1Laboratory of Probiogenomics, Department of Chemistry, Life Sciences, and Environmental Sustainability, University of Parma, Parma 43124, Italy;
2Microbiome Research Hub, University of Parma, Parma 43124, Italy.
Correspondence to: Prof. Francesca Turroni, Laboratory of Probiogenomics, Department of Chemistry, Life Sciences, and Environmental Sustainability, University of Parma, Parco Area delle Scienze 11/A, 43124 Parma, Italy. E-mail: email@example.com
© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
The infant gut microbiota is the set of microorganisms colonizing the baby’s intestine. This complex ecosystem appears to be related to various physiological conditions of the host and it has also been shown to act as one of the most crucial determinants of infant’s health. Furthermore, the mother’s endocrine system, through its hormones, can have an effect on the composition of the newborn’s gut microbiota. In this perspective, we summarize the recent state of the art on the intricate relationships involving the intestinal microbiota and the endocrine system of mother/baby to underline the need to study the molecular mechanisms that appear to be involved.
Infants, gut microbiota, endocrine system, thyroid, hormones
The gut microbiota includes autochthonous and / or allochthonous microorganisms colonizing the intestinal tract. The impact of a correct balance of the gut microbiota on the health and entire physiology of the host from infancy is widely accepted by the scientific community. The establishment of this complex microbiota occurs immediately after birth and is influenced by different factors, such as gestational age, mode of delivery, type of feeding[1,2], antibiotic exposure[3-5], host genetics, and the environment. Other factors related to the mother’s health conditions may also influence the microbiota of the fetus. For example, maternal nutrition during pregnancy, which directly modulates her microbiota, may also impact the initial microbial establishment of the newborn. Maternal diet seems to similarly shape the composition and diversity of breast milk microbiota, especially for macronutrients and soluble/insoluble fibers, plant/animal proteins, and polyphenol composition. Furthermore, maternal dietary interventions, i.e., with vitamin D and polyunsaturated fatty acids, play an essential role in early bacterial colonization in various body districts differently from the gut, such as the lung, by modulating the pulmonary microbiota and thus reducing the incidence of asthma and wheezing in offspring. This supports the fact that the gut microbiota of the mother can be a vehicle for the baby’s health. Therefore, the first months of life are essential in favoring the bacterial colonization of the infant’s gut to the detriment of pathogens. This intestinal microbial population develops rapidly after birth up to three years of age when the microbiota reaches certain stability and complexity. The establishment of a balanced gut microbiota during infancy represents the foundation of health with long-lasting effects in adulthood. For example, in addition to the maternal overweight/obesity condition that can affect some of the infant gut microbiota taxa, associated with subsequent body mass index, the gut microbiota of early childhood could influence the development of obesity in the postnatal life. Moreover, the maternal gut environment during pregnancy contributes in a fundamental way to the metabolic programming of the neonate to prevent metabolic syndrome via neural systems. The maternal gut microbiota confers resistance to obesity in offspring via the free fatty acids receptor stimulation, representing signaling molecules between the gut microbiota and extraintestinal organs.
Another factor highly correlated with the correct establishment of the infant intestinal microbiota is the mother’s immune system and the newborn itself. The transplacental route is the normal avenue through which mothers give natural passive immunization to their babies[13,14]. It seems that the immune status during pregnancy, in terms of immunoglobulins and cytokines levels, can also influence the immune status of the newborn. After birth, the immune system develops in early childhood, mainly through interactions with the gut microbiota. Other important contributors in the development of the immune system at the early stages of life are represented by specific ingredients of the human milk as the human milk oligosaccharides (HMO). These metabolic products can influence the immune system development, specifically reducing mucosal and systemic inflammation. In this context, some species belonging to the genus Bifidobacterium resulted in being specifically enhanced by HMOs, which ultimately are considered to be directly involved in immunoregulation during the first months of life. These early-life immune–microbial interactions appear to affect the risk of allergies, asthma, and other inflammatory diseases, showing that the imprinting of early immunity can influence later health through various mechanisms that are still not fully understood today. The microbiota changes, especially after the introduction of solid foods, evolves during adulthood, and then undergoes a decrease in microbial richness observed in aging populations, linked to various factors (e.g., changed lifestyle habits, reduced food diversity, and introduction of drugs). The gut microbiota has various effects on the gut environment that also impact distant organs and pathways, such as the nervous[19,20] and endocrine systems. These effects are very important given the enormous implications on the individual’s health, but they are still largely unknown. This discourse enters a broader and more fascinating context concerning the different cross-kingdom cell-to-cell signaling involving small molecules[22,23]. Nevertheless, there are several questions to be answered, such as how do hormone-like chemicals produced by intestinal bacteria affect host signaling? How do the mother’s hormones affect the infant’s microbiota composition? What are the molecular tools that should be used to disclose this topic?
This perspective summarizes the scientific evidence currently existing on the molecular mechanisms involved in the interactions between the intestinal microbiota and the endocrine system, which unfortunately are still very limited, thus making this topic a very promising area of research for the next years.
The first indication concerning the existence of a cross-talk between the microbiota and the endocrine system dates back to 1992. Since then, many reports have been published on this topic[21,25,26]. Nowadays, it is known that, in some cases, specific changes in hormone levels are somehow related to the presence and composition of the gut microbiota [Table 1]. Despite this, a large part of the research effort has been placed on attempting to elucidate the specific molecular mechanisms of this interaction, which are far from being fully understood. In this context, it has been shown that the microbiota is involved in both production and secretion and itself is modulated in response to hormones. However, the precise molecular mechanisms of each microbiota-hormone signaling have not yet been clarified. Furthermore, the human microbiota and endocrine cross-talks affect a variety of host responses such as behavior, metabolism, appetite, immune system, and reproduction, emphasizing the complexity of this fascinating topic [Figure 1].
Figure 1. Schematic representation of the relationships between the infant gut microbiota and the endocrine system of newborn/mother. There is a reciprocal interaction between the infant gut microbiota and hormones’ secretion, production, and expression. Additionally, a change in the number of hormones in the pregnant mother impacts her gut microbiota, affecting the baby’s microbiota.
Currently published studies focusing on the hormone-microbiota relationships
|Breast milk-related hormones||Leptin, adiponectin, insulin, ghrelin, obestatin, apelin, resistin, irisin, copeptin, nesfatin, GLP-1, IGF-1, melatonin||[27-29]|
|Reproductive related hormones||Progesterone||[30-33,41,42]|
A significant example of this interaction is represented by the influence of changes in the gut microbiota compositions in response to various appetite-related hormones (e.g., leptin, insulin, and ghrelin), which play key roles in modulating brain behavior and function through the humoral or neural pathway. In postnatal life and throughout adulthood, leptin deficiency causes elevated endoplasmic reticulum stress in various metabolically relevant tissues, particularly in the hypothalamic circuits. Moreover, gut dysbiosis, i.e., a disruption of the natural gut microbiota homeostasis, improves leptin sensitivity and can contribute to the high level of leptin by epigenetically modulating its expression in obese condition.
