key: cord-0846941-kkwveilt
authors: Ebrahimi, Saba; Khatami, Saghi; Mesdaghi, Mehrnaz
title: The Effect of COVID-19 Pandemic on the Infants' Microbiota and the Probability of Development of Allergic and Autoimmune Diseases
date: 2021-12-03
journal: Int Arch Allergy Immunol
DOI: 10.1159/000520510
sha: 627b30bd74623df67dfb6d34821ba07f52d83b09
doc_id: 846941
cord_uid: kkwveilt

The human microbiota plays a significant role in various mechanisms of the body. The formation of a healthy microbiota, especially in early childhood, has a significant effect on maintaining human health. Since the onset of coronavirus disease 2019 (COVID-19), the disease has caused many changes in human life. According to the available information, many of these factors affect the composition and diversity of the body's microbiota, so this pandemic may alter and disrupt the microbiota and consequently increase the incidence of other diseases such as allergic and autoimmune disorders, especially in children and infants born in this era. In this review, the probable impact of the COVID-19 pandemic on body's microbiota and its relationship with the emergence of future diseases is discussed.

Since the onset of coronavirus disease 2019 (CO-VID-19) epidemic and its spread around the world, this disease has had a significant impact on various aspects of the life of individuals and communities and has caused changes in lifestyle, social interactions, eating habits, etc. "Microbiota" refers to microorganisms that live in various parts of the human body such as the skin, mouth, respiratory system, and gastrointestinal tract [1, 2] , which weighs about 1.5 kg and is composed of >100 trillion microorganisms [2, 3]. It has been found that the most important time of exposure to environmental microbial species and nonharmful commensal microbes is during pregnancy, childbirth, and the first months of infancy [4, 5] . Numerous factors such as delivery mode, nutrition, lifestyle, and living environment affect the composition and diversity of microbiota in children [6] ; therefore, lifestyle changes caused by the COVID-19 pandemic can also change the microbiota (shown in Fig. 1 ). Interactions between the human body and microbiota are extensive and include the regulation of immune responses [7] , maintenance of safe intestinal homeostasis, and disease modification [8] . Microbial colonization at the beginning of life plays an essential role in the development of innate and acquired immune systems [9, 10] . The formation of healthy gut microbiota leads to T helper type 1 (Th1) cells dominance in Th1/Th2 balance [11] , while a change in the homeostasis of the host microbiota can shift the Th1/ Th2 cytokines balance toward the Th2 responses [12] . Numerous studies have shown the relationship between the composition and diversity of gut microbiota and its effect on the incidence of allergic diseases in infants and children [13] [14] [15] . Cytokines produced by Th2 cells, especially interleukin 4 (IL-4) and IL-5, are associated with many allergic diseases such as asthma and allergic rhinitis, and IL-4 is the major cytokine that increases IgE production [16] . In addition, many autoimmune diseases have been associated with alterations in the composition and diversity of the body's microbiota [17] [18] [19] . Since changes in the body's microbial composition may lead to loss of immune tolerance, the human microbiome appears to play a key role in the development of autoimmune diseases [20, 21] . If tolerance mechanisms are not completely effective, microorganisms can elicit immune responses against the host body [22] [23] [24] . In this review, we investigate the effects of the COVID-19 pandemic on the microbiota of pregnant women and their infants and the possibility of increasing the incidence of allergic and autoimmune diseases in children born during the CO-VID-19 pandemic.

