INTRODUCTION
Body mass index (BMI) is a globally recognised tool that measures the correlation between an individual’s weight and height. This apparently simple measurement has a significant impact on healthcare. The role of BMI in gastrointestinal (GI) pathologies is poorly understood and challenging to study. BMI has a complex history. It was originally known as the “Quetelet Index” after Adolphe Quetelet, a Belgian astronomer, mathematician, and sociologist who described it in 1830[1]. The main goal of the BMI was to establish statistical patterns of human anthropometry. A century later, and motivated by rising obesity rates, physiologist Ancel Keys modified the BMI[1]. He evaluated multiple anthropometric correlation formulas and found that the BMI is remarkably effective and simple for identifying excess body fat across large populations[2].
Despite its broad clinical utility, BMI has long been a subject of debate, both historically and in contemporary research. Multiple studies have demonstrated that suitability depends largely on the specific parameter being evaluated[3]. When the goal is to assess adipose tissue distribution, which is strongly associated with mortality, dual-energy X-ray absorptiometry (DXA) is one of the most accurate measurement modalities. Similarly, image-based techniques have proven to be superior predictors of total body fat and its regional distribution[3]. Despite providing direct, highly accurate measurements, these methods are used far less frequently than indirect anthropometric techniques, such as BMI. Moreover, they are significantly more expensive, less accessible, and less convenient in routine clinical practice. Consequently, for screening purposes, excess adiposity can be reasonably identified using BMI in combination with at least one additional anthropometric criterion, especially waist circumference (WC)[3,4].
The National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) has recognized the utility of BMI and WC in predicting obesity-related health risk[5]. In accordance with NIH guidelines, as individuals move from normal weight to overweight and obese BMI categories, health risk increases accordingly[5]. Although compelling evidence shows that WC may predict mortality risk more accurately than BMI, further studies are needed to find out whether WC alone can be reliably used as an independent measure of health risk in both clinical and research settings, like BMI. Current evidence shows that adding WC to BMI improves the forecast of metabolic risk as compared to BMI alone. However, when WC is dichotomized into normal vs high-risk categories according to NIH obesity guidelines, BMI remains a significant predictor of metabolic health risk[4,5]. Important conclusions can be drawn from these observations. Accepted classification systems for metabolic risk, such as those advocated by the NIH, may be misleading and could be improved. Although more precise methods for assessing body fat distribution, such as computed tomography (CT), magnetic resonance imaging, DXA, and WC, have demonstrated superior accuracy, their clinical applicability usefulness is limited[4]. Imaging-based techniques require specialized equipment and trained personnel. They are not suitable for repeated use due to cumulative radiation exposure (CT and DXA)[4]. Although WC does not share these limitations, its clinical utility has been restricted by inconsistent use, limited standardization, and variability in cutoff values. Therefore, more accurate and specific methods for assessing adiposity and metabolic risk are available. However, the widespread use and recognition of BMI in both clinical practice and research have led to its consolidation as the standard measure for studies related to weight and metabolic disorders.
Beyond these limitations, alternative anthropometric measures offer a more accurate assessment of adiposity-related inflammatory risk. WC, a surrogate for visceral adiposity, is more strongly associated with GI inflammation than BMI. Abdominal obesity has been independently linked to an increased risk of inflammatory bowel disease (IBD), particularly Crohn’s disease[6]. From a pathophysiological perspective, visceral fat is metabolically active and encourages GI inflammation through pro-inflammatory pathways, intestinal barrier dysfunction, and alterations in the microbiota. Causal associations have been demonstrated between visceral adiposity and multiple GI diseases[7]. Body fat percentage also provides a more direct quantification of total adiposity and has demonstrated stronger associations with systemic inflammatory biomarkers, particularly high-sensitivity C-reactive protein, compared to BMI[8]. The concept of “normal weight obesity” further highlights the limitations of BMI, as individuals with normal BMI but elevated body fat percentage show significantly increased systemic inflammation[9]. While BMI remains a practical and widely used screening tool, it does not account for fat distribution and may underestimate inflammatory risk. In contrast, WC better reveals visceral adiposity and its GI inflammatory implications, whereas body fat percentage provides a more precise estimate of total adiposity. Therefore, the combined use of these measures may improve the diagnosis of individuals at risk of GI inflammation.
