The role of the gut in obesity – new insights into the physiology of therapeutic approaches

In developed countries, the prevalence of overweight (body mass index (BMI) between 25 and 30 kg/m2 in adults) and obesity (BMI>30 kg/m2), with attendant health consequences, is growing rapidly and shows little sign of reaching a plateau. For example, in the United States, a recent analysis indicated that overweight and obesity was found in 75.9% and 72.6% of adult males and females in 2021, which are approximately 10–20 percentage points higher than equivalent data from just 1990 (GRD 2021 US Obesity Forecasting Collaborators, 2024). By 2050, it is projected that more than half of US adults will be obese. The rates of overweight and obesity are also increasing rapidly in children and adolescents, and the rates for all groups are driven predominantly by increases in the prevalence of obesity, with the overweight population actually falling. The growing prevalence of obesity comes at considerable societal and economic costs, contributing to substantial morbidity and mortality. For example, complications of obesity have more than doubled in prevalence over the last 30 years and now represent leading causes of healthcare spending (Dieleman et al., 2020). The forecasted levels of obesity could therefore have devastating consequences if not averted. Even low- and middle-income countries are not immune, with many facing a so-called ‘double burden’ of malnutrition. Even while they continue to battle the impact of infectious diseases and undernutrition, the extent to which both children and adults are overweight or obese is increasing significantly. Obesity is a complex disorder and while fundamentally it reflects an imbalance between energy intake and utilization, this is overlaid by numerous societal factors and other structural drivers, such as geographically determined inequities in the availability of healthy foods and/or safe spaces for physical activity. Thus, there has been intense interest in developing additional clinical approaches to prevent and/or reverse obesity that can be effective even in the face of other factors over which individuals may have little or no control, and in advance of the wide-scale policy actions that would be needed to address obesity at a population level. Newer approaches include the use of therapies based on incretin hormones such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), various forms of bariatric surgery, and manipulation of the gut microbiome, including via specific dietary components. All of these treatments, some of which have been shown to be dramatically effective in securing weight loss, have the common denominator of a dependence on gastrointestinal physiology. In recognition of these advances, therefore, a symposium was organized at the Europhysiology conference held in Newcastle-upon-Tyne in the summer of 2024, with the title ‘The role of the gut in obesity – new insights into the physiology of therapeutic approaches’. Review articles reflecting three of the presentations from that symposium, by Alcaino et al. (2024), Westerbeke et al. (2025) and Kueh et al. (2024) form the nucleus of this special issue. Gratifyingly, the relevance of the area addressed also attracted unsolicited topical reviews from two leaders in the field who were not part of the original programme (Azar & Rehermann, 2025; Camilleri, 2024). The special issue is also rounded out by two papers reporting relevant original research (Davies et al., 2025; Smith et al., 2024) as well as a Translational Perspective commenting on the significance of the Davies et al. study (Keely & Duncanson, 2025). In their highly informative review article, Constanza Alcaino and her mentors Frank Reimann and Fiona Gribble (Alcaino et al., 2024) provide a timely overview of the critical roles of GIP and GLP-1 in coordinating post-prandial metabolic responses such as insulin secretion, as well as limiting subsequent food intake. The authors describe how enteroendocrine cells located in the epithelium of the proximal and distal intestine respond to nutrients (and other luminal factors) by releasing GIP and GLP-1, respectively. These incretins act at multiple target sites including the intestine itself, pancreatic islets and the brain. The biological responses produced range from slowed intestinal motility and reduced gastric emptying, insulin secretion, a reduction in glucagon release (GLP-1 only), and central effects on satiety with reduced food intake, although the latter in fact may be evoked via peripheral incretin receptors on vagal efferents. No matter what the precise underlying mechanisms, it is clear why drugs based on GLP-1 and GIP, as well as more recent peptides that target the receptors for both hormones, should be effective in not only treating diabetes, but also causing weight loss. The authors also point to opportunities for additional research, such as teasing apart the target cells that are relevant for the beneficial effects of drugs acting via incretin receptors, which may further optimize these agents and/or avoid undesirable side effects, such as nausea. Martin Kueh and colleagues, working with senior author Carel le Roux, survey evidence supporting the therapeutic relevance of a newer player in the search for hormones that modulate obesity and associated complications, oxyntomodulin (Kueh et al., 2024). This peptide hormone, derived from proglucagon, was first identified for its ability to inhibit gastric acid secretion from oxyntic glands, from which its name is derived, along with a subtle incretin effect. A possible role for oxyntomodulin in weight loss was surmised from the fact that its levels rise post-prandially, but also following bariatric surgery. Oxyntomodulin reduces food intake while increasing energy expenditure, and the effects of the peptide have been attributed to dual agonism of GLP-1 and glucagon receptors. Analogues of oxyntomodulin are in clinical trials for the treatment of obesity and type 2 diabetes, with efficacy seemingly dependent on the ratio of GLP1 versus glucagon receptor activity. Initial results have been largely promising, albeit with a significant occurrence of gastrointestinal side effects (in common with other anti-obesity pharmacotherapies). Nevertheless, the unique pharmacology of the oxyntomodulin system, along with its ability to elevate energy expenditure, offers hope for a powerful new non-invasive option for patients