From pandemic to syndemic: microbiota, pregnancy, and environment at a crossroad

Abstract Aim SARS-CoV2 is the latest pandemic that have plagued the socio-health system as an epiphenomenon resulting from planetary resources abuse, crucial for biodiversity. The Anthropocene best defines the present epoch in which human activity irreversibly manipulates intricate and delicate geological and biological balances established over eons. The devastating ecological and socio-economic implications of COVID-19, underline the importance of updating the present pandemic framework to a syndemic. This paper stems from the need to suggest to scientists, doctors, and patients a mission that integrates responsibility from individual to collective health, from present to trans-generational, from human to the entire biotic network. Today's choices are crucial for the perspective on all levels: political, economic, and health as well as cultural. Methods Research on PubMed and other specific web-sites journal was performed on the topic “Microbiota”, “Covid-19”, “Pandemic”, “Zoonosis”, “SARS-CoV-2”, “Environmental Pollutants”, “Epigenetics”, “Fetal Programming”, “Human Extinction”. Data collected were analysed for an integrative model of interconnection between environment, pregnancy, SARS-CoV-2 infection, and microbiota. Moreover, systematic literature review allowed to summarise in a table information about the worst pandemics that afflicted the human species recently. Results This paper offers a broad view of the current pandemic starting with pregnancy, the moment when a new life begins and the health trajectories of the unborn child are defined, which will inevitably have repercussions on his well-being. The fundamental role of the biodiversity-rich microbiota in avoiding the development of severe infectious diseases, is therefore highlighted. It is imperative to adjust the current reductionist paradigm based on mostly immediate symptom management towards a broader understanding of the spatial interconnection of ecological niches with human health and the impacts of today's choices on the future. Health and healthcare are elitist rather than egalitarian, therefore focusing on environmental health forces us to make a concerted and systemic effort that challenges political and economic barriers, which are biologically senseless. A healthy microbiota is essential to well-being, both by preventing chronic degenerative conditions, the infectiousness and pathogenicity of bacterial and viral diseases. SARS-CoV-2 should not be an exception. The human microbiota, forged by the first 1,000 days of life, is fundamental in shaping the health-disease trajectories, and by the everlasting exposome that is dramatically affected by the ecological disaster. Individual health is one world health whereas single and global well-being are interdependent in a space-time perspective. Conclusions Is it not a convenient reductionism not to consider the COVID-19 emergency as a bio-social epiphenomenon of a far more devastating and multi-faceted crisis whose common denominator is the global biotic network loss of which humans are still part?


Introduction
The reemergence of another pandemic, and the ongoing waves of SARS-CoV-2 infections, can be interpreted as a vicious circle of merely consumerist globalization, ecological disruption, and impairment of individual health.
The diffusion of SARS-CoV-2 and its severe clinical complications, or COVID-19, is popularly viewed as an unpredictable "black swan" event caused by a single unwanted human mistake, either at a poorly regulated wild-animal market or in a lab, that explodes in an otherwise balanced world scenario. According to this common vision "human technology and business" takes the stage and another problem is solved: the SARS-Cov-2 vaccines, developed in a few months, are once more the solution.
These lines suggest that the current vision does not consider the multiple complex relationships that exist between the many components of the one world we live in. According to the latter, the COVID-19 pandemic could be better defined as a syndemic: "a situation in which interrelated biological factors work together to make a disease or health crisis worse".
Pollution and ecological collapse due to the carbon print of human activities, i.e.-transition from Holocene to Anthropocene, deforestation, disruption of the biodiversity, and unbalanced share of resources both within the metropolitan area of the world and between the metropolis and the periphery of the world, in spite of their closest connections ever due to globalization, can be put in the defendant's bench.
A significant correlation has been reported between the death rate by SARS-Cov-2 infections and particulate matter (PM) of 2.5 mm concentration in the air both in China (48 mg/m 3 ) [1] and in the USA (7.7mg/m 3 ) [2] with an increase of 11% mortality in association to an average 1 mg/m 3 PM 2.5 increment [3]. In Lombardy, Italy, the first large metropolitan area of the western world where the virus wreaked havoc, suffered in the second half of 2020 winter the worst concentration of PM 2.5 and nitric dioxide (300 mmol/m 2 ) [4]. Prolonged exposure to air pollution, leads both to upper airways ciliated epithelium damage and a chronic inflammatory stimulus of lung endothelium [5] even in young and healthy subjects, but to dramatic damage in older patients, the age span that mostly added numbers to the death tally [6][7][8].