The understanding of BMI in relation to GI inflammatory risk must also consider ethnic variability. Evidence from World Health Organization (WHO) expert consultations reveals that Asian populations show higher cardiometabolic and inflammatory risk at lower BMI thresholds as compared to Western populations. Differences in body composition and increased visceral adiposity explain these observations. In these populations, higher risk has been observed at BMI values between 22 and 25 kg/m², below the conventional WHO cut-off for overweight (≥ 25 kg/m²). These findings further reinforce the limitations of BMI as a universal surrogate marker, as similar BMI values may reveal different adiposity profiles and inflammatory risk across populations[10]. In addition, the association between BMI and GI pathology varies across special populations, further complicating its clinical evaluation. In pediatric populations, clinical studies have demonstrated that overweight and obese children show a significantly higher prevalence of functional GI disorders (FGIDs). These involve irritable bowel syndrome, functional constipation, and functional abdominal pain syndromes, compared to their normal-weight counterparts. Excess adiposity has also been identified as an independent risk factor for the presence of at least one FGID. This corresponds to nearly a two-fold increased risk reported in overweight and obese children[11]. In contrast, in older adults, the relationship between BMI and GI inflammatory risk becomes more complex. Age-related changes in body composition, including sarcopenic obesity and altered fat distribution, may modify the association between BMI and GI outcomes[12]. In this population, increased visceral adiposity and immunosenescence have been linked to alterations in gut microbiota composition, impaired intestinal barrier function, and chronic low-grade inflammation. All of these are critical mechanisms in GI pathophysiology[13]. These elements may attenuate or weaken the relationship between BMI and GI disease risk, further highlighting the limitations of BMI as an independent biomarker across different life stages.
Data from the Non-Communicable Diseases Risk Factor Collaboration reveal that obesity currently affects more than 150 million children worldwide and, between 1975 and 2022, prevalence in adults nearly tripled in women and quadrupled in men. This means that more than one billion people worldwide are overweight or obese[14]. This trend underscores the urgent need to address this public health challenge through improved prevention strategies and more effective therapeutic approaches. However, achieving this remains difficult without a comprehensive understanding of the disease itself. Accumulating evidence supports the view that excess body fat, beyond its mechanical and metabolic consequences, transforms adipose tissue into a dysfunctional endocrine–immunological organ[15,16]. This altered tissue state maintains chronic low-grade inflammation and immune dysregulation. This phenomenon has been theorized for several decades as the key underlying mechanism linking obesity to chronic metabolic diseases[15]. Therefore, research has focused on extracellular and intracellular inflammatory signalling pathways, gut microbiota disorders, and immune cell build-dup and triggering. Although inherently imprecise, BMI stratification provides significant clues about the severity of the underlying biomolecular pathophysiological mechanisms leading to GI inflammation[17,18].
In this minireview, studies investigating the impact of BMI on GI inflammation are discussed. The purpose is to analyse up-to-date evidence on the biomolecular pathophysiology and associated GI inflammatory processes.
THE OBESITY PANDEMIC
The WHO classifies obesity as a chronic disease with multiple underlying causes. Overweight is defined as a BMI ≥ 25 kg/m², while a BMI of 30.0-34.4 kg/m², 35.0-39.9 kg/m², and ≥ 40.0 kg/m² are classified as Class I, Class II, and Class III obesity, respectively[19,20]. This complex metabolic disease results from chronic positive energy balance, leading to excessive adiposity, and has become a worldwide healthcare issue. Recent evidence shows that nearly 39% of the world’s adult population is overweight, while an additional 13% meet the criteria for obesity[21]. The incidence of overweight and obesity increases with age, starting around age 20. The highest rates have been reported among people aged 50 to 65, and rates go down slightly thereafter. These long-lasting conditions result in chronic inflammation and altered hormone and immune responses, ultimately leading to systemic metabolic dysregulation. The development and prevalence of these disorders are supported by a multifactorial aetiology: Environmental and behavioural elements, and socio-economic status. Accordingly, overweight and obesity are major risk factors for many of the most prevalent chronic diseases worldwide: Diabetes, hypertension, cardiovascular disease, kidney disease, chronic respiratory diseases, and different types of cancer[22,23].
Incidence rates of overweight and obesity have more than doubled compared to 30 years ago. Therefore, metabolic diseases have increased accordingly. This explains the wide diversity of clinical symptoms and outcomes, especially those involving inflammation of the GI tract (Figure 1). The extraordinary prevalence of overweight and obesity was once regarded as a significant health issue only for individuals in high-income countries due to socio-economic status, the adoption of high-fat diets, and less active lifestyles. However, most of these countries have been stable since the 2000’s, whereas low- and middle-income countries have shown rapid increases in their prevalence[24-28].
