Doha, Qatar: Obesity is increasingly viewed as a complex disease that cannot be attributed to a single cause. Instead, it arises from the interplay of genetic, environmental, and lifestyle factors. While genetics are estimated to account for roughly 40 percent of the risk, much of this influence remains unexplained. This gap – known as the “missing heritability” problem – reflects the fact that identified genes account for only a fraction inherited obesity risk.
“While genes are a major factor in obesity, they are not the only one,” explains Dr. Souhaila Al Khodor, Director of the Reproductive and Perinatal Health Division and Principal Investigator, Laboratory of Microbiome and Biomarkers Discovery at Sidra Medicine, a member of Qatar Foundation. “There is polygenic obesity, which results from changes in hundreds of genes; monogenic obesity, caused by a single rare mutation; and a third type, syndromic obesity, which occurs as part of broader genetic disorders.”
So, what explains the gap between expected genetic influence and actual outcomes?
“The explanation may lie in the role of epigenetic modifications and in how genes interact with environment exposures during the first 1,000 days of life – from pregnancy through a child’s second birthday. This critical window can permanently influence how the body regulates energy balance and fat storage, shaping long-term susceptibility to weight gain.”
Dr. Al Khodor emphasizes that the gut microbiome – the trillions of microorganisms in the intestines – plays a central role in nutrient absorption and blood glucose regulation, both critical to obesity. The composition of these microbial communities influences how efficiently energy is extracted from food, how appetite and satiety are regulated, and how inflammatory pathways and insulin resistance develop.
She adds that the gut microbiome is shaped by diet, medications, early antibiotic use, mode of delivery, breastfeeding, and genetic factors, making it a critical link between genes and the environment.
A growing body of research has linked alterations in gut microbiome composition to excessive weight gain and inflammation, a relationship confirmed in both animal and human studies. In this context, Dr. Al Khodor explains: “Some of the earliest evidence came from studies conducted on germ-free mice. When gut microbes from conventionally raised mice were transferred to germ-free ones, the recipient mice showed amplified fat tissue production, leading to increased body fat and insulin resistance despite reduced food intake.”
She noted that similar patterns have been observed in pediatric studies, saying: “Studies have shown that the guts of children with obesity contain higher concentrations of Firmicutes and lower concentrations of Bacteroidetes, which are two different types of gut bacteria.”
A higher Firmicutes-to-Bacteroidetes ratio has been associated with more efficient energy extraction from food and increased fat storage. Dr. Al Khodor explains that gut microbes influence fat accumulation by producing short-chain fatty acids, which help regulate appetite and improve insulin sensitivity, while other bacteria enhance calorie absorption.
Dr. Souhaila Al Khodor, Director of the Reproductive and Perinatal Health Division and Principal Investigator, Laboratory of Microbiome and Biomarkers Discovery at Sidra Medicine
She stresses that microbiome balance develops gradually during the first 1,000 days of life and is shaped by birth method, feeding practices, and early environmental exposures.
“This early balance determines whether the body will develop a healthy microbial environment that protects against obesity or a disrupted one that increases its risk later in life.”
Expanding on this, she adds: “Some studies have shown that an increased Firmicutes-to-Bacteroidetes ratio is associated with weight gain and obesity, and that reduced microbiome diversity is linked to metabolic dysfunction. Reviews examining around sixty recent studies, including comprehensive and up-to-date microbiome analysis, have found that the phylum most strongly associated with obesity is Proteobacteria.”
Based on this evidence, Dr. Al Khodor underscores that prevention must begin early, as enhancing microbiome diversity through breastfeeding and proper maternal and infant nutrition may offer long-term metabolic protection.
She explains that gene–microbiome interactions peak during the first 1,000 days of life and represent some of the strongest determinants of future obesity risk. This reflects a dynamic three-way relationship between the human genome, the gut microbiome, and environmental factors – where genetics shape microbial colonization, microbes influence gene function and metabolism, and diet and lifestyle continuously remodel the microbiome. Through epigenetic mechanisms, she notes, targeting both the genome and microbiome together may be key to effective obesity treatment.
Dr. Al Khodor also highlights the potential of using microbiome composition as a biomarker to assess obesity risk, as microbial patterns in infancy may predict later weight gain. “Personalized obesity treatments based on gut bacteria – including dietary changes, probiotics, prebiotics, or their combination – are a rapidly evolving field, enabling tailored nutrition and physical activity programs that improve outcomes and reduce relapse.”
Despite this promise, she cautions that precision medicine approaches face challenges, including the high cost of testing, limited specialized expertise, and difficulties integrating microbiome data into routine clinical practice.
“Early identification of metabolic risk factors can support targeted prevention strategies,” Dr. Al Khodor said. “This calls for Qatar-based studies using multi-omics technologies and artificial intelligence to better understand how genetics, diet, and the microbiome interact in the development of obesity.”