Micro-and macro-nutrient malnutrition in synergy with PM action might be the main low-grade inflammation cofactors, whereas for instance excess sugar can facilitate host cell entry via glycosylation of the spike protein that binds more readily to the glycoprotein ACE-2 [9].
Curiously, the trans-generational microbiota loss within mother-child transmission occurs in parallel with the vertiginous planetary biodiversity impairment associated with the disappearance of an average of 50 living species a day, an extinction rate 1000 times higher than the natural rate [10] leading to biotic homogenization phenomenon.
In order to protect public health, long-term ecological solutions including nature conservation, prevention of deforestation, prohibition of wildlife trade, and live animal markets must be implemented to reduce the facilitators of zoonosis. As the previous Zika virus outbreak taught us, community involvement in environmental, climate, and wildlife conservation as an integral part of public health in addition to a medical or psychological approach has been of fundamental importance.
The second most important factor in COVID-19 mortality and morbidity are preexistent co-morbidities, among which are obesity and its related diseases, diabetes, and hypertension. In the metropolis of the world obesity is an epidemic. According to the CDC, "the US obesity prevalence increased in the nearly last two decades from 30.5% to 42.4% (2000-2018). During the same time, the prevalence of severe obesity increased from 4.7% to 9.2%" [11]. Obesity is a man-made epidemic, caused by junk food, and fast-food chains, that mostly affect the lower classes with limited resources for healthy food and poor access to cultural instruments to understand the damage they suffer due to low-cost unhealthy food. Its impact on COVID-19 is epitomized by this sentence from the CDC. Obesity is a common, serious, and costly chronic disease with an increased risk of severe illness from COVID-19. Everyone has a role to play in turning the tide against obesity and its disproportionate impact on racial and ethnic minority groups.
Last but not least, housing conditions of the most deprived social group with a significant prevalence of ethnic minorities in the metropolitan areas are often the cause of high viral loads among manual workers exposed to contacts, and sharing small rooms [12].
COVID-19 syndemic is a proof of concept that oneworld public health is not only a matter of resources invested into the Health Systems, and access to basic medical care independently from the economic status of individuals and nations, it is a matter of understanding that humans are players within a natural framework much larger than our species, whatever our technology achievements are, and the fraction natural forces we can dominate.
A decisive lesson can be learned from the current pan-syndemic by implementing a transdisciplinary vision of social and ecological solidarity, which can facilitate a paradigm shift from mere economic globalization to a universal cooperative model in which "the World will live as one".

Microbiota and microbiome
The human body has to be intended as an holobiont organism born from an evolutionary intertwining between human cells and a wide variety of microorganisms (microbiota) from whom the whole genetic code is the microbiome.
The microbiota is a vast consortium consisting of up to 100 trillion symbiotic microbial cells (outnumbering our $30 trillion human cells) and harbors a microbiome of 2-20 million microbial genes, vastly exceeding our $20,000 "human" genes in our germline genomes [13,14]. Then, the total microbiome mass is about 1-3% of the whole human body (for a 60 kg person that would be 0.6 À 1.8 kg), corresponding to a 1.3: 1 ratio between the microbiome and host number of cells. As a matter of fact, the vast genetic heritage carried by the microbiota represents more than 90% of all the genes that are expressed in our organism and while humans are only $0.1% genetically different within the human genome, they can be up to $90% different in terms of microbial genomes [15,16] (Figure 1). It is, therefore, possible to state that we are a super-organism where all cells, microbial and human, work together in symbiosis and the term hologenome can be used to indicate this whole complex set of viral, prokaryotic, and eukaryotic genes.
The symbiosis has existed since the earliest forms of life. Specifically, mitochondria are primitive bacteria ancestrally incorporated within a eukaryotic cell in order to gain an advantage in terms of ATP energy production through oxidative phosphorylation.
Then, the human microbiota consortium offers a wide range adjustments to environmental threats.
Microbiota and pregnancy: the origins of the microbiota from mother to child Maternal vaginal microbiota undergoes the same female general population classification.
Based on the prevalent microorganisms it can be collected into five distinct groups called community state types (CSTs). These are dominated by L. Crispatus (CST I), L. Gasseri (CST II), L. Iners (CST III), L. Jensenii (CST V). Meanwhile, CST IV is constituted by anaerobic bacteria (Gardnerella, Prevotella bivia, Mobiluncus, Peptococcus species, etc.) [23] with a poor presence of Lactobacilli. Typically, women, especially the African-American, who belong to the latter (CST IV) are affected by bacterial vaginosis [24,25].