Figure 1 Schematic representation of gastrointestinal inflammation as a central correlation in obesity-associated metabolic dysregulation.
Chronic positive energy balance leads to increased body mass index and excessive adiposity, which are associated with alterations in gut microbiota (dysbiosis) and increased intestinal permeability. These changes encourage translocation of microbial products and triggering of local and systemic immune responses, resulting in low-grade chronic inflammation. The digestive tract is instrumental in the development of metabolic syndrome and gastrointestinal symptoms, reinforcing systemic metabolic dysfunction. This interconnected network highlights the gastrointestinal tract as a key interface among environmental, metabolic, and immune factors involved in the pathophysiology of overweight and obesity-related chronic diseases. GI: Gastrointestinal; BMI: Body mass index.
The origins of obesity are often introduced in overly simplistic terms: An imbalance between calorie intake and energy expenditure. While this approach is fundamentally correct, it fails to highlight the biological importance of excessive calorie consumption. Furthermore, not all calories are metabolically equivalent. Theoretically, all calories have the same energy content. However, the body’s highly unequal capacity to process, transform, and store energy results in significant differences in the calories ultimately absorbed and utilised. In accordance with these observations, recent findings further underscore the importance of “fat quality”; rather than quantity in modulating inflammatory responses (Figure 2)[15]. Animal studies have shown that mice fed a high-fat, lard-based diet develop significantly greater intestinal inflammation than those fed a high-fat, coconut-based diet, despite similar fat content[29,30]. Based on this knowledge, dietary regimens were implemented in patients with a recent history of myocardial infarction. Specifically, pro-inflammatory fatty acids (saturated fats) were replaced with linoleic acid and omega-6 fatty acids. These patients showed reductions in low-density lipoprotein cholesterol levels. However, the risk of recurrent myocardial infarction and overall mortality increased by 62% and 70%, respectively[15]. Similarly, diets rich in processed meat have been associated with higher concentrations of pro-inflammatory macrophages (P2) in the duodenum. Furthermore, it has been demonstrated that dairy products and soft drinks increase monocyte CD14+ recruitment, while lower transepithelial resistance was observed among obese consumers of a Western diet (Figure 2)[30,31].
Figure 2 Dietary patterns and influence on gastrointestinal inflammation.
Healthy dietary patterns, such as the Mediterranean diet, suppress inflammatory cascades. Unhealthy dietary patterns, such as the Western diet, increase macrophage activity and promote intestinal inflammation. GI: Gastrointestinal.
It is essential to bear in mind that reducing dietary fat intake alone does not necessarily improve health. However, polyunsaturated fatty acids (PUFAs) and monounsaturated fatty acids, along with dietary fibre, vitamin E, folate, and magnesium, have been consistently linked to the suppression of inflammatory cascades[32]. This relationship has been supported by histopathological evidence demonstrating increased macrophage accumulation in the stomach when vegetable consumption is reduced[30]. Taken together, these findings show that unhealthy dietary patterns are positively correlated with intestinal inflammation (Figures 1 and 2).
BMI AND GI MOTILITY
FGID are among the most common healthcare issues worldwide and are directly associated with increased BMI. Symptomatology varies by two factors: BMI category and gender. Therefore, adiposity is a prevalent key element in the severity of the disease[18]. The influence of increased BMI on GI pathology has been well documented, with studies showing a correlation between high BMI and oesophageal cancer. However, current knowledge is inconsistent in assessing the association between BMI and GI symptoms[17]. These discrepancies result from methodological inaccuracies. These include but are not limited to the use of BMI cut-offs that do not conform to the WHO categories and comparisons across different populations. Other common methodological errors are inconsistencies in weight measurements and data collection. These limitations were identified and underestimated in large community-based randomised controlled trials performed in the United Kingdom[33]. This study demonstrated a positive correlation between increased BMI and gastro-oesophageal (GE) reflux symptomatology. Regurgitation and heartburn prevalence increased by almost three-fold compared with those of normal weight.
