April 2021, Volume 71, Issue 4

Narrative Review

Gut microbiome skin axis in the development of atopic dermatitis

Hitham Abduarhman Alghamdi  ( Department of Biological Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. )
Ahmed Behieldin  ( Department of Biological Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. )
Sherif Edris  ( Department of Biological Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. )

Abstract

Atopic dermatitis mostly starts with children in early life. Besides the aetiological factors, like environmental, dietary or medical exposures, gut-skin axis microbiome studies have an impact to investigate and to understand the relation between the gut microbiome and changes to the skin microbiom as well as resulting skin diseases like atopic dermatitis. Infants start forming their microbiome in early life and some studies suggest that this phase has a crucial role in AD development. Balanced bacterial composition is important to maintain healthy skin as the gut microbiome dysbiosis may result in dramatic shifting in the skin microbiome that gives better chance for some bacteria, such as staphylococcus aureus, to prevail which has been reported to contribute to AD development. Among several factors, immunological activity has a strong relation to microbiome, changed composition and AD development. Supplements of prebiotic and probiotic could be a positive treatment approach. More studies regarding the gut-skin axis microbiome in general and diseases associated with microbiome, such as AD, are needed.

Keywords: Gut microbiome, Skin microbiome, Atopic dermatitis.

DOI: https://doi.org/10.47391/JPMA.1415

 

Introduction

 

Many studies have linked the gut microbiome dysbiosis with the development of atopic dermatitis (AD), especially among infants.1,2 The human body is colonised by tons of microbial cells, especially in the gut, which outnumber the body's cells, and their genetic material is much more than the humane genomes.3 Metabolite activities in the bodies, for example, are considered to be limited without the aid of the huge amount of metabolic activity that gut microbiome provide to the human body.4-6 Microbiome in the bodies are composed of different microorganisms, including viruses, archaea and bacteria, as well as other eukaryotic microorganisms, such as yeast and fungus. However, the main focus of most studies regarding microbiome is on bacteria.7,8

Infants' microbiome starts forming upon delivery through the mother's skin, vagina microbiome and nursing. However, the mother's microbiome itself tends to change over the course of pregnancy due to usage of, for example, antibiotics. Moreover, the delivery method, whether caesarean section (CS) or normal delivery, has a significant impact on the infant microbiome.9,10 Some studies found that bacterial diversity is different in pregnant and non-pregnant women, with bacteria being less diverse in pregnant women, and also changing with the age factor.11 Microbiome has a role of protecting the foetus. One study shows that pregnant women's vagina would have increase prevalence of lactobacilli, which helps to keep potential of hydrogen (pH) level low and results in decreasing the diversity of bacteria and preventing them from reaching the uterus.12,13 The new-borns obtain most of the microbiome from their mothers' vagina, faeces and skin.14-16 Breastfeeding in the first days of life promotes the growth of the babies' gut microbiome.17 Microbiome for the infant takes evolutionary steps to reach a complex microbiome composition by the end of the first year of life and reaches an adult-like microbiome by the age of three years.8-21 In addition, infant immune and metabolic systems are developed by the microbiome interaction.22,23 However, dysbiosis of infants' microbiome may result in metabolic and autoimmune diseases.24,25

Studies have shown that bacterial diversity within the gut is a sign for gut health and overall health status is associated with it as healthy individuals tend to have more diverse bacterial status in the gut than it is in those who are linked to immune-related and inflammatory disorders as well as obesity.26-30 There are some factors that may affect the stability and balance of gut microbiome and that is suggested to lead to some diseases.31,32 Diet habit alteration or antibiotic consumption, for example, cause a microbiome shifting, especially in the gut33 and that would result in certain diseases, such as inflammatory bowel disease (IBD),34 other autoimmune diseases, such as rheumatoid arthritis,35 or allergy diseases, like AD.36 The current narrative review was planned to focus on the link between the gut microbiome and AD devolvement in children.

 

Gut Microbiome

 

In childhood, microbiome may have an important role in protecting children from various diseases and boost their health status by contributing to the development of the immune system through the cross-talk process with the host cells.37-39 Therefore, it is substantial to know what constitutes the normal health status of children gut microbiome in order to better understand and spot any defects that may lead to certain diseases. It has been reported that a healthy child's gut microbiome, on average, is composed mostly of two phyla among other bacteria; bacteroidetes and firmicutes.40,41 Although microbiome are more diverse in adults, children gut microbiome are found to be richer in genes that are essential to their development.42,43 Thus metabolite production by some types of bacteria in cases of gut microbiome dysbiosis throughout infancy to adulthood results in some kind of defects of immune system that contributes in some ways to disease development, like AD.44,45 Among environmental factors, such as stress and pollutants, direct factors, like antibiotic consumption and diet, have a substantial role in forming the composition of the gut microbiome, especially in early life of the host, and some studies have even found the connection between the patient age, severity and even the AD phenotype along with other factors and the gut microbiome which substantially affect AD development.44,46-48 The relation between the gut microbiome and specific microbes to AD is still not clear and more studies in this area are needed.2