Indeed, ethnicity is also related to susceptibility to adverse pregnancy outcomes [26]. Maternal infection is the main cause of preterm birth in Black women, but not in Whites. The different genetic background, intended as variations in the rate of functional gene polymorphisms among ethnic groups, implies different degrees of predisposition to develop infectious diseases that can lead to preterm delivery under specific circumstances. It is well known that a too-vigorous pro-inflammatory immune response to infection during pregnancy triggers a sequence of events that culminates in premature contractions and preterm delivery. Therefore, Black and White women raised outside their habitat trigger an inadequate immune response to infectious disease, which does not occur if they remain in their ethnically selected habitat [26].
During pregnancy, the microbiota is subjected to an adaptative adjustment, mainly due to hormonal changes, characterized by a progressive microbial biodiversity reduction and a parallel Lactobacilli augmentation [25]. Indeed, the high circulating estrogen level increases glycogen deposition in the vaginal epithelium and stimulates Lactobacilli proliferation and their production of lactic acid, leading to a lower pH (<4,5) and its vaginal acidity uniqueness among all mammals. In this way, the vaginal microbiota reaches that stability essential in providing immune protection during pregnancy.
On the fetal side, the placenta is finally not a sterile organ having its own specific microbiome [27][28][29] highlighting microbial colonization being simultaneous to the dawn of life. Also, a similarity between the placenta microbiome and the oral cavity has been reported [29]. A link between oral infections, in particular Fusobacterium nucleatum, and adverse pregnancy outcomes has been hypothesized. There are two major hypotheses regarding the underlying mechanism: one is that oral dysbiosis causes systemic abnormal immunological changes leading to systemic inflammation and the other suggests that pathogens from the oral environment cause direct infection of the placenta [30]. Moreover, the detection of oral pathogens in atherosclerotic plaques of placental samples of women with preeclampsia [31] suggested that the microbiome might also play a role in the development of such disease.
The most crucial lifespan exposure to microorganisms happens during newborn delivery. Specifically, the new microbiota is influenced by the maternal one (mostly determined by anthropometric and physical exercise asset, diet and drugs -mostly antibioticsassumption, general health, and psycho-emotional status), pregnancy itself (namely, gestational age, type, and place of birth) and later by several environmental factors, such as air pollution. Indeed, neonatal bacteria genus inheritances are highly determined following vaginal delivery (Lactobacillus dominance and Bacteroides prevalence) versus cesarean delivery (mostly, Staphylococcus and Clostridium presence). Elective cesarean delivery (generally performed before labor onset) is associated with a reduction of breast milk microbial diversity and richness [32]. Therefore, the role of labor has been investigated as a bacterial translocation enhancer from the gut to breast glands and, consequently, to maternal colostrum [33]. However, the microbiota evolution is tailored in the first 6 weeks mostly by skin-to-skin contact and breastfeeding, regardless of the delivery type [34] and to its opposite compromised by exposure to antibiotics, indoor urban life, and air pollution [35].
From a wider perspective, epidemiological data highlighted that abdominal birth may be a stigma for Non-Communicable Chronic Diseases onset.
If it is true that the human body colonization by these microorganisms begins during intrauterine life, could there be a relationship in epigenetic setup?
Furthermore, the microbiota is part of those exogenous factors like diet, environment, and medication that contribute to epigenetic and, as demonstrated below, can induce a reversible modulation of genes [36]. That is very important to notice because as Barker's theory states, the first 1,000 days of Homo sapiens life (from conception to two years of age) are essential in shaping the health and disease trajectories. Specific events during pregnancy, childbirth and weaning become a crossroads in defining the microbiota structure of the future adult.
The placenta is actually capable to translate the outside environment to the fetus through epigenetic molecular changes that do not involve a mutation in the DNA sequence, but rather affect transcription (e.g. via acetylation or methylation of histone proteins, or methylation of DNA itself) [37]. The study by Vahamiko et al. is an example of how the microbiome and epigenetic interact with each other. In fact, it shows that DNA methylation was reduced in the promoters of the obesity-associated genes, FTO and MC4R, in women who had probiotic supplementation with Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12, and their children during pregnancy. It is from this result that it raises the question of whether probiotic supplementation in intra-uterine life and the resulting changes in gene expression may influence long-term health consequences in children [38].
Pregnant women get a small risk of SARS-CoV-2 infection with most of the infection occurring in the third trimester with a small increase in hospitalization, admission to the intensive care unit (ICU), mechanical ventilation, preterm birth, and increased cesarean sections [44,45].
