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Pediatrics

Implication of gut microbiota in the association between infant antibiotic exposure and childhood obesity and adiposity accumulation

Abstract

Background

In animal studies early life antibiotic exposure causes metabolic abnormalities including obesity through microbiota disruption, but evidence from human studies is scarce. We examined involvement of gut microbiota in the associations between infant antibiotic exposure and childhood adiposity.

Methods

Infant antibiotic exposure in the first year of life was ascertained using parental reports during interviewer-administered questionnaires. Primary outcomes were childhood obesity [body mass index (BMI) z-score > 95th percentile] and adiposity [abdominal circumference (AC) and skinfold (triceps + subscapular (SST)) measurements] determined from ages 15–60 months. At age 24 months, when the gut microbiota are more stable, stool samples (n = 392) were collected for the gut microbiota profiling using co-abundancy networks. Associations of antibiotic exposure with obesity and adiposity (n = 1016) were assessed using multiple logistic and linear mixed effects regressions. Key bacteria associated with antibiotics exposure were identified by partial redundancy analysis and multivariate association with linear models.

Results

Antibiotic exposure was reported in 38% of study infants. In a fully adjusted model, a higher odds of obesity from 15–60 months of age was observed for any antibiotic exposure [OR(95% CI) = 1.45(1.001, 2.14)] and exposure to ≥3 courses of antibiotics [2.78(1.12, 6.87)]. For continuous adiposity indicators, any antibiotic exposure was associated with higher BMI z-score in boys [β = 0.15(0.01, 0.28)] but not girls [β = −0.04(−0.19, 0.11)] (P interaction = 0.026). Similarly, exposure to ≥3 courses of antibiotics was associated with higher AC in boys [1.15(0.05, 2.26) cm] but not girls [0.57(−1.32, 2.45) cm] (P interaction not significant). Repeated exposure to antibiotics was associated with a significant reduction (FDR-corrected P values < 0.05) in a microbial co-abundant group (CAG) represented by Eubacterium hallii, whose proportion was negatively correlated with childhood adiposity. Meanwhile, a CAG represented by Tyzzerella 4 was positively correlated with the repeated use of antibiotics and childhood adiposity.

Conclusions

Infant antibiotic exposure was associated with disruption of the gut microbiota and the higher risks of childhood obesity and increased adiposity.

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Fig. 1: Co-abundant network analysis of the child gut microbiota at 24 months and key co-abundant groups associated with the antibiotic exposure by partial redundancy analysis (partial RDA).
Fig. 2: Heatmap of key co-abundant groups (CAGs) associated with antibiotic exposure identified by the partial RDA and Spearman’s correlation between identified CAGs and the accumulation of adiposity at 24 months.

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Acknowledgements

The authors thank the GUSTO study group, which includes Allan Sheppard, Amutha Chinnadurai, Anne Eng Neo Goh, Anne Rifkin-Graboi, Anqi Qiu, Arijit Biswas, Bee Wah Lee, Birit F.P. Broekman, Boon Long Quah, Borys Shuter, Carolina Un Lam, Chai Kiat Chng, Cheryl Ngo, Choon Looi Bong, Christiani Jeyakumar Henry, Claudia Chi, Cornelia Yin Ing Chee, Yam Thiam Daniel Goh, Doris Fok, E Shyong Tai, Elaine Tham, Elaine Quah Phaik Ling, Evelyn Xiu Ling Loo, FY, Falk Mueller-Riemenschneider, George Seow Heong Yeo, Helen Chen, Heng Hao Tan, Hugo P. S. van Bever, Iliana Magiati, Inez Bik Yun Wong, Ivy Yee-Man Lau, IBMA, Jeevesh Kapur, Jenny L. Richmond, Jerry Kok Yen Chan, Joanna D. Holbrook, Joanne Yoong, Joao N. Ferreira., Jonathan Tze Liang Choo, Jonathan Y. Bernard, Joshua J. Gooley, KMG, Kenneth Kwek, KHT, Krishnamoorthy Niduvaje, Kuan Jin Lee, Leher Singh, Lieng Hsi Ling, Lin Lin Su, LWC, Lourdes Mary Daniel, LP-CS, Marielle V. Fortier, Mark Hanson, Mary Foong-Fong Chong, Mary Rauff, Mei Chien Chua, Melvin Khee-Shing Leow, Michael Meaney, MTT, NK, Ngee Lek, Oon Hoe Teoh, P. C. Wong, Paulin Tay Straughan, PDG, Pratibha Agarwal, Queenie Ling Jun Li, Rob M. van Dam, Salome A. Rebello, Seang-Mei Saw, See Ling Loy, S. Sendhil Velan, Seng Bin Ang, Shang Chee Chong, Sharon Ng, Shiao-Yng Chan, Shirong Cai, Shu-ES, Sok Bee Lim, Stella Tsotsi, Chin-Ying Stephen Hsu, Sue Anne Toh, Swee Chye Quek, Victor Samuel Rajadurai, Walter Stunkel, Wayne Cutfield, Wee Meng Han, Wei Wei Pang, Y-SC, Yin Bun Cheung, Yiong Huak Chan, YSL, and Zhongwei Huang.

Funding

This research is supported by the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC), Singapore—NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014. Additional funding is provided by the Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore. Study sponsors were not involved in the design of the study, statistical analysis and results interpretation. KMG is supported by the UK Medical Research Council (MC_UU_12011/4), National Institute for Health Research (NIHR Senior Investigator (NF-SI-0515–10042), NIHR Southampton 1000DaysPlus Global Nutrition Research Group and NIHR Southampton Biomedical Research Centre) and by the European Union (Erasmus+ Programme Early Nutrition eAcademy Southeast Asia-573651-EPP-1-2016-1-DE-EPPKA2-CBHE-JP).

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L-WC conducted statistical analysis, interpreted the data, and wrote the first draft of the paper. JX conducted the microbiota analysis, interpreted the data, and co-wrote the first draft of the paper. SES acquired antibiotic exposure data. NK and JAG generated the microbiota data and contributed to the microbiota analysis. L-WC, JX, SES, IMA, and MT-T contributed to data collection, cleaning, and analysis. PDG, KHT, LP-CS, Y-SC, FY, KMG, and YSL designed the GUSTO study. All authors critically revised and approved the final manuscript. YSL had primary responsibility for the final content.

Corresponding author

Correspondence to Yung Seng Lee.

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Conflict of interest

KMG, Y-SC, and YSL have received reimbursement for speaking at conferences sponsored by companies selling nutritional products. NK, KMG, and Y-SC are part of an academic consortium that has received research funding from Abbott Nutrition, Nestec and Danone. The other authors have no financial or personal conflict of interest to declare.

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Chen, LW., Xu, J., Soh, S.E. et al. Implication of gut microbiota in the association between infant antibiotic exposure and childhood obesity and adiposity accumulation. Int J Obes 44, 1508–1520 (2020). https://doi.org/10.1038/s41366-020-0572-0

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