The dramatic increase in global rates of obesity has reached pandemic proportions. Aptly named ‘globesity’, this global health trend has outmaneuvered scientific advances and Government policies to reach rates of 43% amongst adults in 2022, an increase from 25% in 1990 (1).

Since the introduction of GLP-1 receptor agonist (GLP-1rA) medications in 2023-2024, data indicates a stabilization of obesity rates for the first time in decades (2). While these results are promising, it is important to recognize the limitations of relying on pharmacological interventions alone to reverse this concerning health phenomenon. Rather, these insights present an opportunity to improve our understanding of, and therefore address, the root cause/s of obesity through the identification of a broader range of therapeutic tools.

Dysbiosis of the gut microbiome is an area of obesity research that has gained significant momentum in recent years. The discovery of obesogenic microbes, and their ability to cause disease in germ-free (GF) animal models post-transplantation has inspired a plethora of research, including a focus on the close ties between gut microbes and GLP-1 receptor pathways (3).

Obesity is characterized by abnormal or excessive fat accumulation, resulting in a body mass index (BMI [kg/m²]) of greater or equal to 30 (4). Classified as non-communicable, obesity is a condition associated with an increased risk of other non-communicable diseases (NCDs), such as cardiovascular disease, diabetes and musculoskeletal disorders, and can significantly reduce life quality and expectancy (4).

The mechanism that drives obesity has long been recognized as long-term imbalances between the consumption and expenditure of caloric energy. However, the triggers behind these mechanisms remain poorly understood, despite decades of research. A combination of genetic and environmental factors has been proposed yet has failed to sufficiently explain the indiscriminate rise of obesity amongst different nationalities, genders, cultures, diets, lifestyles, ethnicities and age groups (4).

Much like communicable diseases, obesity exhibits patterns of transmission influenced by shared environments, social behaviors, and microbial signatures (5). While the very definition of NCDs excludes a causative role of pathogenic microbes, new research highlights a role of microbial composition in the pathogenesis of NCD’s, giving cause to rethink. Transmissibility of obesity has been shown to occur via fecal microbial transplant (FMT) between obese and lean mice, leading to the discovery of obesogenic microbes (6). Additionally, dysbiotic patterns such as reduced bacterial diversity, an increased ratio of the bacterial phyla Firmicutes to Bacteroides, imbalances in Akkermansiamuciniphila species and microbial metabolites, are common findings in people with obesity, highlighting that microbes do indeed play an important role in its pathogenesis (7).

Whether obesogenic microbes are associated with cause or effect requires further investigation. In the meantime, understanding how the microbiome contributes to the pathogenesis of obesity is of upmost interest.

The link between the gut microbiome and obesity is best understood within the context of the gut-microbiome-metabolism axis; a multi-directional communication network between the gut microbiome and host metabolic pathways (8).

Microbially-derived signaling molecules, such as short chain fatty acids (SCFAs) and secondary bile acids, influence hormone and inflammatory cytokine profiles, contribute to host metabolic phenotype, homeostasis and disease risk (9). Several proposed pathways are likely at play, including modulation of nutrient and energy availability, immune system function and barrier integrity (7). Dysbiosis of the microbiome can disrupt these pathways, contributing to a loss of intestinal barrier integrity, seepage of bacteria and their components, and a subsequent increase in low-grade systemic inflammation—a key precursor of obesity (9).

Interestingly, barrier integrity has been proposed as a key mechanistic pathway of GLP-1rA medications, contributing towards their effect on enhancing insulin response, delaying gastric emptying, reducing appetite and body weight (10). Studies investigating efficacious and non-efficacious groups of patients taking GLP-1rAs have found significant differences in gut microbiome composition between both groups, suggesting an association between gut microbiome composition and GLP-1rA treatment outcomes (11). While certain changes within gut microbiome composition may explain the benefits of GLP-1rA medications, they may also be linked to their side effects, as has been shown with other microbiome-disruptive medications (12).

Therefore, the identification of dietary, lifestyle and nutritional interventions that support the health and function of gut-microbiome-metabolism axis pathways, may provide stand alone and/or adjunctive therapeutic opportunities in the battle against obesity.

Industrialization has dramatically altered human lifestyles, with profound effects on gut microbiome composition. The association between environment, microbes and host health was brought into focus by the hygiene hypothesis, which highlighted the differences in the incidence of allergic disease between urban and rural populations (13). The science underpinning this hypothesis has since evolved to recognize a multitude of modern-day drivers of reduced microbial diversity, including birthing and feeding practices, exposure to a diverse range of xenobiotics, sleep disruption, psychological stress, sedentary behavior and extensive sanitization (14).The cumulative exposure to this environmental exposome can tip the balance between pro- and dys-biotic factors, reducing microbiome diversity, and ultimately contributing to a process described as ‘dysbiotic-drift’; an intergenerational, progressive loss of important microbial species which in turn has contributed to a rise of non-communicable disease (15).

While many lifestyle factors driving dysbiosis are heavily influenced by social, geographic, economic, political and commercial forces, dietary interventions are accessible to most, and can have a profound impact on both microbiome and host health (16).

Diet is a cornerstone of gut microbiome modulation, directly influencing microbial composition and function. High-fiber diets can be considered the gold standard for promoting eubiosis, due to their consistent effects in promoting SCFA-producing bacteria like Bacteroidetes, which confer metabolic benefits by enhancing insulin sensitivity and reducing inflammation (17). Conversely, diets rich in ultra-processed foods and low in fiber favor the expansion of pro-inflammatory taxa, exacerbating metabolic dysregulation (18).

