Mini-Review on the Possible Interconnections between the Gut-Brain Axis and the Infertility-Related Neuropsychiatric Comorbidities.

Following early studies into the relationship between humans and bacteria, attained through a series of microscopic observations [ 1 ], came the largest research project dedicated to all-commensal, symbiotic and pathogenic entities three and a half centuries later [ 2 ]. In 2008, this Human Microbiome Project (HMP) was launched. The main objective(s) of the initial, or “Jumpstart” phase, were to develop new algorithms (libraries with reference sequences), technologies and tools dedicated to the assessment of the intestinal microflora [ 3 ]. It has been concluded that all the microorganisms which colonise our body are grouped into four major microbial categories. The gastrointestinal microbiota (GM) exceeds the oral, urogenital and skin microbiota, and even outnumber the total number of the human somatic and germ cells by a factor of 10 [ 4 ]. The microbes are spread throughout the entire gastrointestinal tract [ 5 , 6 ], with anaerobic microorganisms sub-divided into three enterotypes: Ruminococcus , Prevotella and Bacteroides [ 7 ]. The most abundant bacterial collections are the Firmicutes , Bacteroidetes , Actinobacteria and Verrucomicrobia phyla [ 8 ], collectively unifying over 1000 species that have been cultured and analysed phylogenetically [ 9 ]. The Integrative Human Microbiome Project (iHMP) then centred its focus on the influence of the gut’s flora on transient episodes—more precisely, between eubiosis and dysbiosis. There are three aspects to the second research phase; each aspect is considered in the context of the commensal, enteric bacteria. These phases were (I) pregnancy, delivery method and premature births; (II) irritable bowel syndrome (IBS) and its potential triggers; and finally, (III) the influence of stressors in the pathophysiology of prediabetes [ 10 ]. The gastrointestinal microbiota is composed of distinct cell types [ 11 , 12 , 13 , 14 ] which fulfil key roles [ 15 ] in order to prevent a dysbacteriosis. These different cell types initiate specific responses, defining its crucial role in maintaining the integrity of the neurohormonal axes [ 16 ]. Even if the concept regarding the two-way path between the intestinal flora and the brain is generally accepted, these relations are still insufficiently understood. The gut–brain axis (GBA) is a dense network which unites a number of fundamental physiological pathways, such as the central nervous system (CNS), the neuro-endocrine and -immune systems as well as the sympathetic and parasympathetic components of the autonomic nervous system (ANS) and the enteric nervous system (ENS). The hypothalamic–pituitary–adrenal (HPA) axis also plays a pivotal role alongside the GBA in many stress-related disorders [ 17 ]. Recent findings support the notion of a “personalised microbiome”, with an inter-individual variation through a series of endo- and exogenous factors. The commensal microbiota are influenced by interactions with pathogens [ 18 ] along with dietary differences [ 19 ], and prolonged exposure to medications [ 20 ]. The myriad of influencing factors contribute to the formation of the individual human virome [ 21 ], as well as the ‘gut resistome’ or antibiotic resistance [ 22 ]. Other factors that can affect the micro-environment include a lack of physical exercise [ 23 ], as well as the influence of heritable components [ 24 ], and the culmination of these factors promotes transitions of bacteria in different sites along the gut [ 25 ]. Apart from the metabolism of the gut microbiota, characterised by a wide variety of metabolites involved in a host’s eubiosis [ 26 , 27 ] based on the exogenous supply, these microbial associations as well participate in shaping a newborn’s microbiota [ 28 ].

