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The microbiome of the gut and skin can impact one another in health and disease. Numerous dermatologic disorders can be traced to gastrointestinal etiologic origins.1 Incorporating discussion of the latest findings on the cutaneous and gut microbiome expands our understanding of the origin of dermatologic disease. In this column, the focus is on the most common cutaneous conditions in which the skin microbiome is believed to play an important role, but the gut microbiome also has effects on the skin microbiome that are just being elucidated. Although we do not yet know enough to give our patients definitive advice about probiotics, the knowledge in this field is rapidly expanding and is an exciting area to watch. Certainly, everything applied to the skin or ingested in the diet plays a role in the skin and gut microbiome. Therefore, the savvy dermatologist understands that personal care products, including cosmeceuticals, will affect the microbiome. At this point, we do not yet know what is beneficial, but we do know that diversity of organisms is important and is the preferred state as compared to having fewer types of organisms on the skin.

Dr. Leslie S. Baumann, a dermatologist, researcher, author, and entrepreneur who practices in Miami.
Dr. Leslie S. Baumann

Acne

Acne has long been known to have a multifactorial etiologic pathway. It is increasingly thought that understanding the role of the skin (and possibly gut) microbiome in acne pathophysiology may lead to enhanced treatments.2 New gene sequencing technologies, particularly those based on recA and tly loci, are teaching us more about the anaerobic bacterium Propionibacterium acnes (now called Cutibacterium acnes).3

In 2017, Dréno et al. studied the skin microbiota in 26 subjects with mild to moderate acne. The microflora were characterized using a high‐throughput sequencing approach that targets a portion of the bacterial 16S rRNA gene. The samples were obtained before and after 28 days of treatment with erythromycin 4% or a cosmeceutical containing lipohydroxy acid, salicylic acid, linoleic acid, niacinamide, piroctone olamine, a ceramide, and thermal spring water. Upon conclusion of the study, Actinobacteria were reduced in both groups while staphylococci were reduced only in the dermocosmetic group.4 The interesting point of this study was that the cosmeceutical had a greater impact on staphylococci than did topical erythromycin, demonstrating that personal care products can have profound effects on the microbiome.

Early in 2018, Kelhälä et al. compared the impact of the systemic acne treatments isotretinoin and lymecycline on cutaneous microbiota in the cheeks, back, and axillae of mild to moderate acne patients using gene sequencing. They found that acne severity positively correlated with Propionibacterium acnes levels. P. acnes levels were decreased by both treatments, but isotretinoin resulted in a greater decrease. Increased microbiome diversity was seen on the cheek and back in all treated subjects, but diversity was highest in those treated with isotretinoin.5 The authors postulated that the diversity resulted from a decrease in P. acnes levels. To learn more about what to tell your patients about acne and the microbiome, read my blog


 

 

 

Atopic dermatitis

Atopic dermatitis (AD) is associated with dysbiosis of cutaneous microbiota and diminished diversity in microbial communities.6,7 There is also a robust epidemiologic relationship between the cutaneous and gut microbiomes and AD.8 Many studies have looked at the role of the microbiome in AD, including the role of Staphylococcus aureus, because it selectively colonizes the lesional skin of AD patients but is notably lacking on the skin of most healthy people.

In a 2017 literature review, Bjerre et al. found that while the data were not extensive, AD-affected skin was characterized by low bacterial diversity with S. aureus and Staphylococcus epidermidis more abundant. Also that year, Williams and Gallo reported on a prospective clinical trial in children that colonization by S. aureus occurred before the emergence of AD symptoms.9 In 2018, Clausen et al. reported on an observational case-control study of 45 adult healthy controls and 56 adult patients with AD between January and June 2015 to evaluate skin and nasal microbiome diversity and composition and to elucidate the relationship between disease severity and filaggrin gene mutations in AD patients. Next-generation sequencing targeting 16S ribosomal RNA was used to show that microbiome diversity was lower in the lesional skin, nonlesional skin, and nose in AD patients compared with controls. Such diversity was also found to be inversely correlated with disease severity, and microbiome composition in nonlesional AD skin was found to be associated with filaggrin gene mutations. The authors concluded that host genetics and skin microbiome may be connected in AD.10