A huge number of antibiotics are prescribed for children and up to one-third of these prescriptions are avoidable.49 Antibiotics are responsible for low diversity in gut microbiome. One study followed some children for the first three years of their lives where some of them were exposed to antibiotics and some were not, and the results showed less diverse composition of bacterial species and strains in the gut of those exposed to antibiotics.50 Antibiotic over-prescriptions have contributed greatly not only in microbiome dysbiosis, but also to many cases of adverse effects related to antimicrobial drug use and promoting a superbug development, according to the World Health Organisation (WHO).51 For infants' gut microbiome, antimicrobial resistance gene prevalence increases with age, and infants delivered by CS mode tend to obtain greater quantity of antimicrobial resistance genes which are reported to have a role in the increasing events of mortality and morbidity.49,52

Another factor having a clear effect on the gut microbiome and playing a huge role in dysbiosis and rebalance is diet. Milk is the first form of nutrition that infants consume for a few months until other source of food start to be included in their diet. Thus, one of the major observations was between the infants who were breastfed and the infants who had non-human source of "formula" milk. The breastfed infants harboured different microbiome in abundance, like bifidobacteria and lactobacilli, than the formula-fed infants who had enterococci and enterobacteria.49,53 Also, there were differences in microbiome profiles between the two groups in terms of total count.54 Human milk has probiotic (milk microbiome), prebiotic (bacterial growth factors) and antimicrobial properties, such as secretory immunoglobulin A (SIgA), from the mother's immune system memory.49,55

 

Skin Microbiome

 

Skin is the largest organ, as the modern science would describe it, and has a diverse microbiome that contributes to some health conditions of the skin.56 While knowledge regarding gut microbiome is more broadened now, skin microbiome is less comprehended and needs more studies. Microbiome colonisation of a newborn starts with the exposure to the close surrounding environment as well as the mother's microbiome.57 Following the acquisition of a complex variation of microbiome phyla, maintaining a balanced microbiome harmony is affected by number of factors, such as change in pH, water content, transepidermal water loss (TEWL),58 and lipid content is strongly associated with some disease development. AD in particular has been shown to have elevated levels of long-chain unsaturated fatty acids and ceramide AS (a-Hydroxy fatty acid/sphingosine base) which are linked with higher abundance of propionibacteria and corynebacteria, which, in turn, are responsible for requiring outer free fatty acids (FFAs) because they do not produce fatty acids synthase, and staphylococcus (S.) aureus, respectively.59 Another sensitive risk factor regarding AD development is the filaggrin gene (FLG) encoding mutation which plays a critical role in the skin barrier function, like maintaining good level of pH regulation and epidermal hydration.60 In an effort to find the relation between skin microbiome composition and FLG and the link to AD, one study found a higher abundance of S. caprae in AD nonlesional skin patients compared to the healthy controls.61

Balanced abundance and richness of the skin microbiome is a key to healthy skin. One study tested the skin microbiome diversity of 339 AD patients; 169 of them being children aged 2-12 years.62 Microbiome diversity reduced significantly in case of methicillin-sensitive S. aureus (MSSA), and more reduction was encountered with methicillin-resistant S. aureus (MRSA) colonisation. Streptococcus and propionibacterium, for example, had a dramatic decrease in samples with MSSA and MRSA high abundance compared with AD samples with no S. aureus detection. Moreover, skin is the first line of defence against external agents, including skin microbiome, which helps in the development of the immune system. Cytokine production by the skin T cells responded weakly to inflammation in germ-free mice compared to normal mice.57,63,64

 

Possible microbial mechanisms of microbiosis in AD

 

There are three factors that contribute to skin microbiosis and AS development, which are skin barrier, immune system and pathogen.65 Disruption of the bacterial environment on the skin has been noticed to influence the change of the bacterial composition of an AD case. One of the factors that have a role in skin microbiome disruption is pH. S. aureus growth, for example, is promoted by the rising level of pH on the skin surface.66,67 Another factor is that certain surface markers of keratinocytes basal cells in the skin, such as fibronectin and fibrinogen, are found expressed on the cell surface when exposed directly to microbes, and this expression promotes S. aureus because it binds to fibronectin-binding proteins (FnBPs).68,69

Disrupting the harmony of the skin microbiome can be attributed to immunological factors. One of the most important defence lines in the skin is antimicrobial peptides (AMPs). It has cathelicidin and beta-defensins (DEFBs) types which have an essential role in fighting off pathogenic microbes, such as S. aureus.70,71 The reduction of  AMP expression has been associated with the development of AD lesions.72 AMP stimulation reduction is due to the activity of T helper cells2 (Th2) cytokines which may result from allergy effect.73 Thus, this insufficient expression of AMPs would promote the growth of S. aureus.

