Gut bacteria and genes work together to shape obesity risk, review reveals hidden links

Gut bacteria and genes work together to shape obesity risk, review reveals hidden links

A new scientific review shows how gut microbes can be passed from mother to child.

Impact of gut microbiota on BMI through hypothalamic control of appetite and metabolism and mechanisms underlying the transgenerational effects of gut microbiota on heritability of BMI.

In a study recently published in the journalNutrientsResearchers in Germany and Great Britain examined 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. In addition, there are more than 50 conditions associated with obesity, such as hypertension, type 2 diabetes, obstructive sleep apnea, fatty liver disease, dyslipidemia and polycystic ovary syndrome.

The pathogenesis of obesity is complex and poorly defined, involving an interplay between adesogenic environment and genetic architecture. The public understanding of the development of obesity is shrouded in myths and misconceptions. The present study explained that obesity has a significant genetic component and emphasized the heritability of BMI. The review also advocates for greater public education and compassion to reduce obesity stigma and recognize the multifactorial biological and environmental drivers.

BMI heritability

Twin studies provide some of the best evidence for the heritability of BMI. A Chinese study of 1,421 pairs of twins estimated BMI heritability of 72% and found that heritability of cardiometabolic traits and BMI decreased with age and environmental factors played a greater role than genetics in older individuals. In an Israeli study, the heritability between mean parental and offspring BMI was 39%.

These studies indicate that BMI, and implicitly obesity, has high heritability, with overall heritability estimated at 40% to 50%. Nevertheless, differences in BMI heritability were observed by BMI subgroup. BMI heritability is about 30% for people of normal weight and 60% to 80% for people with obesity. Genome-wide association studies (GWAS) for obesity have uncovered over 1,000 variants that affect BMI, with most alleles contributing just a few grams to body weight.

Obesity-shaped alleles have a greater effect in people prone to obesity or weight gain, but have a minimal effect in people of normal weight. Thus, the penetrance of alleles affecting BMI varies depending on BMI. Notably, there is a lack of causal understanding for most GWAS-identified BMI-influencing loci. Even when combining thousands of genetic variants, polygenic risk scores only explain about 8% of BMI variation, indicating that most remains heritable (“missing heritability”). However, gene variants that affect body mass are expressed primarily in the central nervous system, particularly in the hypothalamic centers of appetitive and metabolic control. The review highlights that gene-environment interactions can 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 metabolism and appetitive control

The gut microbiota and its metabolic byproducts communicate with the brain through direct and indirect mechanisms. The gut microbiome shapes the tendency to gain weight and BMI via central metabolic and appetitive control. Gut microbiome composition correlates with body weight, with overweight and lean individuals having different compositions. Diet and lifestyle factors also influence the composition of the gut microbiome.

The gut microbiome influences hypothalamic control of metabolism and appetite through effects on the modulation of hormonal signals from enteroendocrine cells in the intestinal wall. Some of these effects arise from metabolic byproducts of the gut microbiota such as short-chain fatty acids (SCFAs). One study found that SCFAs stimulated G protein-coupled receptor 41 (GPR41), which increased 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, which induces satiety and supports appetite control. SCFAs may meaningfully influence hypothalamic control of metabolism and appetite via direct central and indirect effects and represent a biological contribution to BMI, although the precise effects and benefits of all SCFAs and their interaction are still areas of active investigation. The review notes that while animal studies provide important insights, direct causal evidence for these microbiome-brain-BMI connections in humans is still emerging, and results may vary between different types of fiber and metabolic outcomes.

The gut microbiota can also influence neurotransmitters and neuroreceptor receptivity in the brain. A rodent study found that chronic consumption of Lactobacillus rhamnosus caused changes in the expression of gamma-aminobutric acid (GABA) receptors, which in turn were associated with reduced anxiety and depressive-like behaviors.

Furthermore, the absence of such effects in vagotomized mice supports an important role for the vagus nerve in mediating signals between the brain and the gut microbiota. The vagus nerve connects the gut microbiota to the liver and communicates with the hypothalamus to control feeding behavior, appetite, and metabolism. However, these neuro-humoral and neurotransmitter effects have been demonstrated mainly in animal models and extrapolation to humans should be made cautiously.

Gut microbiome heritability

The gut microbiome could only contribute to BMI heritability if it is inherently heritable. Caesarean section (c) section eliminates neonatal contact with maternal microbes during parturition; Therefore, the newborn gut microbiota is derived from environmental sustainability. During vaginal delivery and also through breastfeeding via the entero-mammary route, newborns are exposed to the maternal microbiome. A systematic review found that vaginal delivery resulted in better colonization patterns and overall diversity of gut microbiota for children compared to cesarean section.

Vaginal delivery and breastfeeding also enable the transmission of maternal gut microbiota to offspring, supporting the heritability of the gut microbiota. Maternally derived microbes colonize the infant gut with vaginal delivery or breastfeeding, while non-maternal microbes are typically transient. Persistence of maternal microbes suggests compatibility between infant and maternal gut microbes, which may be genetically mediated. Although 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) may contribute to similarities in gut microbiota among family members by shaping microbial composition through common dietary interventions. The review distinguishes between these environmental effects and true biological heritability, highlighting that both contribute to familial patterns in gut microbiota and BMI.

Closing remarks

Overall, BMI is highly heritable, but GWASS has only identified a small portion of this heritability. Given that heritability involves an inherited biological trait, searching the human genome is necessary to uncover some of the missing heritability. The gut microbiome likely contributes to the heritability of BMI through its impact on metabolic and appetitive control and the transmissibility of the gut microbiome across maternal-offspring generations. However, it is important to note that the original paper acknowledges that much of the current evidence for the effects of the gut microbiota on appetite control comes primarily from rodent studies, and the hypothesis is based largely on observational data from human studies, which currently lacks comprehensive validation from large human intervention trials. This highlights the need for further human-based studies and caution in extrapolating results. The review also advocates for a broader public health approach that promotes better understanding and reduces stigma. It recommends that all individuals, not just women of reproductive age, strive to optimize their gut microbiome through a diverse, plant-based, fiber-rich diet.

Given gut microbiome heritability, at least in the context of vaginal delivery and/or breastfeeding, women of reproductive age should optimize their gut microbiome during the prenatal, prenatal and postnatal periods, perhaps through diets rich in diverse non-fermented plant foods and specific fermented foods that have been suggested. Improved public understanding of the pathogenesis of obesity and BMI is largely inherited through genetics, and the gut microbiome may promote a cultural shift in societal attitudes toward obese people.

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