Only recently, it emerged that the microbiota plays an important role in the endocrine system, especially in the reproductive system of woman, interacting with estrogen[30,31], androgen[32,33], insulin[34,35], and other hormones[21,25]. Moreover, an imbalanced gut microbiota composition has led to various diseases and disorders, such as adverse pregnancy outcomes, pregnancy complications, polycystic ovary syndrome (PCOS), endometriosis, and cancer. However, the actual molecular mechanisms underlying this phenomenon have not yet been clarified.
Nutritional and hormonal disruptions that occur early in human life can promote an alteration of the individual’s metabolic programming later in life and modify the gut microbiota composition. Indeed, changes in the gut microbiota composition, in response to alterations of sex hormones, may trigger the gene expression response, via miRNAs, in the host.
Early evidence shows that some hormones appear to have a direct effect on specific bacterial taxa, as steroid hormones have been shown to increase the growth of Prevotella intermedia and Prevotella melaninogenica in the oral cavity.
Furthermore, gut bacteria produce different metabolites that could act as signaling molecules to several cell types within the mucosa. On the other hand, enteroendocrine cells produce and secrete several hormones, which have regulatory roles in key metabolic processes such as insulin sensitivity, glucose tolerance, fat accumulation, and appetite.
Another important sign underlying the existence of a direct cross-talk between hormones and microbiota is represented by the fact that the gut microbiota, as well as the vaginal, oral, and skin microbiota, undergoes changes during different pregnant trimesters, thus suggesting that sex hormones could be responsible for these modifications[39,40]. It has been shown that reproductive hormones, specifically progesterone, which is the main hormone produced during pregnancy, impact the gut microbiota shifts during pregnancy and lactation in Phayre’s leaf monkeys.
Interestingly, in vitro and in vivo experiments showed that progesterone promotes the growth of key gut microbiota members such as bifidobacteria during late pregnancy [Figure 1]. Although the precise mechanism has not yet been clarified, it has been proposed that it may depend on the presence of the hydroxysteroid dehydrogenase (HDS) enzyme in bifidobacteria or on a specific unknown regulator stimulated by progesterone. The increase of bifidobacteria load during late pregnancy might not only be helpful for pregnancy (i.e., reduction in the incidence of pre-term births) but also reflect an evolutionary process of preparation for birth and feeding time. In fact, bifidobacteria represent the dominant gut microbiota members in the early stages of life that are vertically transmitted from the mother to the newborn[45,46].
Recently, in both human and animal studies, an intriguing relationship between the composition of the gut microbiota and the sex of the individual has been shown. Changes in gut microbiota communities due to sex are linked to the interaction of sex hormones with the immune system[47,48]. In addition, it has been proposed that, since bile acids are different in composition between men and women, and since these chemical compounds exploit a key role in the gut microbiota composition, this could represent a possible mechanism explaining that sexual differences influence the gut microbiota composition.
The so-called microbiota gut-brain axis communication occurs primarily with the interaction of the intestinal microbiota and the hypothalamic-pituitary-adrenal (HPA) pathway[52,53] [Figure 2]. The HPA axis is a neuroendocrine pathway constituted by the hypothalamus, the hypophysis, and the adrenal glands. The activation of this axis, given by stress exposure, leads to an adaptation to environmental requests through the activation of corticotrophin-releasing hormone by the hypothalamus, which induces the production of the adrenocorticotrophic hormone (ACTH) secreted by the hypophysis. ACTH in turn leads to the release of glucocorticoids, including cortisol, from the adrenal cortex. This steroid hormone regulates a wide range of processes throughout the body; for example, hyper-secreted cortisol induces an increase in visceral adiposity, decreases lean mass (muscle and bone), and suppresses osteoblastic activity.
Figure 2. Schematic representation of the relationship between the HPA (hypothalamus-hypophysis-adrenal cortex) axis and the gut microbiota of both mother and child. Traumatic and stressful events during pregnancy lead to a hyper-activation of the hypothalamus with the release of corticotrophin-releasing hormone(CRH) that induces the production of the adrenocorticotrophic hormone (ACTH) secreted by the hypophysis. In addition, ACTH causes the release of cortisol from the adrenal cortex. Cortisol is a glucocorticoid that directly and indirectly changes the composition of the child’s gut microbiota. This hormone is transmitted to the baby via breastfeeding and likewise from the mother’s bloodstream through the placenta barrier. Moreover, cortisol affects the composition of the mother’s gut microbiota, which is then passed on to the child through vertical transmission.
The intestinal microbiota activates this neuroendocrine pathway, affecting the secretion of cortisol and the physiological response to stressors because of the release of mediators such as pro-inflammatory cytokines, microbial antigens, and prostaglandins, which are able to cross the blood–brain barrier. In the case of intestinal dysbiosis, the microbiota may induce a constant hyperactivity of the HPA axis, leading to deleterious effects on the organism. At the same time, a condition of acute or chronic stress, together with an increment of cortisol levels, can increase the gut permeability, inducing autoimmunity and reducing the diversity of the gut microbiota[52-54]. Many studies have suggested that there is a strong link between changes in the gut microbiota composition and the outbreak of psychological outcomes such as anxiety-like symptoms and depression already at a young age. Experimental results in mice suggest that a dysbiosis of the gut microbiota could turn into psychological disrupted behavior, promoting the establishment of depression[56,57]. The molecular pathway underlying this relationship is not yet understood, but a strong indication supporting this hypothesis is that the early changes in the composition of the gut microbiota can affect different aspects of brain function and behavior later in adulthood through the HPA axis and stress response. As mentioned above, a mother’s intestinal health during pregnancy contributes in a fundamental way to the metabolic programming of the newborn through the nervous system. The mother’s well-being positively affects the infant’s health in the same way conditions of physical or mental illness can adversely influence the developing fetus[59-61]. Much evidence indicates that women who suffered from stressful events such as depression or exposure to trauma during pregnancy (e.g., food insecurity, low social support, and socioeconomic hardship] display dysregulation of the HPA pathway). As a main consequence, an increase of circulating cortisol, a steroid hormone that regulates a wide range of processes throughout the body, has been detected in salivary samples of pregnant women. Moreover, infants of mothers who experienced traumatic events or who presented elevated levels of cortisol during pregnancy had a lower relative abundance of Lactobacillus and Bifidobacterium. In addition, they displayed significantly higher relative abundances in other microbial groups including potentially pathogenic bacteria such as Enterobacteriaceae, Streptococcaceae, and Veillonella in their gut microbiota[59,61]. Three main mechanisms have been proposed to explain how maternal cortisol affects the infant gut microbiota. First, a high cortisol level interferes with the mother’s gut microbiota composition, influencing the transmission of intestinal bacteria from mother to infant. Second, cortisol can also cross the placenta barrier, directly increasing the circulating level of this hormone in the fetus with a dysregulation of the HPA axis. Third, cortisol is transmitted through breast milk, ultimately shaping the infant gut microbiota since it is widely accepted that components of breast milk, such as HMOs, largely influence infants’ gut microbiota[Figure 2].