Studies have shown the relation between some alteration upon certain bacteria and AD development and severity. One important example is S. aureus. There are two factors that S. aureus uses in its contribution to AD development and severity level.74 One factor is superantigens (SAgs) (Table),

which bind to major histocompatibility class II (MHCII) molecules on both antigen-presenting cells (APCs) and T cell receptor, making the cells more interactive without specific need for an antigen which results in T cell cytokine over-production, leading to cytotoxicity. Also, SAgs have a role in prompting immunoglobulin E (IgE) response as an allergen factor.74 The other factor that is suggested to increase the severity of AD is alpha (a)-Toxin that causes cell lysis as a result of heterodimer complex formation on the cell membrane besides being very toxic to keratinocytes cell.75,76 Similarly, corynebacterium (C.) bovis has been linked to acute AD feature due to intense Th2 cell response. However, further investigation is needed to actually link it to AD development as abnormal colonisation of C. bovis has been noted with high IgE syndrome (HIES).77 On the contrary, S. epidermidis is reported to have a protective role in the skin against S. aureus colonisation and other pathogens. Also, a study revealed support to immune system by boosting T cell efforts (IL-1).63 On top of that it has other pro-immunity activities both in vivo and in vitro, such as the protective role of AMP expansion, preventing S. aureus biofilm formation in the nasal cavity, and in the skin it can inhibit some pro-inflammatory bacteria, such as propionibacterium acnes which has a role boosting the synthesis of IL-6 and tumour necrosis factor-alpha (TNF-a).78-82

 

Gut-Skin Axis

 

To better comprehend the relation between the gut and the skin in a manner of health and diseases, immunological, metabolic and neuroendocrine pathways have to be well understood. A brief overview about the pathways and how they are related to AD is essential.2

Immunological pathway, besides the skin barrier physical factor, has been well associated with AD development.2 Especially with infants, gut microbiome alteration might have a great effect on the immune system development.83 About 70% of the immune systems are located in gastrointestinal (GI) mucosa and gut-associated lymphoid tissue (GALT) where most probiotic interaction takes place.84 Imbalance of Th1/Th2 result in Th2 cytokines production, such as IL-13, IL-5 and IL-4, which is the reason behind high IgE production which is also followed by S. aureus binding to AD skin.85

Fibres from dietary food sources can only be digested and turned into short chain fatty acids (SCFAs) by some of the gut microbiome, like akkermansia muciniphila, low-level prevalence of which is associated with inflammatory diseases, such as AD.86-88 Low level of SCFAs was associated with a group of children who had eczema compared to a non-allergic group of children where SCFAs were found to be anti-inflammatory by reducing and controlling some types of pro-inflammatory cytokine, metalloproteinases, nitric oxide expression as well as lymphocyte proliferation.89,90 Another study showed the effect of some strains of faecalibacterium prausnitzii in reducing the prevalence of bacteria responsible for high production of SCFAs. Butyrate and propionate, in particular, are producers, including faecalibacterium prausnitzii strain A2-165.87 Metabolites can possibly have either good or bad influence over the body. One study had linoleic acid and 10-hydroxy-cis-12-octadecenoic acid given to a mouse which resulted in changing their gut microbiome composition and thus increasing AD development. Another example of feeding AD mice with bifidobacterium animalis subsp. lactis LKM512 probiotic had the opposite effect as the metabolite kynurenic acid level increased and resulted in lowering the side-effect of AD, such as scratching behaviour.91

Neuroendocrine molecules are another factor added by studies related to the equation that link gut and skin microbiome to each other. Alteration of gut microbiome may influence the neurotransmitters and neuromodulators which are not only related to AD symptoms degree, but also affect the skin permeability and immune response defection which are key factors in AD development.92,93 There are direct and indirect ways gut microbiome affects skins.94 An example of the direct way is when the gut microbiome produces tryptophan and cause an itchy feeling in the skin, while gamma (g)-aminobutyric acid (GABA) produced by lactobacillus species and bifidobacterium species have repealing effect on the skin itching.92,95 On the other hand, neuroendocrine molecule levels are subjected to change by the effect of cytokines produced and altered by the microbiome composition formed in the gut. Cytokines in the bloodstream have an influence upon the brain function, stress and anxiety which have a side-effect of raising the level of cortisol that lead to gut microbiome alteration and therefore results in gut epithelium permeability and barrier function changes.92-94,96 It is all connected with each other, so each organ is linked and affect another.