However, the role of S. aureus in AD and the effect of its presence on microbiome diversity is still unclear. Marrs and Flohr note that the eradication of S. aureus does not appear to account for improvement in AD and increase in bacterial diversity after the use of antimicrobial and anti-inflammatory therapy.11
 

Rosacea

Rosacea is a chronic inflammatory skin condition long associated with Demodex mites (Demodex folliculorum and Demodex brevis).12 In rosacea-affected skin, Demodex mites are found to occur in greater density than in unaffected skin.13 Other microbiota-linked alterations have been detected on the skin and in the small intestines in cases of rosacea.14 One twin study showed that increased levels of Gordonia correlated with rosacea severity.15 A study in Korean women with rosacea demonstrated a reduction of Peptococcaceae, Methanobrevibacter, Slackia, Coprobacillus, Citrobacter (genus), and Desulfovibrio and an increased amount of Acidaminococcus, Megasphaera, and Lactobacillales in women with rosacea.16

Other studies have shown that treating bacterial overgrowth in the gut can improve rosacea.17 In my favorite recent study,18 complement appeared to affect microbial diversity and richness of the skin and the gut in mice, demonstrating that the immune system plays an important role in rosacea and the skin and gut microbiome. Certainly we have a lot to learn before we can make specific recommendations, but I feel certain that this area of research will unlock some of the mysteries of rosacea. To read more about what to tell your patients about the microbiome and rosacea visit the blog at STSfranchise.com.

 

 

Conclusion

In recent years, it has become increasingly clear that the cutaneous microbiome is a factor in various skin disorders. Some authors such as Egert et al. advocate the use of pre- and probiotics, including topical microbiome transplantation therapies, to treat acne, rosacea, and AD.14 I believe that we do not yet have enough data to support this approach or predict which ones may be effective. Stay tuned for more developments.



Dr. Baumann is a private practice dermatologist, researcher, author and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at dermnews@mededge.com.

References

1. O’Neill CA et al. Bioessays. 2016 Nov;38(11):1167-76.

2. Rocha MA et al. Arch Dermatol Res. 2018 Apr;310(3):181-5.

3. McDowell A. Microorganisms. 2017 Dec 21. doi: 10.3390/microorganisms6010001.

4. Dréno B et al. Exp Dermatol. 2017 Sep;26(9):798-803.

5. Kelhälä HL et al. Exp Dermatol. 2018 Jan;27(1):30-6.

6. Rodrigues Hoffmann A. Vet Dermatol. 2017 Feb;28(1):60-e15.

7. Bjerre RD et al. Br J Dermatol. 2017 Nov;177(5):1272-8.

8. Knaysi G et al. Curr Allergy Asthma Rep. 2017 Jan;17(1):7.

9. Williams MR et al. J Invest Dermatol. 2017 Dec;137(12):2460-1.

10. Clausen ML et al. JAMA Dermatol. 2018 Mar 1;154(3):293-300.

11. Marrs T et al. Br J Dermatol. 2016 Oct;175 Suppl 2:13-18.

12. Patra V et al. Front Microbiol. 2016 Aug 10. doi: 10.3389/fmicb.2016.01235.

13. Igawa S et al. Transl Res. 2017 Jun;184:68-76.

14. Egert Met al. Clin Pharmacol Ther. 2017;102(1):62-9.

15. Zaidi AK et al. Exp Dermatol. 2018 Mar;27(3):295-8.

16. Nam, JH et al. Exp Dermatol. 2018 Jan;27(1):37-42.

17. Porubsky CF et al. “The Role of Probiotics in Acne and Rosacea,” IntechOpen. 2018 Nov 5. doi: 10.5772/intechopen.79044.