with obesity. The final symposium review summarizes the talk presented by Florine Westerbeke (Westerbeke et al., 2025) and takes a converse view to the prevention of obesity. Dietary fructose consumption has risen substantially over recent decades such that it now represents, on average, more than 10% of daily caloric ingestion for US adolescents and adults, and rising in parallel with the rise of obesity and metabolic diseases,. Fructose ingestion is also higher in ethnic groups with a higher prevalence of these conditions. Westerbeke and her colleagues set out to determine whether these factors are causally related. Fructose is relatively poorly absorbed by the gut in many individuals, leaving it to spill over to the distal small intestine where it can influence the composition and function of the microbiota. The resulting fructose fermentation produces ethanol and acetate that can exert deleterious health effects; absorbed fructose is also metabolized by the liver where it can trigger lipogenesis and steatosis. Overall, the article highlights the relevance of dietary choices in the generation of obesity and points to the need for additional studies on the effects of fructose ingestion, particularly on the small intestinal microbiota. This special issue also includes two reviews from well-known contributors to the field of gastrointestinal endocrine signalling. Michael Camilleri discusses the importance of the stomach in satiation and thus obesity prevention, and addresses how the actions of incretins on gastric function contribute to their effectiveness in causing weight loss (Camilleri, 2024). He concludes that the impact of incretin-based drugs on gastric function is not only integral to their properties as anti-obesity therapies, but that gastric modulation is also implicated in the effectiveness of surgical and endoscopic therapies for the condition. Meanwhile, Azar and Rehermann address crosstalk between adipose tissue, the immune system, and the microbiota (Azar & Rehermann, 2025). They conclude that the gut microbiota can regulate white and brown adipose tissue homeostasis both via the metabolites it produces as well as modulation of innate and adaptive immune responses, especially early in life. An appropriately balanced post-natal action of the microbiota via these mechanisms may protect against obesity throughout life. Rounding out the special issue are two reports of original research that are relevant to the theme. The first of these (Davies et al., 2025), which was also highlighted by a Translational Perspective (Keely & Duncanson, 2025), provides results from a randomized controlled trial that tested the hypothesis that metabolic health improvements caused by exercise and energy restriction are mediated by changes in the gut microbiome. Adult participants who were overweight or obese were randomized to participate either in a three-week energy restriction trial plus five sessions weekly of vigorous exercise, or to continue their habitual lifestyle as controls. While calories were reduced in the test subjects, the composition of their diet was maintained. Contrary to the hypothesis, while the test subjects lost weight and showed improved cardiometabolic health, there was no evidence for a change in their microbiome or the short chain fatty acids it produces. Caveats include the relatively short-term nature of the study, and the fact that detailed analyses of the functional metagenomic and transcriptomic features of the microbiota in the two participant groups, which could have revealed subtle yet important differences in the microbiota, were not performed. In total, nevertheless, the work implies that we still have more to learn about the interplay between the microbiota, diet and exercise that may ultimately allow us to improve metabolic health and to treat obesity. Finally, Smith et al., also from the Reimann/Gribble lab, used single cell transcriptomics to provide unprecedented detail about the characteristics of enteroendocrine cell populations in organoids derived from human small intestinal specimens. The use of organoids allowed genetic modification such that enteroendocrine cell lineages could be purified and analysed, overcoming the limitations of the relative rarity of these cells in single-cell studies of the entire epithelial compartment from intact tissue. Contrary to conventional wisdom, the findings reveal that many enteroendocrine cells express more than one hormone. On the other hand, the cells could be clustered based on their expression of receptors that allow them to respond to specific luminal constituents (e.g. glucose, bile acids). The work implies that differences in the nutrient-sensing machinery of specific enteroendocrine cell clusters likely contribute to distinct patterns of post-prandial hormone release, and may have implications both for normal gastrointestinal physiology and the treatment of obesity. In sum, the contributions featured in this special issue provide valuable and timely insights into the complexities of gut signalling, as well as crosstalk with the microbiota and brain, that have implications for food preferences, nutrient ingestion and energy balance. In light of the millions of individuals now taking incretin-based anti-obesity drugs, greater insights into these topics may allow further optimization of the effectiveness of these regimens while limiting side effects and as yet unknown long-term sequelae (particularly since current indications are that these drugs may need to be taken indefinitely to maintain weight loss). They may also point the way to non-invasive substitutes for the current gold standard of bariatric surgery for the treatment of severe obesity, and perhaps ultimately allow for short-term, targeted interventions that could reset metabolic and nutritional homeostasis such that obesity can thereafter be avoided. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests declared. S.K. and K.B. conceived or designed the work; drafted the work and revised it critically for important intellectual content; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. This work was supported by Science Foundation Ireland (Grant #: 16-IA-4445)and The Journal. We are grateful to The Journal for providing partial financial support for the symposium that formed the nucleus of this special issue. Related work from the laboratory of SJK has been supported by funding from Science Foundation Ireland (Grant #: 16-IA-4445).