Alteration of glucocorticoid levels during the prenatal period as well as during infancy and early childhood development could have long-term effects. The activity of the HPA axis has been estimated by measuring cortisol levels in salivary samples taken before and after a mild physical stress (heel stick) from infants around one month of age. Together with the information of the microbiota composition of fecal samples taken from the infants, these data suggest that certain bacteria, such as Staphylococcus, Prevotella, and other microbial genera belonging to the order Clostridiales, may be associated with increased cortisol reactivity following physical stress. The increase in cortisol level can produce several consequences, such as immune stimulation production of bile acid in the liver[59,63], affecting the intestinal motility, and alterations in the integrity of the epithelial barrier, which could, in turn, affect the gut microbiota. These dysregulations would induce a pro-inflammatory state with neurological relapses. Consequently, altered basal and reactive cortisol patterns can impact the development of the child’s emotional and behavioral regulation systems, later causing social problems and psychopathology. Other studies suggest that the restoration of healthy gut microbiota with the administration of probiotics belonging to the Lactobacillus and Bifidobacterium genera can improve anxiety-like symptoms resulting from HPA axis hyperactivity[58,65]. Fecal microbiota transplantation administered to neonates born by caesarean section represents a promising frontier of study in imprinting the correct development of the intestinal microbiota. Another possible intervention strategy is represented by probiotics that specifically target the mediated functions and behaviors of the central nervous system, called psychobiotics. These products act through immune, humoral, neural, and metabolic pathways to not only improve intestinal function but also produce an antidepressant and anxiolytic capacity. Nevertheless, further in-depth studies are required to explore the relationship existing between the infant gut microbiota and the HPA axis, which might be crucial to develop novel therapies/strategies to reduce unhealthy stress responses by interfering with the infant microbiota.
Maternal milk contains different nutrients that are changing in their nature and amounts over the time of breastfeeding due to the mother’s hormonal, physiological, and neuroendocrine mechanisms[69,70], as well as being influenced by genetic and environmental factors and eating habits [Figure 3]. Besides the fundamental constituents, namely proteins, lipids, carbohydrates, and vitamins[71,72], maternal milk contains bioactive molecules that shape and develop the newborn’s gut microbiota and immunological system, such as immunoglobulins, cytokines, and chemokines[70,72]. It is also a source of bacteria, mainly belonging to the genus Bifidobacterium, which are important for establishing the infant gut microbiota. Together, all these chemical compounds predispose the newborn’s optimal physiological and neurological development. In addition, the importance of other molecules, such as hormones including leptin, adiponectin, insulin, ghrelin, obestatin, apelin, resistin, irisin, copeptin, nesfatin, glucagon-like peptide-1 (GLP-1), and insulin-like growth factor-1 (IGF-1), has emerged, and their involvement with the baby’s growth and development has intrigued the scientific community [Table 2]. These hormones immediately control the newborn’s sense of satiety, and, in the later stages of life, they influence the energy balance. Breastfed infants display lower circulating insulin and IGF-I levels than babies who are not fed with human milk. In fact, these compounds are not found in artificial formula, suggesting that breastfed infants are less likely to gain weight than those bottle-fed. The strong correlation between the health of the mother and that of the child is also highlighted by the fact that obese mothers have a higher concentration of insulin, leptin, and pro-inflammatory fatty acids in breast milk than normal-weight mothers. Furthermore, in this same category of mothers, breast milk is characterized by less microbial diversity and a reduction in Bifidobacterium spp. levels and cytokine content[75-77]. Another milk-related hormone influencing baby behavior is melatonin, produced primarily in the pineal gland. Following a circadian cycle, this hormone reaches breast milk, where it plays a role in regulating sleep and seems to have a possible involvement in gut-brain communications. Melatonin displays a wide range of biological functions such as antioxidants, anti-inflammatory, antinociceptive, immune regulators, and maintaining gut-barrier integrity.
Figure 3. Schematic representation of the human milk breast components. Breast milk is the vehicle for essential compounds, not only nutritional, listed in the figure. The components that directly influence the gut microbiota composition are highlighted in bold.
Functions and effects of the hormones contained in human breast milk
|Hormone||Function||Effects on newborns||Ref.|
|Leptin||Suppress the appetite||Early sense of satiety|||
|Adiponectin||Improves glucose metabolism by increasing the insulin sensitivity||Higher adiponectin concentration is associated with more significant neonatal weight gain|||
|Insulin||Energetic homeostasis||Decreased lean mass|||
|Ghrelin||Intestinal motility, energy homeostasis||Its concentration is positively correlated with the weight and size of the neonate|||
|Obestatin||Associated with the bodyweight decrease||No effects reported yet|||
|Resistin||Inhibits adipocyte differentiation||No effects reported|||
|Irisin||Transforming the white adipose tissue in brown adipose tissue||Stimulate thermogenesis in white adipose tissue|||
|Copeptin||Regulation of water excretion||No effects reported yet|||
|Apelin||Fasting plasma levels positively correlate with BMI||No effects reported yet|||
|Regulation of appetite|
May stimulate weight gain
|No effects reported yet|
No effect reported yet
Major rate of growth of the infant during the first month of life
|Cortisol||Increase the blood glucose level through gluconeogenesis, suppress the immune system||May support to program metabolic functioning and childhood obesity risk.|
Have been associated with infant temperament
|Melatonin||The antioxidant, anti-inflammatory, antinociceptive, immune regulator, and maintaining gut-barrier integrity||Help to sleep |
May modulate gut microbiota
Melatonin appeared to increase the relative abundance of gut Actinobacteria in a suckling pigs. In addition, it influences the swarming activity of the intestinal bacteria Enterobacter aerogenes , suggesting a possible inter-kingdom communication mechanism. This first result underlines that the field of intestinal hormone–microbiota relationships is very complex, vast, and still largely unknown, especially for the molecular mechanisms involved in the interaction between microbes and maternal hormones. Therefore, a very fascinating and promising area of research will be to dissect the impact of all the human breast milk hormones [Table 2] on the various members of the infant gut microbiota and how each hormone could affect the transcriptomes of the different infant gut microbes.
