Unraveling the Balance Between Genes, Microbes, Lifestyle and the Environment to Improve Healthy Reproduction
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G C A T T A C G G C A T genes Review Unraveling the Balance between Genes, Microbes, Lifestyle and the Environment to Improve Healthy Reproduction Valeria D’Argenio 1,2,3,* , Lara Dittfeld 4, Paolo Lazzeri 4, Rossella Tomaiuolo 5 and Ennio Tasciotti 1,3,4 1 Department of Human Sciences and Quality of Life Promotion, San Raffaele Open University, via di Val Cannuta 247, 00166 Roma, Italy; [email protected] 2 CEINGE-Biotecnologie Avanzate, via G. Salvatore 486, 80145 Naples, Italy 3 IRCCS San Raffaele Pisana, Via di Val Cannuta 247, 00166 Roma, Italy 4 Aella Labs GmbH, Ra Curta 1, 6967 Lugano, Switzerland; [email protected] (L.D.); [email protected] (P.L.) 5 Università Vita-Salute San Raffaele, Via Olgettina 58, 20132 Milano, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-081-3737909 Abstract: Humans’ health is the result of a complex and balanced interplay between genetic factors, environmental stimuli, lifestyle habits, and the microbiota composition. The knowledge about their single contributions, as well as the complex network linking each to the others, is pivotal to understand the mechanisms underlying the onset of many diseases and can provide key information for their prevention, diagnosis and therapy. This applies also to reproduction. Reproduction, involving almost 10% of our genetic code, is one of the most critical human’s functions and is a key element to assess the well-being of a population. The last decades revealed a progressive decline of reproductive outcomes worldwide. As a consequence, there is a growing interest in unveiling the role of the different factors involved in human reproduction and great efforts have been carried out to improve its outcomes. As for many other diseases, it is now clear that the interplay between the underlying genetics, our commensal microbiome, the lifestyle habits and the environment we Citation: D’Argenio, V.; Dittfeld, L.; live in can either exacerbate the outcome or mitigate the adverse effects. Here, we aim to analyze Lazzeri, P.; Tomaiuolo, R.; Tasciotti, E. how each of these factors contribute to reproduction highlighting their individual contribution and Unraveling the Balance between providing supporting evidence of how to modify their impact and overall contribution to a healthy Genes, Microbes, Lifestyle and the Environment to Improve Healthy reproductive status. Reproduction. Genes 2021, 12, 605. https://doi.org/10.3390/genes12040605 Keywords: human reproduction; infertility; genetic factors; microbiome; lifestyle; environment Academic Editor: Peter Ellis Received: 17 March 2021 1. Introduction Accepted: 17 April 2021 Our health is determined by the contribution of intrinsic and extrinsic factors that affect Published: 20 April 2021 the way our cells, tissues, organs and body work as an integrated system. Similarly, many pathological conditions affecting the proper functioning of our body are also determined Publisher’s Note: MDPI stays neutral by a mixture of causes, generally ascribed to congenital and external elements. Dissecting with regard to jurisdictional claims in what has the greatest effect and what can be changed or not has been an ongoing debate published maps and institutional affil- and is probably one of the key challenges scientists are facing today. iations. For many years, researchers have focused on the impact of our genetic code on health and disease. Since the completion of the human genome program in 2003 [1], we have spent a great deal of resources in understanding the role of single genes and the relative contribution of multiple genes in the determination of a particular phenotype. As of Copyright: © 2021 by the authors. today, we have a much deeper understanding of the function of many individual genes Licensee MDPI, Basel, Switzerland. and a better comprehension of their involvement in the definition of complex traits, but This article is an open access article we are still far from having a complete picture of the causes and effects that link our distributed under the terms and genetic background to the multitude of possible outcomes that humans face in their lives. conditions of the Creative Commons Gene expression and regulation, as well as the interaction between multiple genes still Attribution (CC BY) license (https:// remain debated questions that will require more studies. The advent of faster sequencing creativecommons.org/licenses/by/ 4.0/). Genes 2021, 12, 605. https://doi.org/10.3390/genes12040605 https://www.mdpi.com/journal/genes Genes 2021, 12, x FOR PEER REVIEW 2 of 30 Genes 2021, 12, 605 2 of 30 debated questions that will require more studies. The advent of faster sequencing tech- nologies together with