The time and mode of delivery are important and influential factors in the composition of gut microbiota [25] . Cesarean section is increasing worldwide [26, 27] , but it has several complications for both mother and child [27, 28] . The rate of cesarean section in women infected with COVID-19 is even higher than the general population [29] . In a study of 108 pregnant women with COVID-19, cesarean section accounted for 92% of all deliveries, and only 8% of participants in this study had vaginal deliveries [30] . In another study, all pregnant patients with CO-VID-19 pneumonia were delivered by cesarean section [31] . Among the reasons for cesarean section in women with COVID-19 were worsening of the mother's condition, severe preeclampsia, history of cesarean delivery, and fetal distress [31, 32] . In addition, concern about the risk of mother-to-child virus transmission during vaginal delivery has been another reason for cesarean section [32] . It has been observed that in infants, who are born by cesarean section (instead of vaginal delivery and crossing the birth canal, i.e., colonized with the maternal microbiota), the gut microbiota is formed with delay, and its colonization has a pattern similar to that of the mother's skin [25] (shown in Fig. 2 ). The study of the effect of this difference in microbiome on the incidence of allergic diseases has shown that cesarean delivery reduces microbial diversity and reduces Th1-cell responses in the early years of life [33] . Also, several research studies have linked cesarean section to the development of asthma, eczema, and allergic rhinitis [34] [35] [36] . Furthermore, some studies have shown the effect of cesarean section on increasing the risk of autoimmune diseases in children. According to a study by Sevelsted et al. [37] , the cesarean section was associated with a significant increase in the risk of asthma, juvenile arthritis, and inflammatory bowel disease in children. Another study found that children born by cesarean delivery, especially the elective ones (which has been done at mothers' request, probably due to her fear of childbirth), were at higher risk for diseases related to immune dysfunction [38] . The pandemic has also affected the early days after delivery. The birth of a new baby in a family is usually accompanied by family and friends celebrating the event, but during the COVID-19 pandemic, gatherings and cel- ebrations are strictly limited. In small gatherings, the guests are asked to use a mask, wash their hands, and maintain a distance of about 2 m with the neonate [39] . It has been observed that social relationships are associated with diversity in fecal microbiota [40] . Therefore, reducing family and friendly gatherings during the pandemic can also alter the baby's microbiome.

In addition to the mode of delivery, the infant's feeding pattern plays an important role in the formation of microbiota in the first year after birth [41] . Microbiota is transmitted through nonsterile breast milk [42] , and breastfeeding has an important influence on the gut microbiome compared to formula feeding [43] . The mucosal immune system, in which gut microbiota are involved, suppresses immune responses to nonharmful ingested antigens [44] . Diseases caused by a deficiency in the immune system have been observed to be less common in breastfed infants [45] . The results of a study by Cardwell et al. [46] showed that breastfeeding for >3 months, or exclusively for >2 weeks after birth, is related with a 15-30% decrease in the risk of developing type 1 diabetes in children. Another study found that exclusive breastfeeding for >2 weeks is associated with a reduction in the risk of type 2 diabetes in the future life [47] . Other studies have examined the association between breastfeeding and other autoimmune diseases. The results of a study showed that breastfeeding, regardless of its duration, reduces the risk of rheumatoid arthritis [48] . Another study found that among HLA-DR4-negative infants, those who had a positive rheumatoid factor were less likely to be breastfed for >3 months compared to infants whose rheumatoid factor was negative [49] . Some studies have also shown an association between breastfeeding and a reduced risk of multiple sclerosis [50, 51] . In addition, according to the results of a meta-analysis, the risk of developing celiac disease was significantly lower in infants who were breastfed at the time of gluten intake compared with those who were not breastfed [52] .

Based on the available documents, there has been no evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the breast milk of mothers suspected to or with COVID-19 and its transmission to the infant through breastfeeding [53, 54] . Therefore, it is recommended that suspicious mothers, and even those infected with SARS-CoV-2, continue breastfeeding [55] . However, these mothers should use a mask while breastfeeding, wash their hands with soap before touching the baby, and/or use alcohol-based disinfectants [55] .