During growth, thyroid hormones play a crucial role in some physiological processes; in fact, these are regulators of growth as well as in the myelination process of the nervous system, metabolism, and other organ functions. Consequently, the normal proper functioning of the thyroid gland contributes to maintaining the internal balance of the whole organism. In this context, adequate diagnosis and management of thyroid disease during pregnancy are important for maternal and fetal health.
In recent years, particular attention has been placed on the possible relationship between microbiota and thyroid function (thyroid-gut axis) . Moreover, experimental data highlight that intestinal microbiota transplantation from hypothyroid mice to healthy mice leads to decreased thyroid function in the latter, suggesting a clear association between thyroid function and intestinal bacteria. However, we are still far from understanding the real mechanisms of the connection between microbiota and thyroid function in humans, especially in pregnant women, and the possible consequences in clinical practice. Nevertheless, some data from animal model-based studies allow us to suggest various potential roles, among them the action of the microbiota on the metabolism of iodothyronines and the absorption of micronutrients, which are essential for normal thyroid function (iodine, iron, copper, zinc, and, above all, selenium). Furthermore, several studies in humans have shown, albeit unevenly, the presence of dysbiosis in Helicobacter pylori (HP)and Hashimoto’s thyroiditis (HT) patients. In the latter case, a correlation between the abundance of selected types of bacteria and diagnostics parameters has been observed, connected with autoimmune thyroiditis, such as antibodies to the thyroid gland peroxidase (anti-TPO) and thyroglobulin (anti-TG). Moreover, in subjects affected by hyperthyroidism, there are differences in the microbial composition of the gut microbiota; specifically, there is a high Firmicutes/Bacteroidetes ratio, which, interestingly, was proposed but not accepted as a biomarker of obesity.
Studies on the relationship between microbiota and the bioactivity of the drugs currently used to achieve a normal functional level in thyroid diseases are of particular interest. Bioactivity deserves particular interest because it can explain the high inter-individual variability of the therapeutical response, such as l-thyroxine (LT-4), which is known to be the drug of choice in the treatment of hypothyroidism. In addition, this is a fascinating new area of research called pharmacomicrobiomics, whose purpose is to demonstrate how the microbiota can, directly or indirectly, modify the efficacy of many drugs, in addition to antibiotics whose effects on the gut microbiota are known. On the one hand, it is well known that synthetic drugs used to treat HP or Graves’ disease (GD) patients may modify the gut microbiota in vivo during disease treatment. For example, Yao et al. showed that the gut microbiota of hypothyroid patients, treated with L-thyroxine, varied among individuals dependently by L-thyroxine dosages. Similarly, Sun et al. verified that methimazole and propylthiouracil, which represent the first line of hyperthyroidism treatment, altered the gut microbiota composition. Moreover, the gut microbiota can also metabolize some synthetic drugs, modulate the expression of some host cytochrome enzymes that can metabolize drugs, and directly produce some enzymes that participate in drug absorption, activation, and inactivation.
L-thyroxin is absorbed in the small intestine and metabolized by peripheral deiodination, but it also undergoes a conjugation in the liver. Glucuronidation of thyroxine is a major metabolic pathway facilitating its excretion through biliary flow. In humans and rats, it has been demonstrated that many conjugated iodothyronines can be hydrolyzed by the gut microbiota, thus showing that intestinal microbiota can mediate this very complex metabolism. In fact, it has been shown that some microorganisms display a glucuronidase activity, and therefore they might metabolize thyroid hormones[94-96]. The deconjugation by gut bacteria prevents the fecal loss of thyroxine, thus enabling the enterohepatic recycling of the hormone. As underlined by Virili et al., there are insufficient data to discern its net contribution to the whole thyroid homeostasis.
Moreover, gut microbiota may significantly modify the intestinal absorption surface by regulating the expression of tight junctions, affecting intestinal permeability, the shape of enterocytes, and the composition of the mucus layer. Moreover, it can be assumed that the gut microbiota composition may influence the efficacy of oral LT-4 by direct binding to bacteria, as has been displayed for E. coli. The relationship between LT-4 therapy and microbiota needs to be further investigated. In this context, a randomized study has shown a better response in normalization of stimulating hormones (TSH)and the ratio FT3/TSH and a lower dosage of LT-4 in hypothyroid patients treated with LT-4 and symbiotic as compared to patients treated with LT-4 e alone.
In addition to the possible modulation of the pharmacological action, many studies have focused on the possible role of the microbiota in the pathogenesis of HT and Graves’ disease, which are two of the most frequent thyroid diseases of which the autoimmune origin is recognized. Furthermore, it is known that there is an interaction between microbiota and immunity, both innate and adaptive, and that in various autoimmune diseases (type 1 diabetes, rheumatoid arthritis, celiac disease, Sjogren’s syndrome, and multiple sclerosis) intestinal dysbiosis has been found. Further studies are needed to understand whether the intestinal microbiota may be one of the triggers that initiate the autoimmune process in predisposed individuals and contribute to the onset of the disease. Moreover, it is necessary to understand if modulation with pro-and prebiotics can be helpful to prevent or slow down this process.
Finally, studies have explored whether variation in the composition of the gut microbiota may have an impact on thyroid cancer and benign nodules[99-101]. In this context, it was observed that people with high-grade thyroid nodules have significant alterations in the overall microbial composition, showing fewer intestinal microbial species and functionally fewer gene families responsible for amino acid degradation and butyrate production, compared to those with lower grade nodules. Furthermore, various microRNAs appear to regulate the signaling of thyroid hormones in tissues. In turn, thyroid hormones modulate the expression of specific miRNAs and their mRNA targets in different types of cells and organs and seem to also be involved in cell proliferation and cancer.
In conclusion, the relationship between thyroid function, thyroid diseases, specific pharmacological therapies on the one hand and variations in the microbiota on the other hand appears complex and is still not well defined. However, various pre-clinical and clinical evidence confirms that this relationship exists and must lead us to address this topic in a systematic way and with more consolidated and updated methodologies.