The underlying pathophysiology is multifactorial. However, a basic mechanism involves both delayed oesophageal emptying and impaired clearance of gastric reflux. This leads to an increase in GE reflux events. Furthermore, several studies have documented increased inspiratory and expiratory intragastric pressures, as measured by manometry, in patients with a higher BMI. This increased pressure forces the gastric contents back into the oesophagus. Specifically, a rise of approximately 0.3 mmHg per unit has been observed during both inspiration and expiration. Interestingly, this association is stronger in men. This sex-based difference has been hypothesised to result from variations in abdominal fat distribution[34]. The correlation between increased BMI and intraoesophageal pressure has been more clearly demonstrated during expiration.
DYSFUNCTION OF THE INTESTINAL BARRIER AND BMI
The intestine represents the largest interface between the internal and external environments and performs as a highly dynamic barrier that adapts to luminal and systemic signals[35]. The barrier comprises multiple, functionally integrated components. Overlaying the epithelium, the mucosal microenvironment, limits microbial adhesion through physical dissociation and immune mechanisms, including IgA secretion. Mucosal microenvironment is composed of the unstirred water layer, glycocalyx, and mucus. While the epithelial layer, sealed by apical junctional complexes, regulates selective transport of luminal contents and reacts to harmful stimuli by releasing chloride ions and antimicrobial peptides. Specialised epithelial Paneth cells, particularly abundant in the crypts, further enhance mucosal defence by secreting defensins and other antimicrobial molecules in response to bacterial products, such as lipopolysaccharide (LPS). Beneath the epithelium, the lamina propria provides immune surveillance through innate and adaptive immune cells that release immunoglobulins, cytokines, and chemokines. In addition, neuroendocrine signalling mediated by the enteric nervous system (ENS)-including neurotransmitters such as serotonin, histamine, and cannabinoids-modulates intestinal secretion and motility, thereby contributing to barrier function and host defence (Figure 3)[36].
Figure 3 Excess adiposity and Intestinal barrier dysfunction represents an immune–metabolic imbalance driven by excess adipose tissue.
Chronic low-grade inflammation marked by increased tumor necrosis factor alpha, interleukin 6, interleukin-1, resistin, and leptin, and reduced adiponectin, triggers key inflammatory pathways (NF-κB, TLR4, NLRP3), promoting meta-inflammation. TNF-α: Tumor necrosis factor alpha; IL: Interleukin 6; NF-κB: Nuclear factor kappa B; TLR4: Toll-like receptor 4; NLRP3: NOD-like receptor family pyrin domain containing 3; LPS: Lipopolysaccharides; CF: Cystic fibrosis; AMPs: Antimicrobial peptides.
Intestinal permeability reveals the integrity of these barrier components and varies according to the nature of epithelial injury and the molecular probes used to assess it[37]. Maintaining a stable intestinal barrier is crucial to preventing luminal substances and pathogens from entering the internal environment. Intestinal homeostasis, the healthy and balanced state of the intestine, is determined by the intestinal epithelium, the gut microbiome, and the host immune system[38]. The gut barrier is a dynamic system influenced by the integration of the intestinal microbiome and the activity of intercellular junctions, and is regulated by hormones, dietary components, inflammatory mediators, and the ENS[39]. Interleukin (IL)-1β, tumour necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) are among the most important modulators of GI barrier function, and when disturbed, may trigger a vicious inflammatory cycle. Intestinal barrier dysfunction represents a specific immune-metabolic dimension. In this context, excess adipose tissue correlates with overproduction of TNF-α, IL-6, IL-1, resistin, and leptin, as well as a significant reduction in adiponectin. As a result, an adipose-derived cytokine imbalance triggers NF-κB, TLR4, and the NLRP3 inflammasome; thereby weakening epithelial integrity and increasing susceptibility to intestinal and systemic inflammation (Figure 4)[40,41].
Figure 4 Dysbiosis–endotoxemia–inflammation–barrier dysfunction cycle induced by a high-fat diet.
Obesity-associated dysbiosis stimulates lipopolysaccharides translocation and tumor necrosis factor alpha/nuclear factor kappa B triggering, with ↓zonula occludens-1, ↑paracellular permeability, and ↓mucin production. At the same time, ↓NOD-like receptor family pyrin domain containing 6-interleukin-18 signaling and ↓aryl hydrocarbon receptor activity damage mucosal integrity, and reduced ethanolamine availability (a phosphatidylethanolamine precursor) may contribute to ↓phospholipid synthesis, increasing epithelial disruption. AHR: Aryl hydrocarbon receptor; IL: Interleukin; LPS: Lipopolysaccharides; NF-κB: Nuclear factor kappa B; TNF-α: Tumor necrosis factor alpha; ZO-1: Zonula occludens-1; NLRP6: NOD-like receptor family pyrin domain containing 6.