18. Chehoud C et al. Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):15061-6.

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Topics
Sections

The microbiome of the gut and skin can impact one another in health and disease. Numerous dermatologic disorders can be traced to gastrointestinal etiologic origins.1 Incorporating discussion of the latest findings on the cutaneous and gut microbiome expands our understanding of the origin of dermatologic disease. In this column, the focus is on the most common cutaneous conditions in which the skin microbiome is believed to play an important role, but the gut microbiome also has effects on the skin microbiome that are just being elucidated. Although we do not yet know enough to give our patients definitive advice about probiotics, the knowledge in this field is rapidly expanding and is an exciting area to watch. Certainly, everything applied to the skin or ingested in the diet plays a role in the skin and gut microbiome. Therefore, the savvy dermatologist understands that personal care products, including cosmeceuticals, will affect the microbiome. At this point, we do not yet know what is beneficial, but we do know that diversity of organisms is important and is the preferred state as compared to having fewer types of organisms on the skin.

Dr. Leslie S. Baumann, a dermatologist, researcher, author, and entrepreneur who practices in Miami.
Dr. Leslie S. Baumann

Acne

Acne has long been known to have a multifactorial etiologic pathway. It is increasingly thought that understanding the role of the skin (and possibly gut) microbiome in acne pathophysiology may lead to enhanced treatments.2 New gene sequencing technologies, particularly those based on recA and tly loci, are teaching us more about the anaerobic bacterium Propionibacterium acnes (now called Cutibacterium acnes).3

In 2017, Dréno et al. studied the skin microbiota in 26 subjects with mild to moderate acne. The microflora were characterized using a high‐throughput sequencing approach that targets a portion of the bacterial 16S rRNA gene. The samples were obtained before and after 28 days of treatment with erythromycin 4% or a cosmeceutical containing lipohydroxy acid, salicylic acid, linoleic acid, niacinamide, piroctone olamine, a ceramide, and thermal spring water. Upon conclusion of the study, Actinobacteria were reduced in both groups while staphylococci were reduced only in the dermocosmetic group.4 The interesting point of this study was that the cosmeceutical had a greater impact on staphylococci than did topical erythromycin, demonstrating that personal care products can have profound effects on the microbiome.

Early in 2018, Kelhälä et al. compared the impact of the systemic acne treatments isotretinoin and lymecycline on cutaneous microbiota in the cheeks, back, and axillae of mild to moderate acne patients using gene sequencing. They found that acne severity positively correlated with Propionibacterium acnes levels. P. acnes levels were decreased by both treatments, but isotretinoin resulted in a greater decrease. Increased microbiome diversity was seen on the cheek and back in all treated subjects, but diversity was highest in those treated with isotretinoin.5 The authors postulated that the diversity resulted from a decrease in P. acnes levels. To learn more about what to tell your patients about acne and the microbiome, read my blog


 

 

 

Atopic dermatitis

Atopic dermatitis (AD) is associated with dysbiosis of cutaneous microbiota and diminished diversity in microbial communities.6,7 There is also a robust epidemiologic relationship between the cutaneous and gut microbiomes and AD.8 Many studies have looked at the role of the microbiome in AD, including the role of Staphylococcus aureus, because it selectively colonizes the lesional skin of AD patients but is notably lacking on the skin of most healthy people.

In a 2017 literature review, Bjerre et al. found that while the data were not extensive, AD-affected skin was characterized by low bacterial diversity with S. aureus and Staphylococcus epidermidis more abundant. Also that year, Williams and Gallo reported on a prospective clinical trial in children that colonization by S. aureus occurred before the emergence of AD symptoms.9 In 2018, Clausen et al. reported on an observational case-control study of 45 adult healthy controls and 56 adult patients with AD between January and June 2015 to evaluate skin and nasal microbiome diversity and composition and to elucidate the relationship between disease severity and filaggrin gene mutations in AD patients. Next-generation sequencing targeting 16S ribosomal RNA was used to show that microbiome diversity was lower in the lesional skin, nonlesional skin, and nose in AD patients compared with controls. Such diversity was also found to be inversely correlated with disease severity, and microbiome composition in nonlesional AD skin was found to be associated with filaggrin gene mutations. The authors concluded that host genetics and skin microbiome may be connected in AD.10