Inter-kingdom cell-to-cell signaling, involving small molecules, i.e., hormones produced by eukaryotes and hormone-like chemicals produced from bacteria, is found among mammals and in plant-bacteria relationships and turns out to be a fascinating field of research for its implication on the physiology of the host. In this context, it is widely accepted by the scientific community that the human microbiota, and in particular the gut microbiota, has a profound impact on human health. Thus, all the possible effector molecules, including small molecules produced by the human body that might modify the gut microbiota composition, could influence the host’s health status. Notably, data are accumulating that show specific alterations in hormone levels might be responsible for modifying the the composition and functionality of the infant gut microbiota. Such a phenomenon is even more important in the pediatric age, where the gut microbiota is more susceptible to modifications influenced by breast milk and the mother’s health. Furthermore, it appears that several mom-related factors also play a significant role in the infant microbiota establishment, i.e., gestational age, mode of delivery, type of feeding, antibiotic exposure, host genetics, environment, and diet, as well as an intricate relationship which involves the immune, nervous, and endocrine systems. In this context, a new avenue of research is opening up on the understanding of the roles exploited by maternal hormones carried during pregnancy or later by human milk on the infant gut microbiome and, ultimately, on the baby’s health status.
Made substantial contribution to conception and design and wrote it: Turroni F
Involved in drafting and writing the manuscript: Rizzo S M
Supervised and critically revised it: Ventura M
Wrote, supervised and critically revised the manuscript: Bernasconi SAvailability of data and material
Not applicable.Financial support and sponsorship
We thank GenProbio srl for the financial support of the Laboratory of Probiogenomics.Conflicts of interest
All authors declared that there are no conflicts of interest.Ethics approval and consent to participate
Not applicable.Consent for publication
© The Author(s) 2022.
1. Hill CJ, Lynch DB, Murphy K, et al. Evolution of gut microbiota composition from birth to 24 weeks in the INFANTMET cohort. Microbiome 2017;5:4.DOIPubMed PMC
2. Korpela K, Blakstad EW, Moltu SJ, et al. Intestinal microbiota development and gestational age in preterm neonates. Sci Rep 2018;8:2453.DOIPubMed PMC
3. Korpela K, Salonen A, Vepsäläinen O, et al. Probiotic supplementation restores normal microbiota composition and function in antibiotic-treated and in caesarean-born infants. Microbiome 2018;6:182.DOIPubMed PMC
4. de Gunzburg J, Ghozlane A, Ducher A, et al. Protection of the human gut microbiome from antibiotics. J Infect Dis 2018;217:628-36.DOIPubMed PMC
5. Mancabelli L, Mancino W, Lugli GA, et al. Amoxicillin-clavulanic acid resistance in the genus. Bifidobacterium ;87:e03137-20.DOIPubMed PMC
6. Browne HP, Neville BA, Forster SC, Lawley TD. Transmission of the gut microbiota: spreading of health. Nat Rev Microbiol 2017;15:531-43.DOIPubMed PMC
7. Chu DM, Meyer KM, Prince AL, Aagaard KM. Impact of maternal nutrition in pregnancy and lactation on offspring gut microbial composition and function. Gut Microbes 2016;7:459-70.DOIPubMed PMC
8. Cortes-Macías E, Selma-Royo M, García-Mantrana I, et al. Maternal diet shapes the breast milk microbiota composition and diversity: impact of mode of delivery and antibiotic exposure. J Nutr 2021;151:330-40.DOIPubMed PMC
9. Hjelmsø MH, Shah SA, Thorsen J, et al. Prenatal dietary supplements influence the infant airway microbiota in a randomized factorial clinical trial. Nat Commun 2020;11:426.DOIPubMed PMC
10. Milani C, Duranti S, Bottacini F, et al. The first microbial colonizers of the human gut: composition, activities, and health implications of the infant gut microbiota. Microbiol Mol Biol Rev 2017;81:e00036-17.DOIPubMed PMC
11. Stanislawski MA, Dabelea D, Wagner BD, et al. Gut microbiota in the first 2 years of life and the association with body mass index at age 12 in a norwegian birth cohort. mBio 2018;9:e01751-18.DOIPubMed PMC
12. Kimura I, Miyamoto J, Ohue-Kitano R, et al. Maternal gut microbiota in pregnancy influences offspring metabolic phenotype in mice. Science 2020;367:eaaw8429.DOIPubMed
13. Saso A, Kampmann B. Maternal immunization: nature meets nurture. Front Microbiol 2020;11:1499.DOIPubMed PMC
14. Hanson LA, Korotkova M, Lundin S, et al. The transfer of immunity from mother to child. Ann N Y Acad Sci 2003;987:199-206.DOIPubMed
15. Rio-Aige K, Azagra-Boronat I, Massot-Cladera M, et al. Association of maternal microbiota and diet in cord blood cytokine and immunoglobulin profiles. Int J Mol Sci 2021;22:1778.DOIPubMed PMC
16. Sanidad KZ, Zeng MY. Neonatal gut microbiome and immunity. Curr Opin Microbiol 2020;56:30-7.DOIPubMed PMC
17. Henrick BM, Rodriguez L, Lakshmikanth T, et al. Bifidobacteria-mediated immune system imprinting early in life. Cell 2021;184:3884-3898.e11.DOIPubMed
18. Adak A, Khan MR. An insight into gut microbiota and its functionalities. Cell Mol Life Sci 2019;76:473-93.DOIPubMed
19. Clarke G, Grenham S, Scully P, et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 2013;18:666-73.DOIPubMed
20. Karakula-Juchnowicz H, Rog J, Juchnowicz D, et al. The study evaluating the effect of probiotic supplementation on the mental status, inflammation, and intestinal barrier in major depressive disorder patients using gluten-free or gluten-containing diet (SANGUT study): a 12-week, randomized, double-blind, and placebo-controlled clinical study protocol. Nutr J 2019;18:50.DOIPubMed PMC
