Microbial regulation of microRNA expression in the brain–gut axis
Introduction
Recent research continues to expand on the scope of influence of the gut microbiome on the gut–brain axis and to identify an expanding range of microbially regulated molecular targets in both the gut and the brain. In particular the transcriptional landscape in brain regions of functional importance to stress-related psychiatric disorders is markedly impacted by gut microbiome manipulations. Added to this portfolio is the ability to exert an impact on the expression of microRNAs in discrete brain regions. Moreover, there is a reciprocal impact of host-derived miRNAs locally in the gut. In this review, we provide a brief overview of the fundamentals of miRNAs and then discuss the most important recent advances in this area and their implications for host-microbe interactions.
Section snippets
What do MicroRNAs do?
MicroRNAs (miRNAs) are small, non-coding, single-stranded RNAs that post-transcriptionally regulate the expression of cellular mRNAs that contain miRNA binding sites. Their expression is widespread [1••], and they have a broad influence on cellular development and function [2]. Since the discovery of the first miRNA, lin-4, in Caenorhabditis elegans in 1993 [3], an additional layer of complexity has been added to the regulation of gene expression in many healthy and pathological cell processes.
MicroRNA structure and target recognition
In humans, miRNAs can exist in numerous genomic contexts, recognised miRNAs are encoded by introns from coding and non-coding regions, and miRNAs can also be encoded by exonic regions [4]. Many miRNAs located within the same genomic region can form functional clusters that can be transcribed together [5]. miRNAs are directed to their mRNA targets by base pairing [6] with much of this base pairing occurs within the seed region (nucleotides 2–8) of the miRNA (see Figure 1, Figure 2) and the
Functions of gastrointestinal miRNAs and their impact on the gut microbiota
Through modifying gene expression, their ubiquitous expression and an ability to modulate multiple cell pathways, miRNAs are powerful signalling molecules [10,11]. Recent studies have confirmed that miRNAs can contribute significantly to cell–cell communication due to the fact that multiple bodily fluids such as blood, plasma, urine, seminal fluid, breast milk, saliva and cerebrospinal fluid contain miRNAs [12]. MiRNAs are generally stable in these fluids and survive extended storage making
Impact of the gut microbiome on brain function and behaviour: a role for miRNAs?
The gut and the brain signal with each other in a manner similar to hormones, with microbes in the gut able to communicate with the brain and the brain able to influence microbes in the gut. The method by which this bi-directional communication takes place still remains to be fully explained but endocrine, neural, metabolic and immune pathways are likely to be involved [18,29,30]. One such communication pathway, the vagus nerve, represents a key neural route which facilitates communication
Conclusion
How the microbiome influences the expression of miRNAs, their target genes and subsequently how miRNAs influence behaviours mediated in the brain remains to be fully understood. The brain–gut axis represents an attractive starting point and much of this evidence has come from work on vagus nerve signalling [57,58], and short chain fatty acids (SCFAs) that affect the central nervous system indirectly [59]. How miRNAs can induce signalling pathways via either pathway of communication will offer
Conflict of interest statement
JFC and TD have research funding from Dupont Nutrition Biosciences, Crema SA, Alkermes Inc, 4D Pharma PLC, Mead Johnson Nutrition, Nutricia Danone, Suntory Wellness. JFC, TD and GC have spoken at meetings sponsored by food and Pharmaceutical companies. All other authors report no conflict of interest.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
APC Microbiome Ireland is a research center funded by Science Foundation Ireland (SFI), through the Irish Government’s National Development Plan (grant no. 12/RC/2273). GC, JFC and TD are supported by the Irish Health Research Board (Grant number ILP-POR-2017-013) and by the US Airforce Office of Scientific Research (Grant number FA9550-17-1-006).
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