One of the earliest interactions of the foetus with the maternal urogenital microbiota take place once the foeus passes into the birth channel [ 28 ]. The colonisation process could actually be initiated in utero; Collado et al. [ 29 ] identified that Proteobacteria is the most prevalent phylum in both the placenta as well as the amniotic fluid. Data obtained following the analysis of the meconium suggest a mother–foetal transfer, with infants’ microbiota being similar to that found in the colostrum after almost one week. The neonatal microbial communities are influenced by several processes such as preterm deliveries along with the method of delivery. Aagaard et al. [ 30 ] have highlighted the existence of a temporary niche formed during pregnancy, which unites four phyla: Firmicutes , Tenericutes , Proteobacteria , Bacteroidetes and the Fusobacteria genus. While Bifidobacterium , Lactobacillus , Bacteroides and Clostridium are passed via the placenta [ 31 , 32 ], Lauder et al. [ 33 ] concluded that there are no significant differences between the number of copies following a q-PCR analysis between the placental strains and the negative controls. However, whether or not the placenta possesses beneficial microorganisms is still under question, mainly because some recent evidences supports the notion of favourable conditions for certain pathogen proliferation—in particular, Group B streptococcus [ 34 ]. Stout et al. [ 35 ] established that 27% of the basal plates of placentas possess intracellular bacteria which is, therefore, a possible route for intra-uterine colonisation. The finding of placental intracellular bacteria was found in 54% of the studied cohort who had a spontaneous preterm delivery, and in only 26% of term-spontaneous deliveries. There were no major differences in the predisposition for intra-amniotic infections or Group B Streptococcus in preterm births. Intrauterine infections are known to be a cause of both spontaneous preterm labour (PTL) and/or preterm prolonged rupture of membranes (PPROM) [ 36 , 37 ]. As the bacterial DNA has been detected in 70% from all the placental tissues, the authors concluded that the placental membranes possess bacteria, but it is not a cause of preterm labour or PPROM [ 38 ] following a caesarean section (C-section). On the other hand, no signatures of bacterial DNA have been detected compared with term vaginal deliveries, the positivity being around 50% [ 39 ]. The gestational age of an infant can correlate to the diversity seen in the commensal bacteria that are acquired by the infant, which is suggestive of prenatal influences [ 40 , 41 ]. Interestingly, Hu et al. [ 42 ] have concluded that the meconium unites microbial strains, arguing that the mode of birth does not influence the microbial diversity. However, the microbial composition of the meconium was significantly influenced by the maternal diabetes status. It is intriguing that one of the microbes involved in the metabolism of levodopa in patients with Parkinson’s disease has been identified in meconium samples. With a rate of 1 to 5 samples, Enterococcus faecalis has been identified in almost 80% of all the samples after the meconium has passed within the first two hours [ 43 ]. Hansen et al. [ 44 ] evaluated the microbiota contained within the meconium, and they found that bacteria was detectable in two-thirds of the meconium samples through the use of fluorescence in situ hybridization (FISH) and 7% by standard polymerase chain reaction (PCR), while a significant percentage of sterile samples have been defined by a minimum inhibitory concentration (MIC). Enterococcus , Streptococcus , Staphylococcus , or Propionibacterium were the predominant strains in the umbilical blood cord [ 43 ], while in the amniotic fluid the bacterial composition was dominated by species such as Sneathia sanguinegens , Leptotrichia amnionii and an uncharacterised bacteria [ 45 ]. Shao et al. [ 46 ] have identified that the bacterial composition can be influenced by delivery method, as they demonstrated a disruption to the transmission of the maternal Bacteroides in caesarean sections, with C-sections proving to detriment the Enterococcus , Enterobacter and Klebsiella species. In addition, preterm infants often receive treatment with antibiotics in order to prevent possible infections, but a recent research article has demonstrated the subsequent existence of resistome as a result of prolonged exposure to various drugs [ 47 ], suggesting that an infant’s commensal microbiome will be impacted by these antibiotics.

Turnbaugh et al. [ 48 ] revealed that even monozygotic (MZ) pairs have distinct signatures of commensal microbiota. The stool samples collected were compared to 1095 bacterial communities that are commonly found in the gut and other body habitats, from related and unrelated individuals. In over one million bacterial reads, the α-diversity indicated approximately 800 following the analysis of the hypervariable V2 region. Goodrich et al. [ 49 ] have reproduced an association between the lactic bacteria belonging to the Bifidobacterium , which is usually heritable between the UK twins, and the LCT gene locus, being responsible for the hydrolysation of lactose in the upper GI tract. The faecal samples collected from mono (MZ)- and dizygotic (DZ) twin individuals from the United States and South Korea have revealed the existence of a unique microbiome. Based on the sequences obtained following the analysis of the bacterial V2 region, Lee et al. [ 50 ] have concluded that this variation seems to be the result of a combination between some temporal and spatial variables. This hypothesis also applies to a much smaller degree in brothers. In a study conducted by Schloss et al. [ 51 ], a metagenomic shotgun analysis of 16S rRNA’s V3-V5 region has been conducted with the aim of distinguishing the microbial communities of each family member having as reference individuals which live in the same geographic area. Bifidobacterium and Escherichia have been the most dominant strains encountered in all siblings, with the mention that the microbiota of the two-year-old was more similar to her weaned siblings. Twelve operational taxonomic units (OTUs) have been identified within the family, from which four were location specific, belonging to the genus Bacteroides and Subdoligranulum and family Lachnospiraceae . Recently, Kato et al. [ 52 ] revealed the presence of the CC genotype in 1068 Japense adults at rs4988235 and the GG at rs182549, in addition to those previously reported (rs145946881, rs41380347, rs41525747 and rs869051967). They found that there was positive correlation between the CC genotype and a low abundance of Bifidobacterium [ 53 , 54 ]. C/T(-13910) has been mainly reported as the predominant lactase locus in Europeans, while G/A(-22018) in Japanese–Brazilian and Chinese populations [ 55 ]. In addition, bathtub water has proved to be a potential vehicle for the bacterial transfer and it is not strictly a mother-to-infant axis. Odamaki et al. [ 56 ] enrolled 21 Japanese individuals from five families and, after the isolation of the faecal and bathtub samples, Bifidobacterium longum was shown to be the most abundant microorganism exchanged between the members, compared with those which do not adopt this tradition. A comparative study conducted by the same author demonstrated that Bifidobacterium longum subsp. longum is present throughout the entire life, regardless of age. Their results suggest that some bacteria are distributed across family members [ 57 ]. Laursen et al. [ 58 ] have evaluated how early infections, having older brothers or pets could disrupt the normal colonisation of the gut. David Strachan’s hygiene hypothesis has been certified in the present study, with the presence of older siblings being positively correlated with the bacterial diversity and richness of Firmicutes and Bacteroidetes or with Faecalibacterium prausnitzii [ 59 ]. On the other hand, pets or early infections had less contribution towards the gut flora, without any significant data correlation. Dill-McFarland et al. [ 60 ] have emphasised in his study an attribute acquired as social human beings. The analysis of the faecal samples collected from 177 individuals, from which 94 were spouses and 83 were siblings, revealed that their taxa is more similar and diverse when compared with those of related or unrelated individuals, with the cause–effect relating to dietary habits. The faecal samples collected over an interval of two years has showed that are no major fluctuations within these communities, being stable throughout the entire study. The only minor difference was in the case of one person after an intervention that required medication, and no foreign or major change regarding species density has been reported [ 61 ].