21. Qi X, Yun C, Pang Y, Qiao J. The impact of the gut microbiota on the reproductive and metabolic endocrine system. Gut Microbes 2021;13:1-21.DOIPubMed PMC
22. Hughes DT, Sperandio V. Inter-kingdom signalling: communication between bacteria and their hosts. Nat Rev Microbiol 2008;6:111-20.DOIPubMed PMC
23. Boukerb AM, Cambronel M, Rodrigues S, et al. Inter-kingdom signaling of stress hormones: sensing, transport and modulation of bacterial physiology. Front Microbiol 2021;12:690942.DOIPubMed PMC
24. Lyte M, Ernst S. Catecholamine induced growth of gram negative bacteria. Life sci 1992;50:203-12.DOIPubMed
25. Neuman H, Debelius JW, Knight R, Koren O. Microbial endocrinology: the interplay between the microbiota and the endocrine system. FEMS Microbiol Rev 2015;39:509-21.DOIPubMed
26. Busnelli M, Manzini S, Chiesa G. The gut microbiota affects host pathophysiology as an endocrine organ: a focus on cardiovascular disease. Nutrients 2019;12:79.DOIPubMed PMC
27. Han H, Yi B, Zhong R, et al. From gut microbiota to host appetite: gut microbiota-derived metabolites as key regulators. Microbiome 2021;9:162.DOIPubMed PMC
28. Park S, Aintablian A, Coupe B, Bouret SG. The endoplasmic reticulum stress-autophagy pathway controls hypothalamic development and energy balance regulation in leptin-deficient neonates. Nat Commun 2020;11:1914.DOIPubMed PMC
29. Yao H, Fan C, Fan X, et al. Effects of gut microbiota on leptin expression and body weight are lessened by high-fat diet in mice. Br J Nutr 2020;124:396-406.DOIPubMed
30. Song CH, Kim N, Nam RH, Choi SI, Lee HN, Surh YJ. 17β-Estradiol supplementation changes gut microbiota diversity in intact and colorectal cancer-induced ICR male mice. Sci Rep 2020;10:12283.DOIPubMed PMC
31. Kaliannan K, Robertson RC, Murphy K, et al. Estrogen-mediated gut microbiome alterations influence sexual dimorphism in metabolic syndrome in mice. Microbiome 2018;6:205.DOIPubMed PMC
32. Harada N, Minami Y, Hanada K, et al. Relationship between gut environment, feces-to-food ratio, and androgen deficiency-induced metabolic disorders. Gut Microbes 2020;12:1817719.DOIPubMed PMC
33. Colldén H, Landin A, Wallenius V, et al. The gut microbiota is a major regulator of androgen metabolism in intestinal contents. Am J Physiol Endocrinol Metab 2019;317:E1182-92.DOIPubMed PMC
34. Caricilli AM, Saad MJ. The role of gut microbiota on insulin resistance. Nutrients 2013;5:829-51.DOIPubMed PMC
35. Lee CJ, Sears CL, Maruthur N. Gut microbiome and its role in obesity and insulin resistance. Ann N Y Acad Sci 2020;1461:37-52.DOIPubMed
36. Han Q, Wang J, Li W, Chen ZJ, Du Y. Androgen-induced gut dysbiosis disrupts glucolipid metabolism and endocrinal functions in polycystic ovary syndrome. Microbiome 2021;9:101.DOIPubMed PMC
37. Barroso A, Santos-Marcos JA, Perdices-Lopez C, et al. Neonatal exposure to androgens dynamically alters gut microbiota architecture. J Endocrinol 2020;247:69-85.DOIPubMed
38. Tett A, Pasolli E, Masetti G, Ercolini D, Segata N. Prevotella diversity, niches and interactions with the human host. Nat Rev Microbiol 2021;19:585-99.DOIPubMed
39. Yang H, Guo R, Li S, et al. Systematic analysis of gut microbiota in pregnant women and its correlations with individual heterogeneity. NPJ Biofilms Microbiomes 2020;6:32.DOIPubMed PMC
40. DiGiulio DB, Callahan BJ, McMurdie PJ, et al. Temporal and spatial variation of the human microbiota during pregnancy. Proc Natl Acad Sci U S A 2015;112:11060-5.DOIPubMed PMC
41. Mallott EK, Borries C, Koenig A, Amato KR, Lu A. Reproductive hormones mediate changes in the gut microbiome during pregnancy and lactation in Phayre's leaf monkeys. Sci Rep 2020;10:9961.DOIPubMed PMC
42. Nuriel-Ohayon M, Neuman H, Ziv O, et al. Progesterone increases bifidobacterium relative abundance during late pregnancy. Cell Rep 2019;27:730-736.e3.DOIPubMed
43. Doden HL, Pollet RM, Mythen SM, et al. Structural and biochemical characterization of 20β-hydroxysteroid dehydrogenase from. Bifidobacterium adolescentis ;294:12040-53.DOIPubMed PMC
44. Dahl C, Stanislawski M, Iszatt N, et al. Gut microbiome of mothers delivering prematurely shows reduced diversity and lower relative abundance of bifidobacterium and streptococcus. PLoS One 2017;12:e0184336.DOIPubMed PMC
45. Duranti S, Milani C, Lugli GA, et al. Insights from genomes of representatives of the human gut commensal bifidobacterium bifidum. Environ Microbiol 2015;17:2515-31.DOIPubMed
46. Duranti S, Lugli GA, Mancabelli L, et al. Maternal inheritance of bifidobacterial communities and bifidophages in infants through vertical transmission. Microbiome 2017;5:66.DOIPubMed PMC
47. Markle JG, Frank DN, Mortin-Toth S, et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 2013;339:1084-8.DOIPubMed
48. Li S, Kararigas G. Role of biological sex in the cardiovascular-gut microbiome axis. Front Cardiovasc Med 2021;8:759735.DOIPubMed PMC
49. Org E, Mehrabian M, Parks BW, et al. Sex differences and hormonal effects on gut microbiota composition in mice. Gut Microbes 2016;7:313-22.DOIPubMed PMC
50. Liu P, Peng G, Zhang N, Wang B, Luo B. Crosstalk between the gut microbiota and the brain: an update on neuroimaging findings. Front Neurol 2019;10:883.DOIPubMed PMC
51. Sherman MP, Zaghouani H, Niklas V. Gut microbiota, the immune system, and diet influence the neonatal gut-brain axis. Pediatr Res 2015;77:127-35.DOIPubMed
52. Keskitalo A, Aatsinki AK, Kortesluoma S, et al. Gut microbiota diversity but not composition is related to saliva cortisol stress response at the age of 2.5 months. Stress 2021;24:551-60.DOIPubMed
