By Tarun Sai LomteReviewed by Susha Cheriyedath, M.Sc.May 20 2025
A new scientific review uncovers how gut microbes passed from mother to child may hold the key to obesity's genetic puzzle, offering fresh hope for more effective prevention strategies.
Impact of the gut microbiota on BMI via hypothalamic control of appetite and metabolism, and mechanisms that underlie the transgenerational effects of the gut microbiota on the heritability of BMI.
In a recent study published in the journal Nutrients, researchers in Germany and the United Kingdom explored the heritability of body mass index (BMI).
Obesity is a major public health crisis and a non-infectious global pandemic. Obesity prevalence exceeds 890 million worldwide, with overweight affecting 2.5 billion adults. Further, there are more than 50 conditions related to obesity, such as hypertension, type 2 diabetes, obstructive sleep apnea, fatty liver disease, dyslipidemia, and polycystic ovary syndrome.
Obesity pathogenesis is complex and poorly defined, with an interplay between obesogenic environment and genetic architecture. Public understanding of obesity development is shrouded in myths and misconceptions. The present study discussed that obesity has a substantial genetic component, emphasizing the heritability of BMI. The review also advocates for greater public education and compassion to reduce obesity stigma, recognizing the multifactorial biological and environmental drivers.
BMI heritability
Twin studies offer some of the best evidence for BMI heritability. A Chinese study involving 1,421 twin pairs estimated BMI heritability at 72% and found that the heritability of cardiometabolic traits and BMI decreased with age, and environmental factors had a greater role than genetics in older individuals. In an Israeli study, the heritability was 39% between mid-parental and offspring BMI.
These studies indicate that BMI, and by implication, obesity, has high heritability, with overall heritability estimated at 40% to 50%. Nevertheless, variations in BMI heritability have been observed by BMI subgroup; BMI heritability is about 30% for people with normal weight and 60% to 80% for people with obesity. Genome-wide association studies (GWASs) on obesity have uncovered over 1,000 variants that impact BMI, with most alleles only contributing a few grams to body weight.
Obesity-promoting alleles have a greater effect in people with a propensity for obesity or weight gain but have a minimal impact in normal-weight individuals. Thus, the penetrance of alleles influencing BMI varies by BMI. Notably, there is a lack of understanding of causality for most GWAS-identified BMI-influencing loci. Even when combining thousands of genetic variants, polygenic risk scores explain only about 8% of BMI variation, indicating that most heritability remains unaccounted for ("missing heritability"). However, gene variants affecting body mass are mainly expressed in the central nervous system, especially the hypothalamic centers of appetitive and metabolic control. The review further highlights that gene-environment interactions may amplify genetic risk, and that the complexity of these factors contributes to the challenges in identifying the sources of missing heritability.
Gut microbiome and central metabolic and appetitive control
The gut microbiota and their metabolic byproducts communicate with the brain via direct and indirect mechanisms. The gut microbiome shapes the propensity for weight gain and BMI via the central metabolic and appetitive control. The gut microbiome composition correlates with body weight, with obese and lean individuals exhibiting distinct compositions. Dietary and lifestyle factors also influence the composition of the gut microbiome.
The gut microbiome influences the hypothalamic control of metabolism and appetite via effects on the modulation of hormonal signals from enteroendocrine cells in the gut wall. Some of these effects stem from metabolic byproducts of the gut microbiota, such as short-chain fatty acids (SCFAs). A study found that SCFAs stimulated G protein-coupled receptor 41 (GPR41), enhancing the secretion of peptide YY (PYY), an incretin-like appetite-suppressant hormone.