 

The role of pre and probiotics as a treatment (probiotic therapy)

 

In the United States, 31.6 million people (10.1%) have some form of AD; 9.6 million (13%) of them are children aged <18 years, according to the National Eczema Association.97 In Europe, especially the northern part of it, the percentage of infants and toddlers affected by eczema is up to 23% based on the European Centre for Allergy Research Foundation (ECARF).98 One of the options for AD treatment is to give a course of pre and probiotics supplements.99 The definition of the probiotics, as stated by the Food and Agriculture Organization (FAO) and WHO in 2001, is, "living bacteria that, when administered in adequate amounts, confer a health benefit on the host".100 More studies are emerging as proof of the benefits of probiotics on preventing AD, especially in case of pregnant women and newborns or infants.101,102 Two strains of probiotics, lactobacillus (L.) rhamnosus (LGG) in combination with bifidobacterium animalis subsp lactis (BB-12), were applied to children in their late infancy, aged 8-14 months, prior to attending day-care, and it was found that there was a preventive effect on AD development, but not on other allergic diseases, sensitisation or food allergy.102 Moreover, a study found that L. rhamnosus and L. reuteri microbiome introduced to AD children helped reduce the severity by 56%.103 The other part is prebiotic, which is defined as "non-digestible food components that can promote the growth of certain bacteria in the gut". Some examples of a common prebiotics are galacto-oligosaccharide (GOS) and fructo-oligosaccharide (FOS).104 Similar impact of prebiotic as probiotic in preventing AD was reported when GOS, inulin and pectin were incorporated into the diet of 1-year-old infant who had low AD risk. The preventive effect was not observed at the age of 5 years.105,106 Prebiotic may have a health effect on the skin, including enhancing skin hydration and decreasing the levels of urine and serum phenol that are produced by gut bacteria.107,108 Unlike probiotics, prebiotics, although promising, are far less investigated and need further studies.

 

Conclusion

 

Prebiotic and probiotic supplements could be a positive treatment approach in AD cases. More studies regarding the gut-skin axis microbiome in general and diseases associated with microbiome, such as AD, are recommended.

 

Disclaimer: None.

Conflict of Interest: None.

Source of Funding: None.

 

References

 

1.      Mahdavinia M, Rasmussen HE, Botha M, Tran BTD, den Berg VJP, Sodergren E, et al. Effects of diet on the childhood gut microbiome and its implications for atopic dermatitis. J Allergy Clin Immunol. 2019; 143:1636-7 e5.

2.      Lee SY, Lee E, Park YM, Hong SJ. Microbiome in the gut-skin axis in atopic dermatitis. Allergy Asthma Immunol Res. 2018; 10:354-62.

3.      Sender R, Fuchs S, Milo R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell. 2016; 164:337-40.

4.      Alvarez Y, Glotfelty LG, Blank N, Dohnalová L, Thaiss CA. The microbiome as a circadian coordinator of metabolism. Endocrinology. 2020; 161:bqaa059.

5.      Wilson ID, Nicholson JK. Gut microbiome interactions with drug metabolism, efficacy, and toxicity. Transl Res. 2017; 179:204-22.

6.      Spanogiannopoulos P, Bess EN, Carmody RN, Turnbaugh PJ. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat Rev Microbiol. 2016;14:273.

7.      Dominguez-Bello MG, Godoy-Vitorino F, Knight R, Blaser MJ. Role of the microbiome in human development. Gut. 2019; 68:1108-14.

8.      Vemuri R, Shankar EM, Chieppa M, Eri R, Kavanagh K. Beyond just bacteria: functional biomes in the gut ecosystem including virome, mycobiome, archaeome and helminths. Microorganisms. 2020; 8:483.

9.      Robertson RC, Manges AR, Finlay BB, Prendergast AJ. The Human Microbiome and Child Growth – First 1000 Days and Beyond. Trends Microbiol. 2019; 27:131-47.

10.    Chu DM, Ma J, Prince AL, Antony KM, Seferovic MD, Aagaard KM. Maturation of the infant microbiome community structure and function across multiple body sites and in relation to mode of delivery. Nat Med. 2017; 23:314-26.

11.    Freitas AC, Chaban B, Bocking A, Rocco M, Yang S, Hill JE, et al. The vaginal microbiome of pregnant women is less rich and diverse, with lower prevalence of Mollicutes, compared to non-pregnant women. Sci Rep. 2017; 7:1-16.

12.    Vaneechoutte M. The human vaginal microbial community. Res Microbiol. 2017; 168:811-25.

13.    Reid G. Has knowledge of the vaginal microbiome altered approaches to health and disease? F1000Res. 2018; 7:460.

14.    Zhuang L, Chen H, Zhang S, Zhuang J, Li Q, Feng Z. Intestinal microbiota in early life and its implications on childhood health. Genomics Proteomics Bioinformatics. 2019; 17:13-25.

15.    Sakwinska O, Foata F, Berger B, Brüssow H, Combremont S, Mercenier A, et al. Does the maternal vaginal microbiota play a role in seeding the microbiota of neonatal gut and nose? Benef Microbes. 2017; 8:763-78.

16.    Ferretti P, Pasolli E, Tett A, Asnicar F, Gorfer V, Fedi S, et al. Mother-to-infant microbial transmission from different body sites shapes the developing infant gut microbiome. Cell Host Microbe. 2018; 24:133-45.e5.

17.    Johnson JM, Adams ED, O'Neal PV. Promoting and Protecting the Gastrointestinal Newborn Microbiome Through Breastfeeding Practices. J Perinat Neonatal Nurs. 2020; 34:222-30.