53. Yang I, Corwin EJ, Brennan PA, Jordan S, Murphy JR, Dunlop A. The infant microbiome: implications for infant health and neurocognitive development. Nurs Res 2016;65:76-88.DOIPubMed PMC
54. Misiak B, Łoniewski I, Marlicz W, et al. The HPA axis dysregulation in severe mental illness: can we shift the blame to gut microbiota? Prog Neuropsychopharmacol Biol Psychiatry 2020;102:109951.DOIPubMed
55. Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res 2002;53:865-71.DOIPubMed
56. Kelly JR, Keane VO, Cryan JF, Clarke G, Dinan TG. Mood and microbes: gut to brain communication in depression. Gastroenterol Clin North Am 2019;48:389-405.DOIPubMed
57. Kelly JR, Borre Y, O' Brien C, et al. Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res 2016;82:109-18.DOIPubMed
58. Rosin S, Xia K, Azcarate-Peril MA, et al. A preliminary study of gut microbiome variation and HPA axis reactivity in healthy infants. Psychoneuroendocrinology 2021;124:105046.DOIPubMed PMC
59. Zijlmans MA, Korpela K, Riksen-Walraven JM, de Vos WM, de Weerth C. Maternal prenatal stress is associated with the infant intestinal microbiota. Psychoneuroendocrinology 2015;53:233-45.DOIPubMed
60. Rodriguez N, Tun HM, Field CJ, Mandhane PJ, Scott JA, Kozyrskyj AL. Prenatal Depression, Breastfeeding, and Infant Gut Microbiota. Front Microbiol 2021;12:664257.DOIPubMed PMC
61. Jahnke JR, Roach J, Azcarate-Peril MA, Thompson AL. Maternal precarity and HPA axis functioning shape infant gut microbiota and HPA axis development in humans. PLoS One 2021;16:e0251782.DOIPubMed PMC
62. Weerth C. Do bacteria shape our development? Neurosci Biobehav Rev 2017;83:458-71.DOIPubMed
63. Theiler-Schwetz V, Zaufel A, Schlager H, Obermayer-Pietsch B, Fickert P, Zollner G. Bile acids and glucocorticoid metabolism in health and disease. Biochim Biophys Acta Mol Basis Dis 2019;1865:243-51.DOIPubMed
64. Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci 2015;9:392.DOIPubMed PMC
65. Bloemendaal M, Szopinska-Tokov J, Belzer C, et al. Probiotics-induced changes in gut microbial composition and its effects on cognitive performance after stress: exploratory analyses. Transl Psychiatry 2021;11:300.DOIPubMed PMC
66. Korpela K, Helve O, Kolho KL, et al. Maternal fecal microbiota transplantation in cesarean-born infants rapidly restores normal gut microbial development: a proof-of-concept study. Cell 2020;183:324-334.e5.DOIPubMed
67. Sarkar A, Lehto SM, Harty S, Dinan TG, Cryan JF, Burnet PWJ. Psychobiotics and the manipulation of bacteria-gut-brain signals. Trends Neurosci 2016;39:763-81.DOIPubMed PMC
68. Cheng LH, Liu YW, Wu CC, Wang S, Tsai YC. Psychobiotics in mental health, neurodegenerative and neurodevelopmental disorders. J Food Drug Anal 2019;27:632-48.DOIPubMed
69. Badillo-Suárez PA, Rodríguez-Cruz M, Nieves-Morales X. Impact of metabolic hormones secreted in human breast milk on nutritional programming in childhood obesity. J Mammary Gland Biol Neoplasia 2017;22:171-91.DOIPubMed
70. Wan Y, Jiang J, Lu M, et al. Human milk microbiota development during lactation and its relation to maternal geographic location and gestational hypertensive status. Gut Microbes 2020;11:1438-49.DOIPubMed PMC
71. Bravi F, Wiens F, Decarli A, Dal Pont A, Agostoni C, Ferraroni M. Impact of maternal nutrition on breast-milk composition: a systematic review. Am J Clin Nutr 2016;104:646-62.DOIPubMed
72. Andreas NJ, Kampmann B, Mehring Le-Doare K. Human breast milk: a review on its composition and bioactivity. Early Hum Dev 2015;91:629-35.DOIPubMed
73. Victora CG, Bahl R, Barros AJ, Franca GV, Horton S, Krasevec J, et al. Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect. Lancet 2016;387:475-90.DOIPubMed
74. Lind MV, Larnkjær A, Mølgaard C, Michaelsen KF. Breastfeeding, breast milk composition, and growth outcomes. In: Colombo J, Koletzko B, Lampl M, editors. Recent Research in Nutrition and Growth. S. Karger AG; 2018. p. 63-77.DOIPubMed
75. Cabrera-Rubio R, Collado MC, Laitinen K, Salminen S, Isolauri E, Mira A. The human milk microbiome changes over lactation and is shaped by maternal weight and mode of delivery. Am J Clin Nutr 2012;96:544-51.DOIPubMed
76. Collado MC, Laitinen K, Salminen S, Isolauri E. Maternal weight and excessive weight gain during pregnancy modify the immunomodulatory potential of breast milk. Pediatr Res 2012;72:77-85.DOIPubMed
77. Gomez-Gallego C, Garcia-Mantrana I, Salminen S, Collado MC. The human milk microbiome and factors influencing its composition and activity. Semin Fetal Neonatal Med 2016;21:400-5.DOIPubMed
78. Anderson G, Vaillancourt C, Maes M, Reiter RJ. Breastfeeding and the gut-brain axis: is there a role for melatonin? Biomol Concepts 2017;8:185-95.DOIPubMed
79. Xia S, Gao W, Li Y, et al. Effects of melatonin on intestinal function and bacterial compositions in sucking piglets. J Anim Physiol Anim Nutr (Berl) 2022; doi: 10.1111/jpn.13675.DOIPubMed
80. Paulose JK, Cassone VM. The melatonin-sensitive circadian clock of the enteric bacterium Enterobacter aerogenes. Gut Microbes 2016;7:424-7.DOIPubMed PMC
81. Sinha RA, Singh BK, Yen PM. Direct effects of thyroid hormones on hepatic lipid metabolism. Nat Rev Endocrinol 2018;14:259-69.DOIPubMed PMC
82. Cuan-Baltazar Y, Soto-Vega E. Microorganisms associated to thyroid autoimmunity. Autoimmun Rev 2020;19:102614.DOIPubMed
83. Zhang D, Cai K, Wang G, et al. Trimester-specific reference ranges for thyroid hormones in pregnant women. Medicine (Baltimore) 2019;98:e14245.DOIPubMed PMC
84. Virili C, Centanni M. Does microbiota composition affect thyroid homeostasis? Endocrine 2015;49:583-7.DOIPubMed
85. Su X, Zhao Y, Li Y, Ma S, Wang Z. Gut dysbiosis is associated with primary hypothyroidism with interaction on gut-thyroid axis. Clin Sci (Lond) 2020;134:1521-35.DOIPubMed