Under normal conditions, the intestinal barrier tightly regulates nutrient absorption while preventing the passage of pathogens and harmful substances. When this balance is disrupted, intestinal permeability increases, allowing microbial components and toxic metabolites to translocate into the lamina propria and systemic circulation. This disturbance promotes systemic inflammation, a condition commonly termed ‘leaky gut’[17]. This process occurs through regulated paracellular routes controlled by tight junctions or through unrestricted pathways associated with epithelial damage. Persistent exposure to dysbiosis, oxidative stress, alcohol, allergens, and infections contribute to barrier dysfunction and is strongly linked to obesity and metabolic disorders[41].
Importantly, increased intestinal permeability is an active, immune-regulated process rather than a purely structural defect. Altered immune–microbiota interactions, at the mucosal interface, experience chronic low-grade inflammation, a defining feature of obesity and elevated BMI. This phenomenon encourages epithelial permeability, inflammatory signalling, and the translocation of microbial-derived products that drive metabolic inflammation and insulin resistance. In higher-BMI individuals, important findings include decreased levels of tight junction proteins (claudin-1, -2, and -3, and zonulin-1), which are mainly regulated by TNF-α and NF-κB. Although there is insufficient evidence to establish a definitive association between obesity and increased intestinal barrier permeability (IBP), repeated links have been reported between IBP alterations in obese subjects when zonulin is used as a permeability marker for molecular flow from the intestinal lumen to the extra-intestinal compartment. Zonulin is a protein that has been implicated in intracellular tight junction modulation and epithelial cell tight junction openings. These alterations are further enhanced by concurrent changes in the intestinal microbiota. Accordingly, these correlations provide a strong basis for recognizing IBP impairment and a positive association with increased BMI. This malfunction results in microbiota-derived LPS translocating into the systemic circulation, leading to metabolic endotoxemia. A process that can develop chronic low-grade pro-inflammatory and pro-oxidative stress via TLR4-mediated triggering[31]. Circulating LPS serves as a potent innate immune system activator by stimulating TLR4 on macrophages and Kupffer cells, encouraging sustained TNF-α and IL-6 triggering. This process reinforces a state of systemic metainflammation, underpinning a vicious inflammatory cycle linking intestinal barrier dysfunction to intestinal and systemic damage (hepatic compromise) in individuals with high BMI[42,43].
Innate immune pathways play a most prominent role in maintaining mucosal homeostasis. The NLRP6 inflammasome regulates epithelial integrity by caspase-1-dependent maturation of IL-18 and IL-1β, thereby controlling goblet cell function, mucin production, epithelial repair, and antimicrobial defences. Similarly, TLR5 and NOD2 contribute to microbiota balance and pathogen control. Deficiencies in these receptors lead to dysbiosis, increased T helper 17 responses, intestinal inflammation, and metabolic dysfunction. Regulatory T cells (Tregs) further maintain immune tolerance through IL-10 and transforming growth factor beta, while beneficial microbial taxa promote Treg differentiation and suppress excessive inflammation. Disruption of immune–microbiota crosstalk compromises barrier capacity and promotes chronic inflammation. In obesity, intestinal permeability-particularly in the jejunum-is increased and is closely associated with local and systemic inflammation. This is demonstrated by altered tight junction protein expression, high circulating markers of barrier disruption, and enhanced macromolecule permeability, especially after high-fat dietary intake. Barrier impairment correlates with inflammatory markers and is exacerbated in type 2 diabetes[43]. Although intestinal immune cell infiltration is common in obesity, evidence suggests that epithelial barrier dysfunction can precede overt immune activation in certain circumstances. Nevertheless, the accumulation of pro-inflammatory macrophages and sustained mucosal immune activity remain key drivers of chronic systemic inflammation and immunometabolic dysregulation. Mechanistically, reduced NLRP6-IL-18 signalling and impaired aryl hydrocarbon receptor activity compromise mucin production and tight junction integrity. While obesity-associated dysbiosis and repeated exposure to a high-fat diet preserves a feed-forward cycle of endotoxemia, immune activation, and barrier disruption (Figure 4).