Exposure to chemicals in detergents has been shown to have a significant effect on the composition and function of microbiota [56] . The metabolic activity of gut bacteria plays a vital role in the human body [57] . In one study, fecal diversity and concentration of metabolites including short-chain fatty acids (SCFAs) derived from microbiota were significantly reduced by the use of dishwashing detergents [58] . The results of a study showed that the prevalence of atopy was lower in children who had higher levels of SCFAs in their feces at the age of 1 year. In addition, these children were less likely to develop asthma and be diagnosed with allergic rhinitis and food allergies [59] . The gastrointestinal tract can communicate with the brain through metabolites produced by commensal bacteria such as SCFAs [60, 61] . In patients with multiple sclerosis, a significant reduction in the percentage of bacteria producing SCFAs has been observed [18] . Also, the presence of SCFA-producing bacteria has been shown to maintain intestinal integrity by inducing the production of appropriate amounts of mucin [62] , and changes in the production of SCFAs are associated with type 1 diabetes [62, 63] . Therefore, increased usage of detergents and hand sanitizers to protect infants during the pandemic may increase the incidence of allergic and autoimmune diseases in children (summarized in Fig. 2 ). Many factors limit breastfeeding including the severity of the mother's illness, misconceptions by the medical team and parents about the safety of breastfeeding, hospital policy about mother and infant rooming-in after delivery, and maternal quarantine after discharge. Some mothers with COVID-19 are unable to breastfeed their infants due to the worsening of the disease, for whom, the use of pumped breast milk is recommended [55] ; however, the available evidence has shown that how to breastfeed the baby (directly from the breast vs. the use of pumped breast milk) has a significant effect on the microbiota composition of milk and that indirect breastfeeding is associated with reduced milk richness and bacterial diversity [64, 65] . Bifidobacterium and Lactobacillus are the most important probiotics in breast milk [66] . Many studies have shown the reduction of atopic eczema, one of the most common types of allergies in children, after the use of probiotics [67] [68] [69] . Evidence suggests that the use of pumped breast milk reduces milk Bifidobacteria [64] . Also, antibiotic treatment and cesarean section were associated with a decreased amount of Bifidobacterium and Lactobacillus in the infant's microbiota [25, 70] (summarized in Fig. 2) . In addition, a decrease in colonization with Bifidobacteria in the first year of life has been observed to be associated with allergies in children [71, 72] .

According to studies, up to 47% of COVID-19-infected hospitalized patients give birth prematurely [73] [74] [75] . In one article, inflammation has been reported as one of the most important factors in the occurrence of preterm labor [76] . Although bacterial infections often cause the onset of inflammatory cascades and preterm labor, antibiotic use in the absence of bacterial infections has been associated with the production of inflammatory cytokines and cause cytokine storms [76] . Therefore, antibiotic treatment should not be performed by default for pregnant women with COVID-19 and can only be prescribed if necessary and after confirmation of bacterial infection in these patients [77] . However, some available evidence suggests that many pregnant patients with severe COVID-19 have taken antibiotics, although no evidence of bacterial infection has been reported [78, 79] . According to studies, maternal antibiotic treatment during and even before pregnancy has been associated with the abnormal establishment of gut microbiota in preterm infants [80, 81] . Compared to term neonates, intestinal microbial colonization of preterm infants has been found to be delayed and has limited microbial diversity [82] (summarized in Fig. 2) . In preterm infants, the composition of primary gut microbiota is similar to the bacterial composition of hospital surfaces [83] . In addition, the amount of potentially pathogenic bacteria in these infants is increased, and the amount of essential commensal bacteria is decreased [84, 85] . Premature or low birth weight infants are at the highest risk for antibiotic-related disorders because they typically receive antibiotic treatment at birth to protect them from bacterial infections and earlyonset sepsis [86] [87] [88] . Antibiotic use has destructive effects such as reducing the bacterial diversity of the gut microbiota of these infants [88] . Disruption of the formation of gut microbiota by antibiotic administration may also affect the interaction with the immune system. In fact, taking antibiotics during pregnancy and after birth increases the risk of future illnesses such as asthma and other allergic diseases [89, 90] . Only a few studies have looked into the impact of preterm delivery on the microbiota of breast milk. According to these studies, the bacterial composition found in the milk of mothers, who gave birth prematurely, was different from that found in the mature milk of the same mothers, and the frequency of bacteria in premature milk was lower [91] . Monocytes transmit bacteria from the intestine to the mesenteric lymph nodes and mammary glands via the entero-mammary pathway, which occurs in late pregnancy [92] . Therefore, this pathway may be insufficient in preterm labor and can lead to a decrease in the abundance of bacteria in breast milk.

