environmental variations affect the nutritional composition of food resources . a common example is animals encountering different quality of food depending on a dry or rainy season .
this phenomenon is less evident in human agricultural populations , in which efforts are devoted to maintain consistent food resources , both in their physical and nutritional aspects .
concomitantly , while humans in the industrialized world compensate for environment - induced variations in their own diet by using nutritional supplements , natural animal populations likely rely on genetic programs , such as their physiology and behavior , to compensate for such changes .
the negative impact of natural dietary ingredients on health and fertility has traditionally been the domain of toxicologists or ecologists ( for an in depth review on reproductive toxicological effects see ref . 1 ) .
for example , studies on the chemical defense of plants or animal preys have given deep insights into how organisms cope with diverse diets that potentially include harmful foods .
however , only in recent years , developmental and cell biologists started to explore the impact of environmental compounds on the reproductive capacity of animals .
although it has been noted that the environment and diet can have a negative impact on the plasticity of developmental programs , the impact on germ cell developmental programs has remained relatively unclear .
studies that investigate dietary impact on reproductive cells are greatly aided by the proven advantages offered by genetically tractable model organisms .
in particular , the transparent roundworm caenorhabditis elegans emerged as a powerful system to tackle such questions because : 1 ) food parameters are easily controlled in dietary experiments ; 2 ) its gonads and germ cells are readily accessible ; and 3 ) self - fertile hermaphrodites produce large progeny sizes to satisfy statistical needs .
using c. elegans , we recently reported a genetic program that compensates for dietary variations and preserves the animal s reproductive capacity . our genetic work unveiled a novel diet - dependent sterility phenotype that affects only the reproductive cells and manifests in germline stem cell deterioration and in differentiation defects of female germ cells . due to an accumulation of strong genomic and cellular defects , this diet - induced sterility is irreversible and , intriguingly , only apparent upon concomitant loss of the genetic activity that encodes the nuclear hormone receptor protein nhr-114 .
this presumed transcription factor is present in other nematodes , and is highly related to the mammalian hepatocyte nuclear factor 4 ( hnf4 ) , which is an evolutionary conserved nuclear receptor involved in animal metabolism and gastrointestinal homeostasis .
nutrition and metabolism are long - standing intertwined science disciplines that have been largely ignored by developmental biologists
. however , genetic evidence of dietary influence on animal ontogeny is accumulating and challenges the classical separatist view on physiology and developmental programs .
importantly , this dietary influence does not refer to caloric or nutrient related aspects , but rather refers to variable metabolites primarily produced in the gut .
in addition to the intestinal cells , microbes of the intestinal tract are recognized as contributors to dietary metabolism , likely imposing changes in the physiology of a host organism . moreover
, intestinal microbes may produce diverse metabolites that possess the potential to positively or negatively influence their host .
hence , the emerging theme is that diet , in combination with gut microbes , influences a vast number of metazoan processes , suggesting that animals must possess mechanisms that integrate dietary and microbial  information  into their physiology and developmental pathways .
for example , toll - like receptor signaling in the mammalian intestinal epithelium suggests that genetic pathways detect and respond to intestinal microbial components to promote intestinal function and integrity .
however , it is still unknown to what extent and how dietary variations and intestinal microbes influence animal reproduction .
moreover , given the important roles of intestinal microbes and their metabolites for human health , novel developmental diet - germ cell axis of communication may exist in animals to cope with dietary variation .
virtually all laboratories across the world use as the standard diet of caenorhabditis elegans a specific e. coli bacterial strain that was introduced to the  worm community  by sydney brenner .
surprisingly , in the absence of nhr-114 gene activity , we found that this e. coli b strain induces sterility ; nhr-114-deficient animals are fertile on other diets .
remarkably , the sterility - inducing bacterial diet is converted into harmless food when grown on media supplemented with exogenous tryptophan , underscoring that the metabolic status of the bacteria drastically changes the reproductive capacity of an animal . moreover ,
therefore , our work suggests that somatic nuclear receptor nhr-114 activity has evolved to protect the germ cells from the negative effects of dietary variations and inconsistencies . in natural environments , feeding and reproduction of c. elegans
is associated with colonization of rotten food , which inherently contains a diverse and variable microbial composition .
hence , our findings imply that loss of nhr-114 gene activity may result in restricting natural populations of c. elegans in its dietary options and may confine the reproduction of these populations to specific dietary environments .
therefore , in a natural environment the absence of nhr-114/hnf4 activity would be disastrous for the continuity of natural populations of c. elegans .
only germ cells specialize in passing on genetic information to the next generation ; all other cells in multicellular organisms are somatic and support animal reproduction as a whole .
germ cells of most animals , including invertebrates and humans , develop initially during embryonic and juvenile stages , forming a germline tissue that reaches homeostasis in the adult .
germ cell developmental programs are in synchrony with gonadal development ( a somatic tissue ) and share following unique features : 1 ) an expansion of germ cell precursors into a proliferative pool of germline stem cells ; 2 ) a cell cycle transition from mitosis to meiosis in the maturing germ cells ; and 3 ) sex - specific differentiation into haploid gametes , i.e. , sperm or oocytes . in the adult reproductive organs ,
the somatic support cells maintain the germline tissue and influence germ cell development through 2 types of systemic responses : fixed and transient .