A reduction in the host’s innate eubiosis triggers a pro-inflammatory cascade [ 62 ]. If this state is prolonged it may lead to gastrointestinal disorders [ 63 , 64 ], as well as neurodegenerative [ 65 ] or neuropsychiatric disorders [ 66 ]. In such cases, the HPA axis exerts an antagonistic effect upon the organism. It has been shown that the patients with a major depressive disorder (MDD) have high serum levels of cortisol [ 67 ] and reduced levels of oxytocin [ 68 ]. The results obtained in another study, conducted with a similar design to the previous one, provides additional evidence and further consolidates this strong correlation between the brain and the digestive tract [ 69 ]. There is a lot of controversy regarding the interconnections between the neurological and gastrointestinal disorders [ 63 , 66 ] and even if these disturbances of the central nervous system (CNS) are irremediable, at least the symptoms can be reduced by enhancing the GM. A number of conventional alternatives have been developed in recent years [ 70 , 71 ], presently being considered the most powerful vehicles for the acquisition of the beneficial microorganisms intended for the reconstruction of the GM ( Table 1 ). It has been suggested that intestinal microflora may reduce or even inhibit the treatment for infertility [ 82 ] and, in parallel, gradually promote neuropsychiatric disorders ( Table 2 ). It must be taken into consideration that in Table 2 , we have focused only on those drugs usually administered for infertility with a known potential for a sside effect that include the promotion of a psychiatric disorder. Unfortunately, very little is known regarding the side effect profile of infertility medication. Thus, it can be concluded on the basis of the studies summarised in Table 2 that infertility drugs indeed exert antagonistic effects upon the neurohormonal axis by disrupting its normal functionality. It is difficult for patients and clinicians to figure out which responses are psychological and which are caused by medication, but it is vital to identify the causes in order to determine the future measures.

Infertility can have profound consequences on a person’s psychology, often through the perception of losing control on one’s life [ 94 ]. The issue of infertility can become centric to a relationship with anger and confusion replacing reason [ 95 ]. This is because an adults’ progress and identity often resides with the desire to conceive [ 96 ]. Cousineau [ 97 ] extensively reviewed all the aspects surrounding the issues in relation to the cultural and social effects of infertility, along with the influence on marital status and decision making and the relevant psychological support. Infertility treatment puts a great deal of stress on a couple and as this can culminate in an attitude of resignation, and the aspiration to have a child is replaced by adoption or being child free [ 98 ]. Many couples find it difficult to adapt to this new trajectory, and often find it hard to acquire a new vision beyond this temporary crisis [ 99 ]. They must often make radical lifestyle adjustments, such as re-evaluating decisions surrounding career options, with other important aspirations often postponed [ 100 ]. Aside from the individual lifestyle upheaval, one must adapt to a rigorous medication program [ 101 ]. Infertility should not be viewed as a major impediment, but rather as an unplanned event. The literature highlights a broad array of causes for infertility. The ones that have been most emphasised lately are polycystic ovarian syndrome (PCOS) [ 102 , 103 ], hypothalamic dysfunctions [ 104 ], premature ovarian failure (POF) [ 105 ] and endometriosis [ 106 ]. However, rather than focussing on the organic aetiology behind infertility, we have decided to detail the associated neuropsychiatric comorbidities, given the fact that women are more prone to mixed anxiety–depressive disorders (MAAD) than men. This is why, in Table 3 , we have summarised all the studies conducted between 2010–2020, focussing on large cohorts (≥1000 patients per sample).

The evidence presented in this manuscript suggests that the gut microflora has a profound and complex influence on the psychological profile of each individual. Moreover, changes in this integrative system may serve as a bridge to upcoming CNS disorders, whilst also having the potential to provoke gastrointestinal deficiencies in an early stage. Regarding the infertility medication and the overall “disease”, this topic remains debatable, mainly because the number of studies is limited, but it is clear that it may disrupt the integrity of the GBA–HPA axes. However, an occurring dysbacteriosis not only gradually alters homeostasis, but also amplifies the chances to block entirely the effect of any infertility drug. On the other hand, the techniques dedicated to the restoration of the microbial communities have undergone a fulminant ascension lately but, like any therapy, some disorders have been omitted for unknown reasons, which is why additional studies will further aid our understanding.