18.    Milani C, Duranti S, Bottacini F, Casey E, Turroni F, Mahony J, 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.

19.    Bokulich NA, Chung J, Battaglia T, Henderson N, Jay M, Li H, et al. Antibiotics, birth mode, and diet shape microbiome maturation during early life. Sci Transl Med. 2016; 8:343ra82-ra82.

20.    Derrien M, Alvarez AS, de Vos WM. The gut microbiota in the first decade of life. Trends Microbiol. 2019; 27:997-1010.

21.    Ku HJ, Kim YT, Lee JH. Microbiome Study of Initial Gut Microbiota from Newborn Infants to Children Reveals that Diet Determines Its Compositional Development. J Microbiol Biotechnol. 2020; 30:1067-71.

22.    Baothman OA, Zamzami MA, Taher I, Abubaker J, Abu-Farha M. The role of gut microbiota in the development of obesity and diabetes. Lipids Health Dis. 2016; 15:108.

23.    Wang M, Monaco MH, Donovan SM. Impact of early gut microbiota on immune and metabolic development and function. Semin Fetal Neonatal Med. 2016; 21:380-7.

24.    Neuman H, Forsythe P, Uzan A, Avni O, Koren O. Antibiotics in early life: dysbiosis and the damage done. FEMS Microbiol Rev. 2018; 42:489-99.

25.    Balakrishnan B, Taneja V. Microbial modulation of the gut microbiome for treating autoimmune diseases. Expert Rev Gastroenterol Hepatol. 2018; 12:985-96.

26.    Tseng CH, Wu CY. The gut microbiome in obesity. J Formos Med Assoc. 2019; 118:S3-S9.

27.    Harbison JE, Roth‐Schulze AJ, Giles LC, Tran CD, Ngui KM, Penno MA, et al. Gut microbiome dysbiosis and increased intestinal permeability in children with islet autoimmunity and type 1 diabetes: A prospective cohort study. Pediatr Diabetes. 2019; 20:574-83.

28.    Ghosh TS, Rampelli S, Jeffery IB, Santoro A, Neto M, Capri M, et al. Mediterranean diet intervention alters the gut microbiome in older people reducing frailty and improving health status: the NU-AGE 1-year dietary intervention across five European countries. Gut. 2020; 69:1218-28.

29.    Glassner KL, Abraham BP, Quigley EM. The microbiome and inflammatory bowel disease. J Allergy Clin Immunol. 2020; 145:16-27.

30.    Johnson KVA. Gut microbiome composition and diversity are related to human personality traits. Hum Microb J. 2020;15:100069.

31.    Harrison CA, Taren D. How poverty affects diet to shape the microbiota and chronic disease. Nat Rev Immunol. 2018; 18:279-87.

32.    Falony G, Vandeputte D, Caenepeel C, Vieira-Silva S, Daryoush T, Vermeire S, et al. The human microbiome in health and disease: hype or hope. Acta Clin Belg. 2019; 74:53-64.

33.    Dudek-Wicher RK, Junka A, Bartoszewicz M. The influence of antibiotics and dietary components on gut microbiota. Prz Gastroenterol. 2018; 13:85-92.

34.    McIlroy J, Ianiro G, Mukhopadhya I, Hansen R, Hold G. the gut microbiome in inflammatory bowel disease-avenues for microbial management. Aliment Pharmacol Ther. 2018; 47:26-42.

35.    De Luca F, Shoenfeld Y. The microbiome in autoimmune diseases. Clin Exp Immunol. 2019; 195:74-85.

36.    Paller AS, Kong HH, Seed P, Naik S, Scharschmidt TC, Gallo RL, et al. The microbiome in patients with atopic dermatitis. J Allergy Clin Immunol. 2019; 143:26-35.

37.    Robertson RC. The gut microbiome in child malnutrition.  Global Landscape of Nutrition Challenges in Infants and Children. 93: USA: Karger Publishers, 2020; pp-133-44.

38.    Ma N, Guo P, Zhang J, He T, Kim SW, Zhang G, et al. Nutrients mediate intestinal bacteria–mucosal immune crosstalk. Front Immunol. 2018; 9:5.

39.    Jensen EA, Young JA, Mathes SC, List EO, Carroll RK, Kuhn J, et al. Crosstalk between the growth hormone/insulin-like growth factor-1 axis and the gut microbiome: A new frontier for microbial endocrinology. Growth Horm IGF Research. 2020; 53-54:101333.

40.    Gschw4endtner S, Kang H, Thiering E, Kublik S, Fösel B, Schulz H, et al. Early life determinants induce sustainable changes in the gut microbiome of six-year-old children. Sci Rep. 2019; 9:1-9.

41.    Navarro-Tapia E, Sebastiani G, Sailer S, Toledano LA, Serra-Delgado M, García-Algar Ó, et al. Probiotic Supplementation during the Perinatal and Infant Period: Effects on gut Dysbiosis and Disease. Nutrients. 2020; 12:2243.