such an example of a fixed response is the neuroendocrine control of oocyte maturation in mammals , which occurs under defined developmental circumstances and in a periodic fashion in the adult .
in contrast , transient responses are highly variable because they rapidly integrate changing environmental cues from external sources and the organism s physiology .
such an example of a transient response is the proliferative control of germline stem cells .
reports have shown that the feeding status of an animal affects germline tissue homeostasis and is a major trigger of transient responses in the reproductive organ .
work spearheaded in genetic model organisms revealed a molecular basis of dietary influences on germline stem cells . in response to food abundance ,
studies on invertebrate model systems identified genetic pathways that involve insulin signaling , tumor growth factor- ( tgf- ) signaling , and nuclear hormone receptors to control germ cell proliferation dynamics .
for example , in drosophila melanogaster germline stem cell proliferation activity is low in fasting conditions , but higher in feasting conditions .
similarly , in caenorhabditis elegans , stem cell proliferation activity is controlled by nutrition as a consequence of neuronal insulin and germ cell intrinsic tgf- activity .
these observations in flies and nematodes resonate well with longitudinal studies on adult humans , which have suggested that nutrient - rich and well - balanced diets can help to boost female fertility .
this implies that by the time germ cells are used in reproduction , the entire body has already been exposed to various environmental and dietary influences .
while the accumulation of somatic defects may decrease an individual s health , germ cell defects have the potential to completely hamper an individual s reproductive fitness .
this is particularly problematic when the undifferentiated germ cell precursors  the germline stem cells 
therefore , it is reasonable to assume that genetic mechanisms may have evolved to shield germ cells from potentially irreversible damage caused by dietary influence .
nhrs combine a dna - binding domain ( dbd ) with a ligand - binding domain ( lbd ) that is capable of binding small lipophilic signaling molecules . typically , upon ligand
binding , a conformational change that renders the receptor transcriptionally active is induced that is instrumental for mounting specific transcriptional responses .
indeed , some intestinal nuclear receptors and hnf4 orthologs coordinate dietary homeostasis by coordinating nutrient uptake , eliminating toxic components and protecting against bacterial invasion , or modulating dietary responses .
however , we found that the somatic activity of nhr-114 in the intestine is primarily responsible for protecting the integrity of the germline stem cells in the gonad .
moreover , global gene expression analysis established a correlation between nhr-114 absence , and a genetic downregulation of a detoxification response , suggesting that nhr-114/hnf4 may govern a transcriptional compensatory program that protects immature germ cells from dietary toxins or toxic metabolites . since mammalian hnf4-alfa mediates similar detoxification responses in the gastrointestinal system , this activity may represent an evolutionary conserved intestinal function that also protects the physiology of specific tissues , such as the reproductive system ( for a graphical summary see fig .  1 ) .
different environmental conditions ( arrows ) affect dietary composition , which is further metabolized by gut microbes .
the activity of gastrointestinal nuclear receptors may detect toxins or toxic metabolites and elicit a genetic program that specifically shields germ cells from negative impact .
this protection results in the capacity to efficiently reproduce and increase population size in diverse environments and may , therefore , underlie the colonization of new territories .
therefore , the capacity of a natural population to feed on diverse diets may provide an ecological advantage over those populations that feed on more restrictive diets .
for example , genetic programs that support the metabolism of diverse foods encountered in new environments may facilitate colonization of new territories .
a diversified diet and proper germ cell function are 2 main factors that contribute to the reproductive success of an animal and both ensure the survival of the next generation . since fertility and reproduction rates are tightly linked to the availability of food resources , genetically programmed systemic responses must have evolved to coordinate germ cell homeostasis with food abundance . however , a better molecular understanding of how diet is linked to reproductive stem cells will still be required to understand the underlying physiological soma - to - germ cell interactions that support fertility .
this topic is of increasing importance given that human dietary habits are rapidly changing on a global scale with a continuous population growth .
overall , our findings provide a paradigm for understanding dietary impact on germ cell development .
firstly , our work shows that germline stem cells are exceptionally vulnerable to dietary metabolites . secondly ,
that the dietary impact is at the level of cellular and genomic integrity and the process of cell division , which contrasts to the previously reported nutritional effect on dynamics of germ cell proliferation .
thirdly , our finding that the metabolic status of the dietary bacteria specifically impacts the animal reproductive tissue adds a new angle to microbe - host interactions .
this raises the question of whether the human gut microbiota may also impact fertility and similar genetic programs are in place to protect mammalian germline stem cells .
 animals thrive in environments where food resources are abundant . while this correlation between population growth and food abundance is well established , much less 
 is known about the influence of diet quality on physiological and developmental programs that support animal reproduction . here 
 we discuss dietary impact on fertility , and highlight a recent report on the activity of a nuclear receptor that protects against dietary metabolites to maintain germline stem cell integrity and reproduction . 
Introduction
A Novel Diet-Dependent Type of Sterility
Germline Development is Sensitive to the Nutritional Status
Nuclear Receptors and Dietary/Microbial Interactions
Concluding Remarks