However, the role of S. aureus in AD and the effect of its presence on microbiome diversity is still unclear. Marrs and Flohr note that the eradication of S. aureus does not appear to account for improvement in AD and increase in bacterial diversity after the use of antimicrobial and anti-inflammatory therapy.11
 

Rosacea

Rosacea is a chronic inflammatory skin condition long associated with Demodex mites (Demodex folliculorum and Demodex brevis).12 In rosacea-affected skin, Demodex mites are found to occur in greater density than in unaffected skin.13 Other microbiota-linked alterations have been detected on the skin and in the small intestines in cases of rosacea.14 One twin study showed that increased levels of Gordonia correlated with rosacea severity.15 A study in Korean women with rosacea demonstrated a reduction of Peptococcaceae, Methanobrevibacter, Slackia, Coprobacillus, Citrobacter (genus), and Desulfovibrio and an increased amount of Acidaminococcus, Megasphaera, and Lactobacillales in women with rosacea.16

Other studies have shown that treating bacterial overgrowth in the gut can improve rosacea.17 In my favorite recent study,18 complement appeared to affect microbial diversity and richness of the skin and the gut in mice, demonstrating that the immune system plays an important role in rosacea and the skin and gut microbiome. Certainly we have a lot to learn before we can make specific recommendations, but I feel certain that this area of research will unlock some of the mysteries of rosacea. To read more about what to tell your patients about the microbiome and rosacea visit the blog at STSfranchise.com.

 

 

Conclusion

In recent years, it has become increasingly clear that the cutaneous microbiome is a factor in various skin disorders. Some authors such as Egert et al. advocate the use of pre- and probiotics, including topical microbiome transplantation therapies, to treat acne, rosacea, and AD.14 I believe that we do not yet have enough data to support this approach or predict which ones may be effective. Stay tuned for more developments.



Dr. Baumann is a private practice dermatologist, researcher, author and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at dermnews@mededge.com.

References

1. O’Neill CA et al. Bioessays. 2016 Nov;38(11):1167-76.

2. Rocha MA et al. Arch Dermatol Res. 2018 Apr;310(3):181-5.

3. McDowell A. Microorganisms. 2017 Dec 21. doi: 10.3390/microorganisms6010001.

4. Dréno B et al. Exp Dermatol. 2017 Sep;26(9):798-803.

5. Kelhälä HL et al. Exp Dermatol. 2018 Jan;27(1):30-6.

6. Rodrigues Hoffmann A. Vet Dermatol. 2017 Feb;28(1):60-e15.

7. Bjerre RD et al. Br J Dermatol. 2017 Nov;177(5):1272-8.

8. Knaysi G et al. Curr Allergy Asthma Rep. 2017 Jan;17(1):7.

9. Williams MR et al. J Invest Dermatol. 2017 Dec;137(12):2460-1.

10. Clausen ML et al. JAMA Dermatol. 2018 Mar 1;154(3):293-300.

11. Marrs T et al. Br J Dermatol. 2016 Oct;175 Suppl 2:13-18.

12. Patra V et al. Front Microbiol. 2016 Aug 10. doi: 10.3389/fmicb.2016.01235.

13. Igawa S et al. Transl Res. 2017 Jun;184:68-76.

14. Egert Met al. Clin Pharmacol Ther. 2017;102(1):62-9.

15. Zaidi AK et al. Exp Dermatol. 2018 Mar;27(3):295-8.

16. Nam, JH et al. Exp Dermatol. 2018 Jan;27(1):37-42.

17. Porubsky CF et al. “The Role of Probiotics in Acne and Rosacea,” IntechOpen. 2018 Nov 5. doi: 10.5772/intechopen.79044.