42.    Hollister EB, Riehle K, Luna RA, Weidler EM, Rubio-Gonzales M, Mistretta TA, et al. Structure and function of the healthy pre-adolescent pediatric gut microbiome. Microbiome. 2015; 3:36.

43.    Hourigan SK, Oliva-Hemker M. Fecal microbiota transplantation in children: a brief review. Pediatr Res. 2016; 80:2-6.

44.    Gensollen T, Blumberg RS. Correlation between early-life regulation of the immune system by microbiota and allergy development. J Allergy Clin Immunol. 2017; 139:1084-91.

45.    Zeng MY, Inohara N, Nunez G. Mechanisms of inflammation-driven bacterial dysbiosis in the gut. Mucosal Immunol. 2017; 10:18-26.

46.    Abrahamsson TR, Jakobsson HE, Andersson AF, Björkstén B, Engstrand L, Jenmalm MC. Low diversity of the gut microbiota in infants with atopic eczema. J Allergy Clin Immunol. 2012; 129:434-40.e2.

47.    Lee E, Lee SY, Kang MJ, Kim K, Won S, Kim BJ, et al. Clostridia in the gut and onset of atopic dermatitis via eosinophilic inflammation. Ann Allergy Asthma Immunol. 2016; 117:91-2.e1.

48.    Zimmermann P, Messina N, Mohn WW, Finlay BB, Curtis N. Association between the intestinal microbiota and allergic sensitization, eczema, and asthma: a systematic review. J Allergy Clin Immunol. 2019; 143:467-85.

49.    Vangay P, Ward T, Gerber JS, Knights D. Antibiotics, pediatric dysbiosis, and disease. Cell Host Microbe. 2015; 17:553-64.

50.    Yassour M, Vatanen T, Siljander H, Hämäläinen A, Härkönen T, Ryhänen S, et al. Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability. Sci Transl Med. 2016; 8: 343ra81.

51.    Shehab N, Lovegrove MC, Geller AI, Rose KO, Weidle NJ, Budnitz DS. US emergency department visits for outpatient adverse drug events, 2013-2014. JAMA. 2016; 316:2115-25.

52.    Bäckhed F, Roswall J, Peng Y, Feng Q, Jia H, Kovatcheva-Datchary P, et al. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe. 2015; 17:690-703.

53.    Palmer C, Bik EM, DiGiulio DB, Relman DA, Brown PO. Development of the human infant intestinal microbiota. PLoS Biol. 2007; 5:e177.

54.    Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, et al. Human gut microbiome viewed across age and geography. nature. 2012; 486:222-7.

55.    Rogier EW, Frantz AL, Bruno ME, Wedlund L, Cohen DA, Stromberg AJ, et al. Secretory antibodies in breast milk promote long-term intestinal homeostasis by regulating the gut microbiota and host gene expression. Proc Natl Acad Sci U S A. 2014; 111:3074-9.

56.    Byrd AL, Belkaid Y, Segre JA. The human skin microbiome. Nat Rev Microbiol. 2018; 16:143-55.

57.    Younge NE, Pérez AF, Brandon D, Seed PC. Early-life skin microbiota in hospitalized preterm and full-term infants. Microbiome. 2018; 6:98.

58.    Nagase S, Ogai K, Urai T, Shibata K, Matsubara E, Mukai K, et al. Distinct skin microbiome and skin physiological functions between bedridden older patients and healthy people: A single-center study in Japan. Front Med. 2020; 7:101.

59.    Baurecht H, Rühlemann MC, Rodríguez E, Thielking F, Harder I, Erkens AS, et al. Epidermal lipid composition, barrier integrity, and eczematous inflammation are associated with skin microbiome configuration. J Allergy Clin Immunol. 2018;14:1668-76. e16.

60.    Kim J, Kim BE, Leung DY. Pathophysiology of atopic dermatitis: clinical implications.In: Kim J, Kim BE, Leung DY, eds.  Allergy and asthma proceedings. London: OceanSide Publications, 2019.

61.    Clausen ML, Agner T, Lilje B, Edslev SM, Johannesen TB, Andersen PS. Association of Disease Severity With Skin Microbiome and Filaggrin Gene Mutations in Adult Atopic Dermatitis. JAMA Dermatol. 2018; 154:293-300.

62.    Shi B, Leung DY, Taylor PA, Li H. MRSA colonization is associated with decreased skin commensal bacteria in atopic dermatitis. J Invest Dermatol. 2018; 138:1668-71.

63.    Naik S, Bouladoux N, Wilhelm C, Molloy MJ, Salcedo R, Kastenmuller W, et al. Compartmentalized control of skin immunity by resident commensals. Science. 2012; 337:1115-9.

64.    Scharschmidt TC, Vasquez KS, Truong HA, Gearty SV, Pauli ML, Nosbaum A, et al. A wave of regulatory T cells into neonatal skin mediates tolerance to commensal microbes. Immunity. 2015; 43:1011-21.

