Maternal smoking during pregnancy increases the risk of gut microbiome-associated childhood overweight and obesity

ABSTRACT

Childhood obesity is linked to maternal smoking during pregnancy. Gut microbiota may partially mediate this association and could be potential targets for intervention; however, its role is understudied. We included 1,592 infants from the Canadian Healthy Infants Longitudinal Development Cohort. Data on environmental exposure and lifestyle factors were collected prenatally and throughout the first three years. Weight outcomes were measured at one and three years of age. Stool samples collected at 3 and 12 months were analyzed by sequencing the V4 region of 16S rRNA to profile microbial compositions and magnetic resonance spectroscopy to quantify the metabolites. We showed that quitting smoking during pregnancy did not lower the risk of offspring being overweight. However, exclusive breastfeeding until the third month of age may alleviate these risks. We also reported that maternal smoking during pregnancy significantly increased Firmicutes abundance and diversity. We further revealed that Firmicutes diversity mediates the elevated risk of childhood overweight and obesity linked to maternal prenatal smoking. This effect possibly occurs through excessive microbial butyrate production. These findings add to the evidence that women should quit smoking before their pregnancies to prevent microbiome-mediated childhood overweight and obesity risk, and indicate the potential obesogenic role of excessive butyrate production in early life.

GRAPHICAL ABSTRACT

KEYWORDS:

• Maternal smoking
• gut microbiota
• childhood obesity
• butyrate production

Acknowledgments

The authors thank all the families who participated in this study and the entire CHILD team, which included interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. We also thank Prof. Samuel Yeung-shan Wong, Prof. Kinfai Ho and Miss. Xueqi Wu from the School of Public Health and Primary Care, the Chinese University of Hong Kong for reviewing the manuscript and providing comments and suggestions on the methodologies; Mr. Shilin Zhao from the Department of Medicine & Therapeutics, the Chinese University of Hong Kong for providing advice for the mediation analysis; and Mr. Matthew Wong from the Microbiota I-Center (MagIC), Hong Kong SAR, for reviewing the manuscript.

Author contributions

Study design — Hein Mun Tun, Anita L. Kozyrskyj. Data acquisition — Jaclyn Parks, Tim K. Takaro: environmental exposures, especially smoke exposure; urine metabolite measurement; Catherine J. Field, Piush Mandhane, Theo J. Moraes, Elinor Simons, Stuart E. Turvey, Padmaja Subbarao, Jeffrey R., Brook, James A. Scott: subject recruitment, cohort follow-up, sample collection, biobanking, data registry; James A. Scott: fecal microbiota sequencing; Anita L. Kozyrskyj: measurement of fecal metabolites. Data cleaning — Hogan Kok-Fung Wai, Xi Zhang: cleaning questionnaire data and confirming their accuracy. Data analysis — Ye Peng, Hein Min Tun: Analysis of the microbiota profiles using an updated analytical pipeline, identification of the sub-cohort, associations between smoke exposure and childhood weight outcome, associations between smoke exposure and infant microbiota, mediation analysis. Data interpretation — Ye Peng, Hein Min Tun: all aspects; Hogan Kok-Fung Wai, Jaclyn Parks, Catherine J. Field, Piush Mandhane, Theo J. Moraes, Elinor Simons, Stuart E. Turvey, Padmaja Subbarao, Jeffrey R., Brook, Tim K. Takaro, James A. Scott: epidemiological evidence of the relationship between the exposure, mediator and outcomes; Siew Chien Ng, Xi Zhang, Francis Ka-Leung Chan: potential microbiota-centered mechanisms, clinical implications. Initial drafting — Ye Peng: Introduction, Results, Discussion, Methodologies; Hein Min Tun: Introduction, Results, Discussion. Critical review — Siew Chien Ng, Hogan Kok-Fung Wai, Xi Zhang, Jaclyn Parks, Catherine J. Field, Piush Mandhane, Theo J. Moraes, Elinor Simons, Stuart E. Turvey, Padmaja Subbarao, Jeffrey R., Brook, Tim K. Takaro, James A. Scott, Francis Ka-Leung Chan. All authors approved the final version of the manuscript and agree to be accountable for every aspect in ensuring that questions related to the accuracy of the findings in the manuscript.

Competing interests

Francis Ka-Leung Chan is Board Member of CUHK Medical Centre. He is a co-founder, non-executive Board Chairman and shareholder of GenieBiome Ltd. He receives patent royalties through his affiliated institutions. He has received fees as an advisor and honoraria as a speaker for Eisai Co. Ltd., AstraZeneca, Pfizer Inc., Takeda Pharmaceutical Co., and Takeda (China) Holdings Co. Ltd. Siew Chien Ng has served as an advisory board member for Pfizer, Ferring, Janssen, and Abbvie and received honoraria as a speaker for Ferring, Tillotts, Menarini, Janssen, Abbvie, and Takeda. Siew Chien Ng has received research grants through her affiliated institutions from Olympus, Ferring, and Abbvie. Siew Chien Ng is a founder member, non-executive director, non-executive scientific advisor, and shareholder of GenieBiome Ltd. Siew Chien Ng receives patent royalties through her affiliated institutions. Francis Ka-Leung Chan, Siew Chien Ng, and Hein Min Tun are named inventors of patent applications held by the CUHK and MagIC that cover the therapeutic and diagnostic use of microbiome. All other coauthors have no conflict of interest.

Data availability statement

De-identified data are available from the corresponding author upon reasonable request. Registration and/or proposal applications may be needed depending on the tier of access requested (https://childstudy.ca/for-researchers/data-access/).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2323234

Additional information

Funding

This study was partially funded by the startup funding of the Chinese University of Hong Kong and by grants from the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. 14113923) to Dr. Tun, and the Canadian Institutes of Health Research Canadian Microbiome Initiative grant (Project No. 227312) to Dr. Kozyrskyj. The Canadian Institutes of Health Research and the Allergy, Genes, and Environment (AllerGen) Network of Centres of Excellence provided core support for the Canadian Healthy Infant Longitudinal Development (CHILD) Study. Dr. Ye Peng was partially supported by the Research Committee Postdoctoral Fellowship Scheme of the Chinese University of Hong Kong. This study was also partially supported by InnoHK, the Government of Hong Kong, Special Administrative Region of the People’s Republic of China.