18. Chehoud C et al. Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):15061-6.

The microbiome of the gut and skin can impact one another in health and disease. Numerous dermatologic disorders can be traced to gastrointestinal etiologic origins.1 Incorporating discussion of the latest findings on the cutaneous and gut microbiome expands our understanding of the origin of dermatologic disease. In this column, the focus is on the most common cutaneous conditions in which the skin microbiome is believed to play an important role, but the gut microbiome also has effects on the skin microbiome that are just being elucidated. Although we do not yet know enough to give our patients definitive advice about probiotics, the knowledge in this field is rapidly expanding and is an exciting area to watch. Certainly, everything applied to the skin or ingested in the diet plays a role in the skin and gut microbiome. Therefore, the savvy dermatologist understands that personal care products, including cosmeceuticals, will affect the microbiome. At this point, we do not yet know what is beneficial, but we do know that diversity of organisms is important and is the preferred state as compared to having fewer types of organisms on the skin.

Dr. Leslie S. Baumann, a dermatologist, researcher, author, and entrepreneur who practices in Miami.
Dr. Leslie S. Baumann

Acne

Acne has long been known to have a multifactorial etiologic pathway. It is increasingly thought that understanding the role of the skin (and possibly gut) microbiome in acne pathophysiology may lead to enhanced treatments.2 New gene sequencing technologies, particularly those based on recA and tly loci, are teaching us more about the anaerobic bacterium Propionibacterium acnes (now called Cutibacterium acnes).3

In 2017, Dréno et al. studied the skin microbiota in 26 subjects with mild to moderate acne. The microflora were characterized using a high‐throughput sequencing approach that targets a portion of the bacterial 16S rRNA gene. The samples were obtained before and after 28 days of treatment with erythromycin 4% or a cosmeceutical containing lipohydroxy acid, salicylic acid, linoleic acid, niacinamide, piroctone olamine, a ceramide, and thermal spring water. Upon conclusion of the study, Actinobacteria were reduced in both groups while staphylococci were reduced only in the dermocosmetic group.4 The interesting point of this study was that the cosmeceutical had a greater impact on staphylococci than did topical erythromycin, demonstrating that personal care products can have profound effects on the microbiome.

Early in 2018, Kelhälä et al. compared the impact of the systemic acne treatments isotretinoin and lymecycline on cutaneous microbiota in the cheeks, back, and axillae of mild to moderate acne patients using gene sequencing. They found that acne severity positively correlated with Propionibacterium acnes levels. P. acnes levels were decreased by both treatments, but isotretinoin resulted in a greater decrease. Increased microbiome diversity was seen on the cheek and back in all treated subjects, but diversity was highest in those treated with isotretinoin.5 The authors postulated that the diversity resulted from a decrease in P. acnes levels. To learn more about what to tell your patients about acne and the microbiome, read my blog


 

 

 

Atopic dermatitis

Atopic dermatitis (AD) is associated with dysbiosis of cutaneous microbiota and diminished diversity in microbial communities.6,7 There is also a robust epidemiologic relationship between the cutaneous and gut microbiomes and AD.8 Many studies have looked at the role of the microbiome in AD, including the role of Staphylococcus aureus, because it selectively colonizes the lesional skin of AD patients but is notably lacking on the skin of most healthy people.

In a 2017 literature review, Bjerre et al. found that while the data were not extensive, AD-affected skin was characterized by low bacterial diversity with S. aureus and Staphylococcus epidermidis more abundant. Also that year, Williams and Gallo reported on a prospective clinical trial in children that colonization by S. aureus occurred before the emergence of AD symptoms.9 In 2018, Clausen et al. reported on an observational case-control study of 45 adult healthy controls and 56 adult patients with AD between January and June 2015 to evaluate skin and nasal microbiome diversity and composition and to elucidate the relationship between disease severity and filaggrin gene mutations in AD patients. Next-generation sequencing targeting 16S ribosomal RNA was used to show that microbiome diversity was lower in the lesional skin, nonlesional skin, and nose in AD patients compared with controls. Such diversity was also found to be inversely correlated with disease severity, and microbiome composition in nonlesional AD skin was found to be associated with filaggrin gene mutations. The authors concluded that host genetics and skin microbiome may be connected in AD.10