GUT MICROBIOTA AND INCREASED GUT PERMEABILITY
One of the most important factors underlying the processes described above is dysbiosis: An imbalance in the bacterial communities colonizing the GI tract. Gut microbiota generally involves approximately 100 trillion archaea and bacteria. And nearly 90% are represented by the phyla Firmicutes and Bacteroidetes. Current knowledge shows that changes in body weight have been consistently associated with shifts in this microbial composition. Accordingly, in individuals with obesity, gut microbiota architecture is markedly altered. It is characterised by an increase in Proteobacteria (including Escherichia coli) and a concomitant reduction in Bacteroidetes, Clostridiales, and Actinobacteria[35,44]. These alterations disturb the immune system and host energy storage regulation. This relationship is further supported by experimental evidence showing that faecal microbiota transplantation from obese mice into lean recipients results in increased intestinal permeability and intestinal inflammation. A causal increase in the risk of developing type 2 diabetes was also observed. These findings highlight the critical role of the gut microbiota in mediating the metabolic and inflammatory consequences of obesity[44].
Commensal bacteria are responsible for the production of several metabolites that are beneficial to intestinal homeostasis. These include indole derivatives, conjugated fatty acids, bile acid derivatives and, most notably, short-chain fatty acids (SCFAs). SCFAs are the final products of bacterial fermentation and comprise the primary energy source for intestinal epithelial cells, contributing up to 10% of an individual’s basal energy requirements. A lower number of commensal bacteria that produce SCFAs also means fewer energy sources for colonocytes. Specific bacteria like Akkermansia muciniphila, a mucin-degrading bacterium, have been associated with reinforcement of the mucus layer and upregulation of tight junction proteins such as ZO-1, thereby improving epithelial integrity and reducing permeability. Similarly, members of the Bacteroides family have immunomodulatory effects through the production of bioactive molecules, such as polysaccharide A, which promote both regulatory T cell differentiation and IL-10 secretion. These processes have been demonstrated to improve immune tolerance. And disorders in either the amount or activity of these microorganisms, as observed in obesity-associated dysbiosis, result in reduced SCFA availability, impaired intestinal barrier integrity, increased LPS translocation, and triggering of innate immune pathways[34]. Therefore, low-grade inflammation develops[43].
Although the accurate mechanisms by which microbial alterations contribute to increased intestinal permeability have not been fully elucidated, there has been a consistent association with zonulin. This is a permeability marker for molecular flow from the intestinal lumen to the extra-intestinal compartment. Growing evidence also suggests a strong association between the expression of tight junction complexes, particularly a significant reduction in ZO-1, and alterations in the availability of beneficial microbial metabolites, most notably ethanolamine. ZO-1 is an organic molecule, mainly regulated by TNF-α and NF-κB, present in animal, human, and bacterial cells. This molecule serves as a precursor of the phospholipid phosphatidylethanolamine in cell membranes. It is found freely within the gut lumen, to some extent due to dietary intake and continuous epithelial cell turnover along the GI tract[45]. Its luminal concentration is typically regulated by bacterial metabolism, a process that becomes disrupted in obesity. In this context, Mishra et al[46], demonstrated that ethanolamine levels are raised in obesity due to the previously described microbial imbalance, which reduces the abundance of ethanolamine-utilizing bacteria, particularly in the ileum. The underlying mechanism involves epigenetic regulation. Ethanolamine upregulates the expression of microRNA-101a-3p (miR-101a-3p), for which ZO-1 contains specific binding spots. The attachment of this microRNA reduces ZO-1 stability and ultimately lessens its expression. Additionally, it is believed that ethanolamine exposure and obesity-associated changes in the microbiota, whether in combination or separately, disturbs AT-rich interaction domain 3A. This is a transcription factor that binds the miR-101a-3p promoter, further amplifying its expression. The resulting increase in miR-101a-3p leads to enhanced suppression of ZO-1, destabilisation of tight junctions, increased intestinal permeability, and subsequent antigen translocation, thereby promoting endotoxemia and inflammation (Figure 5). Thus, preservation of ethanolamine-metabolising bacteria, particularly Lactobacillus and Bifidobacterium species, may represent a protective strategy against obesity-related metabolic and inflammatory alterations driven by intestinal permeability and chronic inflammation[47].
Figure 5 Self-amplifying cycle of chronic inflammation in obese adipose tissue.
