Allergy Asthma Immunol Res.  2020 Jan;12(1):137-148. 10.4168/aair.2020.12.1.137.

Antibiotics-Induced Dysbiosis of Intestinal Microbiota Aggravates Atopic Dermatitis in Mice by Altered Short-Chain Fatty Acids

• Kim HJ
• Lee SH
• Hong SJ

• KMID: 2462578
• DOI: http://doi.org/10.4168/aair.2020.12.1.137

Abstract

PURPOSE
Alterations in the intestinal microbiota in early life affects the development of atopic dermatitis (AD) in humans. This study aimed to further investigate the effects of gut dysbiosis in early life in an ovalbumin (OVA)-induced mouse model of AD.
METHODS
The AD mouse model was developed by serial OVA sensitization and mice were treated with an antibiotic cocktail in their drinking water for 2 weeks before primary sensitization. Probiotics (Lactobacillus rhamnosus, 1 × 10⁹ CFU) or 100 µL of fresh fecal supernatant were orally administered daily from 1 week before the first sensitization until the end of the study.
RESULTS
The AD mice which received antibiotics had significantly aggravated phenotypes, including clinical score, transepidermal water loss, and histopathology, compared to those treated with healthy feces or probiotics. Total systemic immunoglobulin E production and skin interleukin (IL) 4 levels were significantly increased in the antibiotic-treated mice compared to the other groups. Antibiotic treatment also increased the levels of IL17 and group 3 innate lymphoid cells (ILC3) in the gut and significantly suppressed the production of short-chain fatty acids (SCFAs) and decreased the number FOXP3⁺ cells.
CONCLUSIONS
Our results suggest that the status of the gut microbiota in early life in the mouse may play a crucial role in AD development through intestinal SCFA production through regulate the numbers of CD4⁺IL17⁺/CD4⁺FOXP3⁺ regulatory T cells and ILC3s.

Keyword

Atopic dermatitis; cytokines; dysbiosis; fatty acids; intestines; microbiota; probiotics

MeSH Terms

Animals
Anti-Bacterial Agents
Cytokines
Dermatitis, Atopic*
Drinking Water
Dysbiosis*
Fatty Acids
Fatty Acids, Volatile*
Feces
Gastrointestinal Microbiome*
Humans
Immunoglobulin E
Immunoglobulins
Interleukins
Intestines
Lymphocytes
Mice*
Microbiota
Ovalbumin
Ovum
Phenotype
Probiotics
Skin
T-Lymphocytes, Regulatory
Water
Anti-Bacterial Agents
Cytokines
Drinking Water
Fatty Acids
Fatty Acids, Volatile
Immunoglobulin E
Immunoglobulins
Interleukins
Ovalbumin
Water

Figure

• 

  Fig. 1 Oral antibiotic administration aggravates clinical signs in a mouse model of AD. (A) Clinical features (erythema and swelling) in the AD mice treated as indicated. (B) TEWL levels. (C) Estimated clinical scores in AD mice treated as indicated. PBS, phosphate-buffered saline; OVA, ovalbumin; AT, oral antibiotic administration; TEWL, transepidermal water loss; AFT, antibiotics + orally administered fecal matter; APT, antibiotics + oral probiotics; AD, atopic dermatitis. *P < 0.05, †P < 0.01, and ‡P < 0.001 by analysis of variance with Tukey's multiple comparison test.

• 

  Fig. 2 Oral antibiotic treatment increases the systemic immune allergic response and Th2 cytokine levels in the skin of AD mice. (A) Total IgE levels in the AD mice treated as indicated. (B) Measurement of IL4 expression in the skin of treated AD mice by real-time polymerase chain reaction. IgE, immunoglobulin E; PBS, phosphate-buffered saline; OVA, ovalbumin; AT, oral antibiotic administration; AFT, antibiotics + fecal administration orally; APT, antibiotics + oral probiotics; IL4, interleukin 4; AD, atopic dermatitis. *P < 0.05, †P < 0.01, and ‡P < 0.001 by analysis of variance with Tukey's multiple comparison test.

• 

  Fig. 3 Oral antibiotic treatment suppresses the production of intestinal metabolites and SCFAs by microbiota. Gas chromatography-mass spectrometry SCFA measurements in atopic dermatitis mice treated as indicated. SCFA, short-chain fatty acid; PBS, phosphate-buffered saline; OVA, ovalbumin; AT, oral antibiotic administration; AFT, antibiotics + oral fecal administration; APT, antibiotics + oral probiotics. *P < 0.05, †P < 0.01, and ‡P < 0.001 by analysis of variance with Tukey's multiple comparison test.

• 

  Fig. 4 Oral antibiotic treatment increases IL-17+ cell-related inflammation and suppresses CD4+FOXP3+ cell levels in the gut of AD mice. (A, C) Population of CD4+IL-17+ cells in the small intestine of treated AD mice as determined by FACS. (B, D) Population of CD4+FOXP3+ cells in the small intestine of treated AD mice as determined by FACS. IL17, interleukin 17; PBS, phosphate-buffered saline; OVA, ovalbumin; AT, oral antibiotic administration; AFT, antibiotics + oral fecal administration; APT, antibiotics + oral probiotics; FACS, fluorescence-activated cell sorting; AD, atopic dermatitis. *P < 0.05 and †P < 0.01 by analysis of variance with Tukey's multiple comparison test.

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