However, the role of S. aureus in AD and the effect of its presence on microbiome diversity is still unclear. Marrs and Flohr note that the eradication of S. aureus does not appear to account for improvement in AD and increase in bacterial diversity after the use of antimicrobial and anti-inflammatory therapy.11
 

Rosacea

Rosacea is a chronic inflammatory skin condition long associated with Demodex mites (Demodex folliculorum and Demodex brevis).12 In rosacea-affected skin, Demodex mites are found to occur in greater density than in unaffected skin.13 Other microbiota-linked alterations have been detected on the skin and in the small intestines in cases of rosacea.14 One twin study showed that increased levels of Gordonia correlated with rosacea severity.15 A study in Korean women with rosacea demonstrated a reduction of Peptococcaceae, Methanobrevibacter, Slackia, Coprobacillus, Citrobacter (genus), and Desulfovibrio and an increased amount of Acidaminococcus, Megasphaera, and Lactobacillales in women with rosacea.16

Other studies have shown that treating bacterial overgrowth in the gut can improve rosacea.17 In my favorite recent study,18 complement appeared to affect microbial diversity and richness of the skin and the gut in mice, demonstrating that the immune system plays an important role in rosacea and the skin and gut microbiome. Certainly we have a lot to learn before we can make specific recommendations, but I feel certain that this area of research will unlock some of the mysteries of rosacea. To read more about what to tell your patients about the microbiome and rosacea visit the blog at STSfranchise.com.

 

 

Conclusion

In recent years, it has become increasingly clear that the cutaneous microbiome is a factor in various skin disorders. Some authors such as Egert et al. advocate the use of pre- and probiotics, including topical microbiome transplantation therapies, to treat acne, rosacea, and AD.14 I believe that we do not yet have enough data to support this approach or predict which ones may be effective. Stay tuned for more developments.



Dr. Baumann is a private practice dermatologist, researcher, author and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at dermnews@mededge.com.

References

1. O’Neill CA et al. Bioessays. 2016 Nov;38(11):1167-76.

2. Rocha MA et al. Arch Dermatol Res. 2018 Apr;310(3):181-5.

3. McDowell A. Microorganisms. 2017 Dec 21. doi: 10.3390/microorganisms6010001.

4. Dréno B et al. Exp Dermatol. 2017 Sep;26(9):798-803.

5. Kelhälä HL et al. Exp Dermatol. 2018 Jan;27(1):30-6.

6. Rodrigues Hoffmann A. Vet Dermatol. 2017 Feb;28(1):60-e15.

7. Bjerre RD et al. Br J Dermatol. 2017 Nov;177(5):1272-8.

8. Knaysi G et al. Curr Allergy Asthma Rep. 2017 Jan;17(1):7.

9. Williams MR et al. J Invest Dermatol. 2017 Dec;137(12):2460-1.

10. Clausen ML et al. JAMA Dermatol. 2018 Mar 1;154(3):293-300.

11. Marrs T et al. Br J Dermatol. 2016 Oct;175 Suppl 2:13-18.

12. Patra V et al. Front Microbiol. 2016 Aug 10. doi: 10.3389/fmicb.2016.01235.

13. Igawa S et al. Transl Res. 2017 Jun;184:68-76.

14. Egert Met al. Clin Pharmacol Ther. 2017;102(1):62-9.

15. Zaidi AK et al. Exp Dermatol. 2018 Mar;27(3):295-8.

16. Nam, JH et al. Exp Dermatol. 2018 Jan;27(1):37-42.

17. Porubsky CF et al. “The Role of Probiotics in Acne and Rosacea,” IntechOpen. 2018 Nov 5. doi: 10.5772/intechopen.79044.

18. Chehoud C et al. Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):15061-6.

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