A study published in Cell Host & Microbe has found that members of the Cuadovirales viral order positively affect cognition in multiple species, including humans.
Viruses in the human body, but not human viruses
Cuadovirales is an order of bacteriophages, which infect bacteria rather than animal cells. Previous research has noted that 80% of bacterial genomes contain viral DNA, which is linked to the diversity of gut bacteria, and therefore a healthy gut microbiome [1].
It has been previously discovered that viral abundance changes with age. Specifically, within the Cuadovirales order, Microviridae goes up and Siphoviridae goes down [2]. This change also occurs in mice fed a high-fat diet [3].
The taxonomy of these viruses is not fully eludicated, and, in fact, has been recently changed; because this change was done after the researchers finished their work, the researchers’ investigation into Siphoviridae now includes two other taxonomic familes as well; however, approximately 90% of the viruses in these three families are still Siphoridae. The researchers refer to members of these three families as “specific Cuadovirales“.
As the gut-brain axis is known to have effects on cognition, the researchers of this study sought to determine the extent of these viruses’ effects, and what they found was substantial.
Effects on bacterial metabolism
Viral infection, as expected, changes how the infected bacteria work. Surprisingly, the researchers found a strong negative association between specific Cuadovirales and multiple aspects of folate metabolism, including DNA repair mechanisms and the use of vitamins B2 and B6 in the folate cycle. However, the researchers also found that many of the bacterial pathways associated with folate metabolism were increased instead.
The researchers point to one specific bacterial gene upregulated by Siphoviridae: thyX, a gene that is known as TYMS in humans and is instrumental in neuroplasticity, neurological development, and memory retention [4]. Specific Cuadovirales also affected bacterial genes associated with multiple other aspects of central nervous system biochemistry, and they were shown to largely infect lactic acid-related bacteria, which are associated with dairy products [5].
Human cognition effects
Using multiple diagnostic tests and a careful examination of gut bacteria, the researchers investigated a discovery cohort of 114 people. Controlling for confounding factors such as age and BMI, the researchers found that specific Cuadovirales were associated with improved performance on the trail-making task B, a measurement of cognitive ability, in women, while Microviridae were associated with decreased performance in both sexes. On the other hand, specific Cuadovirales were associated with the backward digit span test, another measure of cognitive performance, in men but not women.
The researchers then examined a larger validation cohort of 942 people. The results in this cohort were even more pronounced in men; specific Cuadovirales were associated with improved short-term and long-term memory, executive function, and speed of information processing.
Animal results
The researchers also explored the effects of specific Cuadovirales in mice and fruit flies. Transplanting bacteria infected with these viruses into mice improved their scores on the novel object recognition test and increased gene expression associated with cognition; as expected, Microviridae were shown to negatively affect these genes.
In flies, the researchers chose to test specifically Lactococcal 936-type viruses, giving a control group whey without any viruses. Flies given live viruses were found to score better on learning and memory, which, in flies, is represented by an aversive taste test.
Conclusion
This study is extremely detailed with multiple layers of results, and it involves a great many individual viruses, bacteria, proteins, and genes. While some of the contradictory results are not fully elucidated, and the sex-based differences are not explained, this study offers very good insight into these topics, and it provides interesting potential for future development.
This study could be foundational for managing our fecal bacteria, even to the point of genetic manipulation, in order to keep our gut microbiomes functioning as they should to provide our brains with what they need.
Literature
[1] Keen, E. C., & Dantas, G. (2018). Close encounters of three kinds: bacteriophages, commensal bacteria, and host immunity. Trends in microbiology, 26(11), 943-954.
[2] Gregory, A. C., Zablocki, O., Zayed, A. A., Howell, A., Bolduc, B., & Sullivan, M. B. (2020). The gut virome database reveals age-dependent patterns of virome diversity in the human gut. Cell host & microbe, 28(5), 724-740.
[3] Schulfer, A., Santiago-Rodriguez, T. M., Ly, M., Borin, J. M., Chopyk, J., Blaser, M. J., & Pride, D. T. (2020). Fecal viral community responses to high-fat diet in mice. Msphere, 5(1), e00833-19.
[4] Heyward, F. D., & Sweatt, J. D. (2015). DNA methylation in memory formation: emerging insights. The Neuroscientist, 21(5), 475-489.
[5] Mahony, J., & Van Sinderen, D. (2014). Current taxonomy of phages infecting lactic acid bacteria. Frontiers in microbiology, 5, 7.