SCFAs also stimulate GPR43 to complement the effects on GPR41, leading to glucagon-like peptide 1 (GLP-1) secretion that induces satiety and supports appetite control. SCFAs, via direct central and indirect effects, may meaningfully impact the hypothalamic control of metabolism and appetite and represent a biological contributor to BMI, though the precise effects and benefits of all SCFAs and their interplay are still areas of active investigation, with much of the detailed mechanistic understanding currently derived from animal models requiring careful translation to human physiology. The review notes that while animal studies provide important insights, direct causal evidence for these microbiome-brain-BMI links in humans is still emerging, and findings can vary between different types of dietary fiber and metabolic outcomes.
The gut microbiota may also impact neurotransmitters and neuroreceptor receptivity in the brain. A rodent study found that chronic ingestion of Lactobacillus rhamnosus caused changes in the expression of gamma-aminobutyric acid (GABA) receptors, which, in turn, were associated with reduced anxiety and depressive behavior.
Moreover, the lack of such effects in vagotomised mice supports a major role for the vagus nerve in mediating signals between the brain and the gut microbiota. The vagus nerve links the gut microbiota to the liver, communicating with the hypothalamus to control feeding behavior, appetite, and metabolism. However, these neuro-humoral and neurotransmitter effects have been mainly demonstrated in animal models, and extrapolation to humans should be made with caution.
Gut microbiome heritability
The gut microbiome could contribute to BMI heritability only if it is heritable per se. Caesarean (C)-section eliminates neonatal contact with maternal microbes during parturition; as such, the neonatal gut microbiota are environmentally derived. During vaginal delivery, and also through breastfeeding via the entero-mammary pathway, neonates are exposed to the maternal microbiome. A systematic review found that vaginal delivery resulted in better colonization patterns and overall diversity of infant gut microbiota compared to C-section.
Vaginal delivery and breastfeeding also enable transmission of maternal gut microbiota to the offspring, supporting the heritability of the gut microbiota. Maternally derived microbes permanently colonize the infant gut with vaginal delivery or breastfeeding, while non-maternal microbes are typically transient. The permanence of maternal-derived microbes suggests compatibility between infant and maternal gut microbes, which may be genetically mediated. Furthermore, while not strictly a biologically heritable mechanism in the same way as genetic transmission, the research paper notes that shared food environments and dietary habits within families (an environmental influence) can also contribute to similarities in gut microbiota among family members by shaping microbial composition through common dietary exposures. The review distinguishes between these environmental effects and true biological heritability, emphasizing that both contribute to familial patterns in gut microbiota and BMI.
Concluding remarks
In sum, BMI is highly heritable, but GWASs have identified only a small proportion of this heritability. Given that heritability encompasses any inherited biological trait, searching beyond the human genome is necessary to uncover some of the missing heritability. The gut microbiome likely contributes to the heritability of BMI, given its effects on the metabolic and appetitive control and the intergenerational maternal-offspring transmissibility of the gut microbiome. It is important to note, however, that the original paper acknowledges that much of the current evidence for the gut microbiota's impact on appetite control stems primarily from rodent studies, and the hypothesis is largely based on observational data from human studies, currently lacking extensive validation from large-scale human interventional trials. This highlights the need for further human-based studies and caution when extrapolating findings. The review also advocates for a broader public health approach that fosters greater understanding and reduces stigma. It recommends that all individuals, not just females of reproductive age, strive to optimize their gut microbiome through a diverse, plant-based, and fiber-rich diet.
Given the gut microbiome heritability, at least in the context of vaginal delivery and/or breastfeeding, females of reproductive age should aim to optimize their gut microbiome throughout the preconception, antenatal, and postnatal periods, potentially through diets rich in diverse, unprocessed plant-based foods and specific fermented foods as suggested by the researchers. Improved public understanding of obesity pathogenesis and that BMI is largely inherited through genetics and gut microbiome could foster a cultural change in societal attitudes toward obese people.
Journal reference: Barber TM, Kabisch S, Pfeiffer AFH, Weickert MO. The Gut Microbiome as a Key Determinant of the Heritability of Body Mass Index. Nutrients, 2025, DOI: 10.3390/nu17101713, https://www.mdpi.com/2072-6643/17/10/1713