Obesity, recognized as a significant global health challenge, may exhibit complex interactions with gut microbiota dynamics. While existing research within adult populations suggests potential causal relationships, the precise nature of this interaction remains ambiguous, particularly in discerning whether alterations in gut microbiota serve as a precursor to or a consequence of dietary influences impacting both BMI and gut microbiota. Historically, obesity research has predominantly centered around adult populations. However, the escalating prevalence of elevated BMI in children and adolescents globally, necessitates a redirected focus towards these age groups.

Among numerous factors, the role of gut microbiota, the microbial communities residing in the gastrointestinal tract, has sparked significant interest, especially in the context of pediatric and adolescent populations. Recent studies in this age group have demonstrated mixed findings on the direct association between gut microbial composition and high BMI, hinting at a complex interplay with genetic and environmental factors. These inconsistent outcomes underline the need for large-scale, comprehensive studies to better understand this relationship, thus broadening our knowledge of obesity's multifaceted etiology across different life stages.

Aiming to bridge this knowledge gap, this PhD project explores the associations between gut microbiota and BMI development in children and adolescents, utilizing data from two birth cohorts: Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) and COPSAC2000. These cohorts provide extensive data on 700 children and 411adolescents, respectively.

In study 1, within the COPSAC2010 cohort, the association between early-life gut microbiota (from 1 week to 6 years of age) and BMI measurements (from 0-10 years) was examined. The analysis showed no significant correlation between early-life gut microbiota diversity and concurrent BMI, BMI status at age 10, or early adiposity rebound. Some links were noted between bacterial community distribution and BMI measures, and body composition, although these findings did not hold statistical significance post multiple testing corrections. A machine learning approach was employed to predict BMI at 10 years based on early-life gut microbiota, but it did not corroborate the ability to predict high BMI, supporting the idea that the observed gut microbiota-BMI connection in adults may rather reflect lifestyle changes than early microbial compositions.

In Study 2, we utilized the COPSAC2000 cohort data to explore the relationship between BMI and gut microbiota in 18-year-old human participants. This human-based analysis revealed sex-specific correlations between bacterial composition and BMI, particularly in females. Complementing this, an experimental study with a murine model was conducted. Here, we used human-derived fecal microbiota transplantations (FMT) to colonize germfree mice, aiming to investigate the transferability of human phenotypes to the mice, thereby bridging human observational findings with experimental mouse model insights.

While FMT led to successful colonization and subsequent phenotypic similarities to human donors, fecal virome transplantations (FVT) did not exhibit the anticipated modulation of gut microbiota and showed no effect on the measured clinical outcomes of the mice such as body weight, blood glucose, cytokines, hormones, and adipose tissue, underscoring the intricacies surrounding gut microbiota's interaction with host metabolic phenotypes.

In conclusion, these studies significantly contribute to the unfolding narrative surrounding the intricate and possibly age-dependent relationships between gut microbiota and high BMI. Through meticulous analysis across different age groups in children and adolescents, the thesis sheds light on the nuanced interplay of gut microbial composition with BMI, and by extension, its potential role in the onset and progression of obesity. The different results found in early-life and adolescent phases highlight the need for more extensive and thorough research. Such efforts are crucial to better elucidate these interactions across different age groups, and to further explore the evolving hypothesis that lifestyle factors, perhaps more so than early microbial compositions, influence the gut microbiota-BMI link.

The insights provided by this thesis offer a step toward guiding future research, which may contribute to finding better solutions for the global health challenges associated with obesity and metabolic issues.