in the Yu et al. 2017 paper would qualify as torture, if done on humans. This should not have been published.
The second, huge problem with this particular rat model is that such treatments do not induce depression. Instead, they induce extreme stress. I can only imagine the fear that these animals must have felt when they heard the door of the animal facility open. The extreme physical and neurological demands and anxiety induced in these animals are very different than the persistent sadness and loss of interest that are associated with human depression. So the findings of these experiments will have very little, if any, value for patients diagnosed with depression.
The third flaw with this paper is that it does not make much sense to test the effect of depression on the fecal composition in an animal model. Instead, the authors could have studied stool samples from human depression patients and compared these to stool from healthy controls. That would have been “the real deal,” and a much more valuable contribution in the research of this human disease.
Taking these concerns together, this study used disproportionally inhumane animal suffering to study something that has no value for human health, and that could have easily been performed in humans. I would like to call upon the Editorial Board of the Journal of Pharmaceutical and Biomedical Analysis, and Elsevier, the publisher, to consider to retract this paper. Studies that include torturing of animals without any scientific reason should not be published.
I also very much hope that both editors and peer reviewers will be on the lookout for manuscripts that include this or other similarly awful type of animal experiments. Thresholds of the amount of acceptable animal suffering clearly differ from country to country. During my searches for image manipulations, I have regularly seen experiments in which live mice are dipped in boiling water, sewn together, or allowed to walk around with tumors as big as their own body. An approval by an institutional committee does not necessarily mean that peer reviewers and editors should find such animal experiments acceptable too. We can and have to push back on useless studies where the amount of animal suffering goes much beyond what is acceptable in the name of science.
If we can achieve that, then hopefully these poor rats have not died for nothing.
Note: Retraction Watch has contacted the corresponding author of the paper, as well as the publisher of the journal, Elsevier, who told us the handling editor is looking into the matter.
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