Most current dietary recommendations offer a reductionist approach to the diet-host health relationship, focusing on micro and macronutrient value, while ignoring the complex food matrices that have correspondingly complex effects on health and disease. Beyond calories are the metabolic, microbiome, hormonal and immune impacts of different food matrices, highlighting the notion that not all calories were created equal (19).

One such example of a complex food matrix is fermented dairy. Upon superficial observation, dairy products, such as yoghurt and cheese, contribute to saturated fat and calorie load, and theoretically could exacerbate risk of weight gain, obesity and cardiovascular disease. Yet a meta-analysis of 29 prospective cohort studies, including 938,465 subjects, showed fermented dairy products (primarily fermented yoghurt, cheese and milk) were associated with a modestly lower risk of mortality, with cheese showing a significant reduction in risk of coronary artery disease and stroke, despite its higher fat content (20). Additional studies have shown that consumption of fermented dairy products is associated with anti-obesity effects (21). These findings correlate with research into traditional dietary patterns associated with health and longevity, including the ‘French paradox’ and the Sardinian Mediterranean diet, both of which are recognized for their high consumption of fermented dairy products (22, 23). In addition to a nutrient-dense profile, the anti-obesity effect of fermented dairy has been attributed to the presence of live microbes and their metabolites (20, 21).

Specific foods have also shown to positively influence obesity via GLP-1 pathways. For instance, foods such as berries, virgin olive oil and mushroom powder have been associated with an increased postprandial GLP-1 secretion in individuals who were normal weight or over-weight/obese (24). While macronutrient and food combination studies can be inconsistent, overall data suggests that diets higher in protein and fiber are associated with enhanced GLP-1 secretion (24). Therefore, adjusting dietary advice to enhance GLP-1 secretion may provide a more targeted dietary approach to obesity.

Given that patients who take GLP-1rA medications consume less overall food, optimizing the nutritional profile of food choices becomes increasingly important to reduce the risk of macro- and micronutrient deficiencies (25). A recent meta-analysis demonstrated that GLP-1rA medications were associated with a significant loss of lean muscle mass, contributing to approximately 28% of the weight loss, indicating inadequate nutritional consumption (26).

Evidently, the calorie-in/calorie-out dietary approach to obesity is becoming increasingly redundant. Instead, targeted dietary advice should take into consideration the impact of food components and dietary patterns on the gut-microbiome-metabolic axis and GLP-1rA medication outcomes.

Probiotics are an intervention that can target gut microbiome shifts that occur in obesity, and thus research into their effect on weight management has received significant interest. The International Scientific Association for Probiotics and Prebiotics (ISAPP) defines probiotics as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (27). Supplementation with beneficial probiotic species has been linked to several health benefits, including the restoration of intestinal epithelial integrity and a reduction in circulating lipopolysaccharides (LPS) and lipopolysaccharide-binding protein (LBP); known markers of chronic inflammation and obesity (28). Meta-analyses have shown probiotic benefits are often strain, dose and duration specific, with multiple probiotic strains and strain combinations demonstrating anti-obesity effects (28).

For instance, Akkermansia muciniphila are gram-negative, mucous-degrading bacteria that reside in the intestinal mucosa of humans, and have demonstrated the ability to support the integrity of the intestinal mucosa (29). The abundance of A. muciniphila has been negatively correlated with body weight and fasting blood glucose in humans, suggesting a potential role in obesity and diabetes management. One of the proposed mechanisms behind these effects is the enhanced secretion of GLP-1 (28, 29). Clinical studies have shown that supplementation with A. muciniphila alone or in conjunction with other probiotics improves metabolic markers, such as weight, fat mass, hip circumference, insulin resistance, cholesterol, liver function and systemic inflammation without side effects (29).

Additionally, supplementation with the probiotic strain, Bifidobacterium animalis subsp. lactis 420™ (B420), has been shown to support weight maintenance (30). Its effect on weight has been attributed to its ability to increase the prevalence of Akkermansia species and enhance intestinal epithelial integrity, indicating potential cross-feeding benefits (30).

Supplementing with specific strains of probiotics, in particular strains that enhance Akkermansia colonization, may prove a valuable therapeutic tool in the management of obesity. Whether probiotics are more efficacious as standalone treatments, or as adjuncts to diet, lifestyle and/or pharmacological interventions, requires further investigation.

Obesity has increased rapidly on a global scale, remaining resistant to conventional dietary and lifestyle interventions, suggesting other obesogens are at play. Whether by cause or effect, microbial dysbiosis has shown to play a key role in the pathogenesis of obesity (3). As a transducer of environmental signals, the gut microbiome is sensitive to certain environmental cues, including diet, lifestyle and medications, and an increased exposure to a hostile exposome can tip the balance from eubiosis to dysbiosis, a catalyst for metabolic disruption and subsequent weight gain (7). Dietary, lifestyle and pharmacological interventions should take microbiome impacts into consideration and aim to support, rather than disrupt, the gut-microbiome-metabolism axis. GLP-1rAs have shown significant promise in the battle against rising obesity rates, however, relying on pharmacology alone is risky in the absence of understanding their short and long-term impact on microbiome health. Instead, we have an opportunity to leverage these new insights to drive further research that helps identify additional clinically applicable tools that holistically support GLP-1r pathways, incorporating targeted, evidence-based diet, lifestyle and probiotic interventions to support homeostasis of the gut-microbiome-metabolism axis.