Numerous studies have shown that infants' contact with pets at the beginning of life and maternal contact with animals during pregnancy have a significant effect on the formation of gut microbiota in the child and can affect the incidence of atopic diseases [93] [94] [95] . In their study, Azad et al. [96] found that living with pets increased the richness and diversity of infants' gut microbiota. Another study has shown that increasing the number of pets in a child's environment in the first year of life is associated with a decrease in the prevalence of allergic diseases such as asthma and eczema at school age [97] . Due to factors such as quarantine and teleworking, keeping pets at home has increased significantly during the COVID-19 pandemic [98] . This may be in favor of preserving the diversity of microbiota and reducing the incidence of allergic and autoimmune diseases in children born during this period. However, although the available evidence suggests that the risk of animal to human transmission of COVID-19 is low [99] , some pet owners abandoned their animals for the fear of transmitting SARS-CoV-2. Also, a number of people were not able to take care of their pets due to job losses and financial problems happened during the pandemic [100] .

From the beginning of the COVID-19 pandemic, the disease has had a significant impact on human health and lifestyle. Evidence has shown that one of the important effects of this pandemic is to alter the body's microbiota and increase the risk of dysbiosis, and since pregnancy and early infancy are critical times for microbiota formation, pregnant women and their infants are significantly affected by the condition. As numerous studies have confirmed the essential role of healthy human microbiota in regulating immune responses and maintaining body health, the changes and dysbiosis caused by the COVID-19 outbreak could increase the incidence of various disorders in the future, including allergic and autoimmune diseases, especially in children. However, due to the persistence of this pandemic and its unknown long-term effects, at the moment, the exact impact of this condition on children born during COVID-19 pandemic cannot be foreseen and needs to be clarified in future epidemiologic studies.

Based on our current knowledge about the low risk of SARS-CoV-2 transmission from pets and surfaces and the importance of proper formation of microbiota, increased infants' exposure to pets and decreased usage of disinfectants can be helpful in reducing the risk of future diseases. Moreover, mass vaccination will hopefully help returning to normal life, and having normal minimal social interactions could be the most important step toward normal formation of microbiota and immune responses.

The authors have no conflicts of interest to declare.

The authors have no funding sources to declare.

Mehrnaz Mesdaghi contributed to conception of the work, critical revision of the manuscript, and final approval of the manuscript. Saba Ebrahimi contributed to search of articles and data gathering, drafting of the manuscript, and final approval of the manuscript. Saghi Khatami contributed to search of articles and data gathering, drafting of the manuscript, and final approval of the manuscript. 

Caesarean section delivery and the risk of allergic disorders in childhood

A meta-analysis of the association between caesarean section and childhood asthma

Mode and place of delivery, gastrointestinal microbiota, and their influence on asthma and atopy

Cesarean section and chronic immune disorders

Cesarean section and disease associated with immune function

Breastfeeding and caring for newborns: CDC

Close social relationships correlate with human gut microbiota composition

Dynamics and stabilization of the human gut microbiome during the first year of life

Vertical mother-neonate transfer of maternal gut bacteria via breastfeeding. Environ Microbiol

Establishment of the intestinal microbiota and its role for atopic dermatitis in early childhood

Specific oral tolerance induction in childhood

Short duration of breast-feeding as a risk-factor for beta-cell autoantibodies in 5-year-old children from the general population

Breastfeeding and childhood-onset type 1 diabetes: a pooled analysis of individual participant data from 43 observational studies

Does breastfeeding influence risk of type 2 diabetes in later life? A quantitative analysis of published evidence

Breastfeeding and risk of rheumatoid arthritis: a systematic review and metaanalysis