65.    Dou J, Zeng J, Wu K, Tan W, Gao L, Lu J. Microbiosis in pathogenesis and intervention of atopic dermatitis. Int Immunopharmacol. 2019; 69:263-9.

66.    Knor T, Meholjić-Fetahović A, Mehmedagić A. Stratum corneum hydration and skin surface pH in patients with atopic dermatitis. Acta Dermatovenerol Croat. 2011; 19:242-7.

67.    van Smeden J, Bouwstra JA. Stratum corneum lipids:their role for the skin barrier function in healthy subjects and atopic dermatitis patients. Curr Probl Dermatol. 2016; 49:8-26.

68.    Bitschar K. Crosstalk of Keratinocytes with Commensals and Neutrophils shapes Staphylococcus aureus Skin Colonization (Doctoral dissertation, Eberhard Karls Universität Tübingen).

69.    Bausier HP, Pietrocola G, Foster TJ, Speziale P, Dufrêne YF. Fibrinogen activates the capture of human plasminogen by staphylococcal fibronectin-binding proteins. MBio. 2017; 8:e01067-17.

70.    Dean SN, Bishop BM, Van Hoek ML. Natural and synthetic cathelicidin peptides with anti-microbial and anti-biofilm activity against Staphylococcus aureus. BMC Microbiol. 2011; 11:114.

71.    Harder J, Bartels J, Christophers E, Schröder JM. Isolation and characterization of human β-defensin-3, a novel human inducible peptide antibiotic. J Biol Chem. 2001; 276:5707-13.

72.    Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Eng J Med. 2002; 347:1151-60.

73.    Nomura I, Goleva E, Howell MD, Hamid QA, Ong PY, Hall CF, et al. Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J Immunol. 2003; 171:3262-9.

74.    Arad G, Levy R, Nasie I, Hillman D, Rotfogel Z, Barash U, et al. Binding of superantigen toxins into the CD28 homodimer interface is essential for induction of cytokine genes that mediate lethal shock. PLoS Biol. 2011; 9:e1001149.

75.    Bantel H, Sinha B, Domschke W, Peters G, Schulze-Osthoff K, Jänicke RU. α-Toxin is a mediator of Staphylococcus aureus–induced cell death and activates caspases via the intrinsic death pathway independently of death receptor signaling. J Cell Biol. 2001; 155:637-48.

76.    Geoghegan JA, Irvine AD, Foster TJ. Staphylococcus aureus and atopic dermatitis: a complex and evolving relationship. Trends Microbiol. 2018; 26:484-97.

77.    Kobayashi T, Glatz M, Horiuchi K, Kawasaki H, Akiyama H, Kaplan DH, et al. Dysbiosis and Staphylococcus aureus colonization drives inflammation in atopic dermatitis. Immunity. 2015; 42:756-66.

78.    Iwase T, Uehara Y, Shinji H, Tajima A, Seo H, Takada K, et al. Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization. Nature. 2010; 465:346-9.

79.    Otto M. Staphylococcus colonization of the skin and antimicrobial peptides. Expert Rev Dermatol. 2010; 5:183-95.

80.    Xia X, Li Z, Liu K, Wu Y, Jiang D, Lai Y. Staphylococcal LTA-induced miR-143 inhibits Propionibacterium acnes-mediated inflammatory response in skin. J Invest Dermatol. 2016; 136:621-30.

81.    Kumari A, Singh R. Antibiofilm activity of small molecules produced by Staphylococcus epidermidis against Staphylococcus aureus. Appl Environ Microbiol. 2020; 86:e00627-20.

82.    Pastar I, O’Neill K, Padula L, Head CR, Burgess JL, Chen V, et al. Staphylococcus epidermidis boosts innate immune response by activation of Gamma Delta T cells and induction of Perforin-2 in human skin. Front Immunol. 2020;11.

83.    Lee MJ, Kang MJ, Lee SY, Lee E, Kim K, Won S, et al. Perturbations of gut microbiome genes in infants with atopic dermatitis according to feeding type. J Allergy Clin Immunol. 2018; 141:1310-9.

84.    Rangan KJ, Hang HC. Biochemical mechanisms of pathogen restriction by intestinal bacteria. Trends Biochem Sci. 2017; 42:887-98.

85.    Huang YJ, Marsland BJ, Bunyavanich S, O'Mahony L, Leung DY, Muraro A, et al. The microbiome in allergic disease: current understanding and future opportunities—2017 PRACTALL document of the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergy and Clinical Immunology. J Allergy Clin Immunol. 2017; 139:1099-110.

86.    Reichardt N, Duncan SH, Young P, Belenguer A, Leitch CM, Scott KP, et al. Phylogenetic distribution of three pathways for propionate production within the human gut microbiota. ISME J. 2014; 8:1323-35.

87.    Song H, Yoo Y, Hwang J, Na YC, Kim HS. Faecalibacterium prausnitzii subspecies–level dysbiosis in the human gut microbiome underlying atopic dermatitis. J Allergy Clin Immunol. 2016; 137:852-60.