the computational power offered by artificial intelligence and ma- technologieschine learning together have opened with the a new computational frontier in powergenetic offered studies by and artificial offered intelligence the promise and to machinegreatly advance learning the have field opened in the a years new frontierto come in [2,3 genetic]. studies and offered the promise to greatlyConcomitantly, advance the field a growing in the yearsinterest to comehas been [2,3 ].devoted to explaining how the environ- Concomitantly, a growing interest has been devoted to explaining how the environ- ment around us affects our biology, through its interplay with the genetic determinants ment around us affects our biology, through its interplay with the genetic determinants that that govern the cellular mechanisms at the basis of human physiology. External environ- govern the cellular mechanisms at the basis of human physiology. External environmental mental factors, like food, drugs, chemicals, temperature, and light, can influence gene ex- factors, like food, drugs, chemicals, temperature, and light, can influence gene expression pression and determine which genes are turned on and off, thereby affecting the way our and determine which genes are turned on and off, thereby affecting the way our organism organism develops and functions. This has spurred a flourishing interest in assessing how develops and functions. This has spurred a flourishing interest in assessing how lifestyle lifestyle and life choices can alter the genetic program written in our cells, and has resulted and life choices can alter the genetic program written in our cells, and has resulted in a in a growing body of evidence that supports the overall claim that we are the product of growing body of evidence that supports the overall claim that we are the product of both both “nature and nurture” [4]. With the first, we refer to the overall predetermination of “nature and nurture” [4]. With the first, we refer to the overall predetermination of our fate our fate as it is influenced by genetic inheritance and other biological factors. With the as it is influenced by genetic inheritance and other biological factors. With the latter, we latter, we allude to the influence of external factors that result from what we are exposed allude to the influence of external factors that result from what we are exposed to, what we experienceto, what we and experience what we and choose. what we choose. More recently a a third third element element has has appeared appeared on on the the scene scene and and has hasquickly quickly gain gaineded mo- momentummentum in the in research the research laboratories laboratories around around the world: the world: our microbiome. our microbiome. It is now It common is now commonknowledge knowledge that the collection that the collectionof microbes of microbesthat live on that and live inside on and us insidehas the us ability has the to abilitydeeply toaffect deeply how affect we howfunction we function by regulat by regulatinging several several molecular molecular mechanisms mechanisms that thatulti- ultimatelymately influence influence the the performance performance ofof cells cells and and tissues. tissues. Microbes Microbes can can alter alter our metabolism by secreting a a plethora plethora of of factors factors that that have have the the ability ability to crosstalk to crosstalk with with the molecular the molecular ma- machinerychinery of ofour our own own cells cells.. These These factors factors can can either either contribute contribute to to the the m maintenanceaintenance of ourour body or wreakwreak havochavoc andand shortshort circuitcircuit ourour homeostasishomeostasis [[55].]. AsAs fundamentalfundamental newnew studiesstudies continue to appear, itit becomesbecomes moremore andand moremore obviousobvious thatthat manymany explanationsexplanations thatthat werewere not possiblepossible byby leveragingleveraging what what we we knew knew about about genetic genetic or or environmental environmental factors factors could could be givenbe given leveraging leveraging the the role role of of this this third third player, player, microscopic microscopic in in size size but but mightily mightily powerfulpowerful inin scope.scope. As the knowledgeknowledge of the inner working of our organismorganism grows,grows, so does our under- standing of thethe pathologiespathologies that can affect it.it. The rela relativetive impact of each of the above-above- mentioned factorsfactors onon several diseases and complex ailments has been analyzed and today wewe havehave aa moremore comprehensivecomprehensive roadmaproadmap toto addressaddress thethe originorigin ofof severalseveral diseasesdiseases andand toto reachreach aa betterbetter prevention,prevention, fullerfuller diagnosisdiagnosis