86. Knezevic J, Starchl C, Tmava Berisha A, Amrein K. Thyroid-gut-axis: how does the microbiota influence thyroid function? Nutrients 2020;12:1769.DOIPubMed PMC
87. Bargiel P, Szczuko M, Stachowska L, et al. Microbiome metabolites and thyroid dysfunction. J Clin Med 2021;10:3609.DOIPubMed PMC
88. Zhao F, Feng J, Li J, et al. Alterations of the gut microbiota in hashimoto’s thyroiditis patients. Thyroid 2018;28:175-86.DOIPubMed
89. Magne F, Gotteland M, Gauthier L, et al. The firmicutes/bacteroidetes ratio: a relevant marker of gut dysbiosis in obese patients? Nutrients 2020;12:1474.DOIPubMed PMC
90. Koppel N, Maini Rekdal V, Balskus EP. Chemical transformation of xenobiotics by the human gut microbiota. Science 2017;356:eaag2770.DOIPubMed PMC
91. Yao Z, Zhao M, Gong Y, et al. Relation of gut microbes and L-Thyroxine through altered thyroxine metabolism in subclinical hypothyroidism subjects. Front Cell Infect Microbiol 2020;10:495.DOIPubMed PMC
92. Sun J, Zhao F, Lin B, et al. Gut microbiota participates in antithyroid drug induced liver injury through the lipopolysaccharide related signaling pathway. Front Pharmacol 2020;11:598170.DOIPubMed PMC
93. Hazenberg MP, de Herder WW, Visser TJ. Hydrolysis of iodothyronine conjugates by intestinal bacteria. FEMS Microbiol Rev 1988;4:9-16.DOIPubMed
94. Dabek M, McCrae SI, Stevens VJ, Duncan SH, Louis P. Distribution of beta-glucosidase and beta-glucuronidase activity and of beta-glucuronidase gene gus in human colonic bacteria. FEMS Microbiol Ecol 2008;66:487-95.DOIPubMed
95. Dashnyam P, Mudududdla R, Hsieh TJ, et al. β-Glucuronidases of opportunistic bacteria are the major contributors to xenobiotic-induced toxicity in the gut. Sci Rep 2018;8:16372.DOIPubMed PMC
96. Jones BV, Begley M, Hill C, Gahan CG, Marchesi JR. Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome. Proc Natl Acad Sci U S A 2008;105:13580-5.DOIPubMed PMC
97. Virili C, Centanni M. “With a little help from my friends” - The role of microbiota in thyroid hormone metabolism and enterohepatic recycling. Mol Cell Endocrinol 2017;458:39-43.DOIPubMed
98. Virili C, Stramazzo I, Centanni M. Gut microbiome and thyroid autoimmunity. Best Pract Res Clin Endocrinol Metab 2021;35:101506.DOIPubMed
99. Feng J, Zhao F, Sun J, et al. Alterations in the gut microbiota and metabolite profiles of thyroid carcinoma patients. Int J Cancer 2019;144:2728-45.DOIPubMed
100. Zhang J, Zhang F, Zhao C, et al. Dysbiosis of the gut microbiome is associated with thyroid cancer and thyroid nodules and correlated with clinical index of thyroid function. Endocrine 2019;64:564-74.DOIPubMed
101. Li A, Li T, Gao X, et al. Gut microbiome alterations in patients with thyroid nodules. Front Cell Infect Microbiol 2021;11:643968.DOIPubMed PMC
102. Aranda A. MicroRNAs and thyroid hormone action. Mol Cell Endocrinol 2021;525:111175.DOIPubMed
103. Taniguchi K, Uchiyama K, Akao Y. PTBP1-targeting microRNAs regulate cancer-specific energy metabolism through the modulation of PKM1/M2 splicing. Cancer Sci 2021;112:41-50.DOIPubMed PMC
104. Kon IY, Shilina NM, Gmoshinskaya MV, Ivanushkina TA. The study of breast milk IGF-1, leptin, ghrelin and adiponectin levels as possible reasons of high weight gain in breast-fed infants. Ann Nutr Metab 2014;65:317-23.DOIPubMed
105. Perry B, Wang Y. Appetite regulation and weight control: the role of gut hormones. Nutr Diabetes 2012;2:e26.DOIPubMed PMC
106. Whitmore TJ, Trengove NJ, Graham DF, Hartmann PE. Analysis of insulin in human breast milk in mothers with type 1 and type 2 diabetes mellitus. Int J Endocrinol 2012;2012:296368.DOIPubMed PMC
107. Granata R, Gallo D, Luque RM, et al. Obestatin regulates adipocyte function and protects against diet-induced insulin resistance and inflammation. FASEB J 2012;26:3393-411.DOIPubMed
108. Ilcol YO, Hizli ZB, Eroz E. Resistin is present in human breast milk and it correlates with maternal hormonal status and serum level of C-reactive protein. Clin Chem Lab Med 2008;46:118-24.DOIPubMed
109. Kelly DP. Medicine. Irisin, light my fire. Science 2012;336:42-3.DOIPubMed
110. Aydin S, Kuloglu T, Aydin S. Copeptin, adropin and irisin concentrations in breast milk and plasma of healthy women and those with gestational diabetes mellitus. Peptides 2013;47:66-70.DOIPubMed
111. Castan-Laurell I, Vítkova M, Daviaud D, et al. Effect of hypocaloric diet-induced weight loss in obese women on plasma apelin and adipose tissue expression of apelin and APJ. Eur J Endocrinol 2008;158:905-10.DOIPubMed PMC
112. Dong J, Guan HZ, Jiang ZY, Chen X. Nesfatin-1 influences the excitability of glucosensing neurons in the dorsal vagal complex and inhibits food intake. PLoS One 2014;9:e98967.DOIPubMed PMC
113. Schueler J, Alexander B, Hart AM, Austin K, Larson-Meyer DE. Presence and dynamics of leptin, GLP-1, and PYY in human breast milk at early postpartum. Obesity (Silver Spring) 2013;21:1451-8.DOIPubMed PMC
114. Elmlinger MW, Hochhaus F, Loui A, Frommer KW, Obladen M, Ranke MB. Insulin-like growth factors and binding proteins in early milk from mothers of preterm and term infants. Horm Res 2007;68:124-31.DOIPubMed
115. Entringer S. Impact of stress and stress physiology during pregnancy on child metabolic function and obesity risk. Curr Opin Clin Nutr Metab Care 2013;16:320-7.DOIPubMed PMC
116. Esposito S, Laino D, D'Alonzo R, et al. Pediatric sleep disturbances and treatment with melatonin. J Transl Med 2019;17:77.DOIPubMed PMC
Turroni F, Rizzo SM, Ventura M, Bernasconi S. Cross-talk between the infant/maternal gut microbiota and the endocrine system: a promising topic of research. Microbiome Res Rep 2022;1:14. http://dx.doi.org/10.20517/mrr.2021.14