88.    Thorburn AN, Macia L, Mackay CR. Diet, metabolites, and “western-lifestyle” inflammatory Curr Opin Clin Nutr Metab Care. 2012; 15:474-9. diseases. Immunity. 2014; 40:833-42.

89.    Leonel AJ, Alvarez-Leite JI. Butyrate: implications for intestinal function.

90.    Kim HK, Rutten NBMM, van der Vaart BI, Niers LEM, Choi YH, Rijkers GT, et al. Probiotic supplementation influences faecal short chain fatty acids in infants at high risk for eczema. Benef Microbes. 2015; 6:783-90.

91.    Matsumoto M, Ebata T, Hirooka J, Hosoya R, Inoue N, Itami S, et al. Antipruritic effects of the probiotic strain LKM512 in adults with atopic dermatitis. Ann Allergy Asthma Immunol. 2014; 113:209-16. e7.

92.    Jin UH, Lee SO, Sridharan G, Lee K, Davidson LA, Jayaraman A, et al. Microbiome-derived tryptophan metabolites and their aryl hydrocarbon receptor-dependent agonist and antagonist activities. Molecular Pharmacol. 2014; 85:777-88.

93.    Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012; 13:701-12.

94.    Yokoyama S, Hiramoto K, Koyama M, Ooi K. Impairment of skin barrier function via cholinergic signal transduction in a dextran sulphate sodium‐induced colitis mouse model. Exp Dermatol. 2015; 24:779-84.

95.    Akiyama T, Carstens MI, Carstens E. Transmitters and pathways mediating inhibition of spinal itch-signaling neurons by scratching and other counterstimuli. PloS One. 2011; 6:e22665.

96.    O'Neill CA, Monteleone G, McLaughlin JT, Paus R. The gut‐skin axis in health and disease: A paradigm with therapeutic implications. Bioessays. 2016; 38:1167-76.

97.    Association NE. Eczema Stats. [Online] [Cited 2020 May 02]. Available from: URL: https://nationaleczema.org/research/eczema-facts/.

98. Zuberbier PDmDhcT. Atopic Dermatitis [Online] 2017 [Cited 2020 February 09]. Available from: URL: https://www.ecarf.org/en/information-portal/allergicdiseases/ atopic-dermatitis/.

99. Rather IA, Bajpai VK, Kumar S, Lim J, Paek WK, Park YH. Probiotics and atopic dermatitis: an overview. Front Microbiol. 2016; 7:507.

100. Hotel ACP, Cordoba A. Health and nutritional properties of probiotics in food including powder milk with live lactic acid bacteria. Prevention. 2001; 5:1-10.

101. Pelucchi C, Chatenoud L, Turati F, Galeone C, Moja L, Bach JF, et al. Probiotics supplementation during pregnancy or infancy for the prevention of atopic dermatitis: a meta-analysis. Epidemiology. 2012; 23:402-14.

102. Cuello-Garcia CA, Brożek JL, Fiocchi A, Pawankar R, Yepes-Nuñez JJ, Terracciano L, et al. Probiotics for the prevention of allergy: a systematic review and meta-analysis of randomized controlled trials. J Allergy Clin Immunol. 2015; 136:952-61.

103. Rosenfeldt V, Benfeldt E, Valerius NH, Pærregaard A, Michaelsen KF. Effect of probiotics on gastrointestinal symptoms and small intestinal permeability in children with atopic dermatitis. J Pediatr. 2004; 145:612-6.

104. Cabridain C, Aubert H, Kaeffer B, Badon V, Boivin M, Dochez V, et al. Effectiveness of an antenatal maternal supplementation with prebiotics for preventing atopic dermatitis in high-risk children (the PREGRALL study): protocol for a randomised controlled trial. BMJ Open. 2019; 9:e024974.

105. Grüber C, Van Stuijvenberg M, Mosca F, Moro G, Chirico G, Braegger CP, et al. Reduced occurrence of early atopic dermatitis because of immunoactive prebiotics among low-atopy-risk infants. J Allergy Clin Immunol. 2010; 126:791-7.

106. Grüber C, Van Stuivenberg M, Mosca F, Moro G, Chirico G, Braegger CP, et al. Immunoactive prebiotics transiently prevent occurrence of early atopic dermatitis among low-atopy-risk infants. J Allergy Clin Immunol. 2015; 136:1696-8. e1.

107. Kano M, Masuoka N, Kaga C, Sugimoto S, Iizuka R, Manabe K, et al. Consecutive intake of fermented milk containing Bifidobacterium breve strain Yakult and galacto-oligosaccharides benefits skin condition in healthy adult women. Biosci Microbiota Food Health. 2013; 32:33-9.

108. Mori N, Kano M, Masuoka N, Konno T, Suzuki Y, Miyazaki K, et al. Effect of probiotic and prebiotic fermented milk on skin and intestinal conditions in healthy young female students. Biosci Microbiota Food Health. 2016; 35:2015-022.

 

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