The perinatal outcome for the fetus is favorable with low stillbirth and neonatal mortality rates and congenital anomalies absence especially in highincome countries (HIC) [46]. Instead, in low-and middle-income countries (LMIC) an overall increased risk of adverse pregnancy (OR 2.4) concerns abortion (OR 6.2), stillbirths (OR 2.0), and maternal death (OR 7.8). Preterm births and premature rupture of membranes are comparable in both groups.
Nevertheless, even the HIC minorities and disadvantaged groups inherit a worsening risk of susceptibility to SARS-CoV-2 infection due to poor housing, overcrowding, and low-paid essential jobs.
Still, alternative biological and genetic susceptibilities (such as ACE-2 different expression) need investigations [47] as well as the complex interplay between the various biological, social, and cultural factors. For instance, again to deepen the preventive role of cardio-metabolic equilibrium through nutrition and aerobic exercise [48,49].
Whether the discrepancies of the pandemic impact are associated with specific microbial patterns that can explain the correspondence between biological and socio-economic vulnerability remains poorly investigated.
The whole microbiota and its own heterogeneityrather than abundance and the sum of individual species -allows us to understand the biological mechanisms underlying the processes of homeostasis and resilience to pathogens, enabling precise models of infection prediction and clinical exacerbation [50].
Considering COVID-19 as an endothelial damaging disease whose susceptibility is associated with a preexisting inflammatory state, the microbiota role in phlogistic tuning is potentially relevant.
The inflammatory modulation implemented by the microbiota as a host-defender could explain the different spectrum of immune response between over-and under-reaction, particularly in front of the most aggressive form of Coronavirus disease provoking a deleterious cytokine storm [51].
Recent studies show that the function of the indigenous respiratory and intestinal microbiota may be significant in modulating the cross-talk, defensive responses (e.g. surfactin in damaging viral integrity), and metabolic pathways related to carbohydrates (including glycosaminoglycan degradation) and lipids [52].
This can suggest the important role of the upper respiratory tract microbiota as a first defense barrier to viral spreading. Therefore, as well in pregnancy, a specific oral indigenous microbiota can confer the ability to avoid COVID-19 symptoms.

Neonatal outcomes related to SARS-CoV-2 infection
To date, there is little research (mostly case reports) on the impact of SARS-CoV-2 infection on infants, and the extent and mode of vertical mother-to-child transmission remain controversial [53].
Data on vertical transmission are discordant among studies in the literature. Dimitriu et al. reported 2 cases of vertical transmission in 101 maternal-infant dyads studied (2%) [54], likewise Juan et al. notified 3 out of 155 newborns infected. [53].
Placenta of infected fetuses showed unusual pathology findings that can relate to a predisposition of vertical viral transmission [55].
The most frequently reported neonatal outcomes are respiratory distress syndrome, and neonatal respiratory disorder, and hyperbilirubinemia [56], and the level of severity of maternal SARS-CoV-2 disease may be related to them. Preterm delivery in COVID-19-positive mothers occurred in 11.1% of cases, as reported by Donati et al. [57] (Table 1).
Noteworthy, compared to the pre-pandemic period, the frequency of stillbirths and maternal deaths remained unchanged.
The type of delivery is influenced not only by the clinical picture of the woman but also by logisticmanagement variables for which the clinical risk per se of cesarean section cannot be defined.
Moreover, considering the small number of events for many of the outcomes and a large number of statistical comparisons, the data should be interpreted as exploratory.
There's still a lack of studies exploring SARS-CoV2 infection that impact the main delivery outcomes (umbilical cord blood gas analysis, newborn weight, APGAR index).
Environment, COVID-19, and microbiota: are we facing a syndemic? SARS-CoV-2 is the latest of the many pandemics that have plagued the socio-health system as a mere epiphenomenon resulting from the reckless abuse of the planetary resources, which are essential for the conservation of biodiversity. The Anthropocene is the term that best defines the present era in which human activity irreversibly manipulates intricate and delicate geological and biological balances established over eons.
The role of the Wuhanan Seafood Wholesale Market in propagating disease is still debated. Many initial COVID-19 cases were linked to this market suggesting that SARS-CoV-2 transmission from animals to humans happens through the so-called spillover [58].
SARS-CoV-2 could be the last zoonosis that happened in the last 2-3 decades.
From a strict etiologic perspective, it's sadly clear that the zoonosis epidemics are linked to massive ecological niche destruction and highly populated megacities creating the ideal condition for interspecies transfer and spread of virulence germs.
Since these diseases are the result of the proximity between humans and other animals, their higher frequency in the latest years (Ebola, Zika, SARS-CoV-1, SARS-CoV-2, MERS-CoV, HIV, H1N1, H5N1, Dengue and Chikungunya, etc.) should make us consider the ecologic question: humans are progressively and massively exploiting natural habitats of different animal species and compromising the diversity of the biotic component. The latter diversity is more likely to promote germ-host aberration until hypothesized human extinction.