Perinatal and early childhood risk factors associated with rheumatoid factor positivity in a healthy paediatric population

Breastfeeding is associated with lower risk for multiple sclerosis

Reduced duration of breastfeeding is associated with a higher risk of multiple sclerosis in both Italian and Norwegian adult males: the EnvIMS study

Effect of breast feeding on risk of coeliac disease: a systematic review and meta-analysis of observational studies

Breastfeeding and COVID-19

Managing COV-ID-19-positive maternal-infant dyads: an Italian experience

WHO Frequently Asked Questions : Breastfeeding and COVID-19 For health care workers

Is triclosan harming your microbiome?

Faecal microbiota and short-chain fatty acid levels in faeces from infants with cow's milk protein allergy. Int Arch Allergy Immunol

The impact of food additives, artificial sweeteners and domestic hygiene products on the human gut microbiome and its fibre fermentation capacity

High levels of butyrate and propionate in early life are associated with protection against atopy

Gut microbiota-brain axis

Gut/brain axis and the microbiota

Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes

Towards a functional hypothesis relating anti-islet cell autoimmunity to the dietary impact on microbial communities and butyrate production. Microbiome

Composition and variation of the human milk microbiota are influenced by maternal and early-life factors

Origins of human milk microbiota: new evidence and arising questions

The microbiota of human milk in healthy women

Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: a randomized, double-blind, placebo-controlled trial

Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial

Effect of probiotic mix (Bifidobacterium bifidum, Bifidobacterium lactis, Lactobacillus acidophilus) in the primary prevention of eczema: A double-blind, randomized, placebo-controlled trial

Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability

Allergy development and the intestinal microflora during the first year of life

Distinct pattern of commensal gut microbiota in toddlers with eczema

Coronavirus disease 2019 (COVID-19) pandemic and pregnancy. Obstet Anesth Dig

Coronavirus in pregnancy and delivery: rapid review

Severe coronavirus infections in pregnancy: A systematic review

Norooznezhad AH. Antibiotics, inflammation, and preterm labor: a missed conclusion

Global interim guidance on coronavirus disease 2019 (COVID-19) during pregnancy and puerperium from FIGO and allied partners: Information for healthcare professionals

A case of 2019 novel coronavirus in a pregnant woman with preterm delivery

Maternal death due to COVID-19

Impact of prematurity and perinatal antibiotics on the developing intestinal microbiota: a functional inference study

Antibiotic use during pregnancy: how bad is it

Investigation of the intestinal microbiota in preterm infants using different methods

Microbes in the neonatal intensive care unit resemble those found in the gut of premature infants

Establishment and development of intestinal microbiota in preterm neonates

Dynamics and clinical evolution of bacterial gut microflora in extremely premature patients

Antibiotic stewardship in premature infants: a systematic review

Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants

Early empiric antibiotic use in preterm infants is associated with lower bacterial diversity and higher relative abundance of enterobacter

Does antibiotic exposure during infancy lead to development of asthma? A systematic review and metaanalysis

Prenatal antibiotic use and risk of childhood wheeze/asthma: a meta-analysis. Pediatr

biochemical, and immunological properties of colostrum and mature milk from mothers of extremely preterm infants

The origin of human milk bacteria: Is there a bacterial entero-mammary pathway during late pregnancy and lactation?

Birth mode, breastfeeding, pet exposure, and antibiotic use: associations with the gut microbiome and sensitization in children. Curr Allergy Asthma Rep

Exposure to household furry pets influences the gut microbiota of infants at 3-4 months following various birth scenarios

Perinatal pet exposure, faecal microbiota, and wheezy bronchitis: is there a connection?

Infant gut microbiota and the hygiene hypothesis of allergic disease: impact of household pets and siblings on microbiota composition and diversity

Petkeeping in early life reduces the risk of allergy in a dose-dependent fashion

Did the CO-VID-19 pandemic spark a public interest in pet adoption?

Animals and COVID-19: CDC

COVID-19 and pets: when pandemic meets panic