Leaving aside a strictly anthropocentric view, it is not surprising to note that pandemics also upset the plant kingdom, which is a real crossroads for biodiversity and thus for the survival of all animal species.
Furthermore, global yield losses due to plant endemic and acquired diseases (wheat, maize, rice, etc.) are diffused and magnified by climate change, pathogen spillover, transmission with global food exchange networks, and evolution of new pathogen lineages [59].
Emerging plant disease pandemics cause significant losses in food crop production that not only lead to lower yields but also compromise biodiversity and negatively impact downstream on human health.
In our consumerist Era, we are subverting the essential with the ephemeral superfluous leading to a degradation of the planet's resources with consequences of varying degrees that go as far as human extinction.
According to Bostrom, humans face four different categories of existential danger: extinction: we off ourselves before we reach technological maturity stagnation: we stay mired in our current technological and intellectual backwater flawed realization: we advance technologically … in a way that isn't sustainable subsequent ruination: we reach sustainable technological maturity and then destroy it all up anyway.
A severe implication of such exploitation is pollution.
As an analysis of the literature suggests, there is a demonstrated association between ambient PM exposure and the alteration in the microbiota. For instance, PM can indirectly reach the gastrointestinal tract through mucociliary clearance and upon swallowing of saliva and mucus and, once there, distinct bacteria can have the capacity to bloom with PM exposure. This mechanism could actually explain the PM-induced inflammation in the GI tract [75].
Moreover, ultrafine particles (PM 2.5 microns) exposure also seems to alter the airway microbiome inducing a respiratory function decline. The discovery that FEV1/FVC is positively associated with sputum bacteria load, made it possible to state that the PM 2.5 induced changes on the microbiome, increasing the susceptibility to COPD [76].
In light of what has been said, what if there is a link between the COVID-19 pandemic and the alteration in the microbiome induced by pollution? The thinnest PM entering the circulation via the alveolar route contributes to triggering the inflammatory cytokine storm associated with disease severity.
Last but not least, the preventive role of nutrition is unvalued whereas a plant-based diet can decrease up to 73% of adverse covid outcomes by implementing phytochemicals (polyphenols, carotenoids) fiber, vitamins A, C, and E, folate, and mineral (iron, potassium, magnesium) nutrients intake [77].
Considering the devastating ecological and socioeconomic implications of COVID-19, it is time to update the present pandemic framework to a syndemic in the midst of the Anthropocene or Homogenocene [78][79][80].
In a nutshell, a paradigm shift away from a predominantly symptomatic and anthropocentric approach (based mostly on reducing the impact of symptoms) toward an etiological one is therefore mandated. The latter consists of an awareness of the interconnection between the recovery of global (spatial) sustainability and trans-generational (temporal) human and planetary well-being.
Some smart armamentaria already available in the field, such as "the healthy lifestyle habits promotion (HLHP)" strategy, need to be landed on as a reference win-win models of inclusiveness whereas the benefit is both universal and exponential in the social and financial realm, eventually generating an auspicious benevolent tsunami [81].

Conclusions
Bacteria colonizing human body districts are known to have a symbiotic relationship with the host: both bacterial cells and human ones gain an advantage from this consortium. The benefits earned from the host consist in the regulation of various physiological functions, including immunity providing a barrier against pathogenic bacteria and viruses, like SARS-CoV-2.
This protection is acquired during the months of gestation and particularly during vaginal delivery and breastfeeding and depends on the habitat in which an individual grows up.
Therefore, protecting the environment in which we live also ensures human health.
It comes naturally, to wonder whether we are living in a brand-new Copernican Era. The most democratic and sustainable paradigm is the recognition and acceptance of human health as an ineffable by-product arising from its container, namely the environment. In that perspective, human wellbeing is a consequence of the environmental one, contrary to the widespread anthropocentric idea that considers Homo sapiens health above everything. This shortsighted view should be uprooted to make way for a more far-sighted one that includes the health of Nature. Nowadays, health and healthcare are elitist rather than egalitarian, therefore focusing on environmental health forces us to make a concerted and systemic effort that breaks down political and economic barriers, which are biologically senseless.
In conclusion, isn't it a paradox not to place the COVID-19 emergency in a global ecological trajectory?
Isn't it still a paradox not to consider the ecological disaster from a trans-generational perspective?

Disclosure statement
The authors report no conflict of interest.

Funding
The author(s) reported there is no funding associated with the work featured in this article.