Obese adipocytes, undergoing endoplasmic reticulum stress and NOD-like receptor family pyrin domain containing 3 inflammasome triggering, release pro-inflammatory cytokines [tumour necrosis factor alpha, interleukin (IL)-6, IL-1β, IL-18] and recruit M1 macrophages via monocyte chemoattractant protein-1. Infiltrating M1 macrophages also trigger their inflammasomes and secrete additional cytokines, establishing a continuous feedback loop that maintains tissue inflammation. ER: Endoplasmic reticulum; NLRP3: NOD-like receptor family pyrin domain containing 3; TNF-α: Tumour necrosis factor alpha; IL: Interleukin; MCP-1: Monocyte chemoattractant protein-1; CCL2: C–C motif chemokine ligand 2; M1: Classically activated (pro-inflammatory) macrophage phenotype.
Tight junction complexes are integrated by two major structural components: Transmembrane and intracellular elements. The transmembrane components involve occludens, claudins, and junctional adhesion molecules, which are located within the paracellular space. In contrast, the intracellular complexes, integrated by zonula occludens proteins (ZO-1, ZO-2, and ZO-3), anchor these transmembrane proteins to elements of the intracellular cytoskeleton, such as actin[48]. Together, these structures restrict the passage of luminal contents and antigens into the underlying lamina propria and bloodstream. Therefore, exposure to immune cells that would otherwise trigger local and systemic inflammatory cascades is avoided. This phenomenon is observed in obesity-associated GI inflammation and increased permeability.
BIOMOLECULAR PATHOPHYSIOLOGY OF GI INFLAMMATION
Inflammation in obesity represents a complex disruption of homeostatic balance. It triggers compensatory mechanisms to restore balance. This process involves features such as the gut microbiota, increased intestinal permeability, and ethanolamine-driven metabolic endotoxemia, among other contributing pathways. Monocyte chemoattractant protein-1 (MCP-1), also known as CCL2, is an important mediator that links adipose tissue growth to inflammation. High MCP-1 levels from adipocytes and stromal cells attract monocytes, which differentiate into pro-inflammatory M1 macrophages. These cells release more cytokines and develop a self-reinforcing cycle that maintains persistent inflammation in obesity. Along with TNF-α and IL-6, MCP-1 helps develop a pro-inflammatory environment in adipose tissue, disrupting metabolism and distressing the whole body. This complex network of interactions between adipocytes, immune cells, cytokines, and the NLRP3 inflammasome is summarised in Figure 5, which illustrates the self-perpetuating inflammatory cycle in obese adipose tissue.
Inflammatory signalling and cytokine production are essential physiological processes involved in host defence and tissue homeostasis. However, in obesity, these processes are impaired because inflammatory triggering is persistent, does not resolve, and is one of the most important factors in metabolic and GI dysfunction[49]. The primary events occur within the adipocyte itself. Chronic nutrient excess leads to oxidative stress within the cell and the endoplasmic reticulum, driven by sustained overproduction of reactive oxygen species (ROS). This response, along with the accelerated expansion of adipose tissue, results in impaired and dysregulated angiogenesis, ultimately leading to tissue hypoxia. This hypoxic state represents one of the earliest triggers of adipocyte inflammation in obesity. Concurrently, increased oxygen consumption in adipocytes is further exacerbated by the activation of the mitochondrial protein adenine nucleotide translocase 2 (ANT2), which is stimulated by saturated fatty acids. ANT2 promotes uncoupled oxidative phosphorylation, diverting oxygen away from adenosine triphosphate synthesis toward non-productive mitochondrial consumption. The resulting hypoxia inhibits degradation of hypoxia-inducible factor 1-alpha (HIF-1α). This allows HIF-1α intracellular buildup and subsequent chemokine gene transcription, thereby triggering an inflammatory response. These chemokines drive monocyte recruitment and differentiation.
Circulating monocytes give rise to resident macrophages within the GI tract, which constitute the most abundant leukocyte population in this tissue. These cells are traditionally classified into three subsets: Classical, non-classical, and intermediate monocytes which, upon maturation, differentiate into five macrophage subpopulations. These macrophages include P1 and P2 with pro-inflammatory roles; P3, an intermediate population; and P4 and P5, originated from P3 and characterized as anti-inflammatory, tissue-resident macrophages. Studies exploring these leukocytes, in the context of the so-called “sterile inflammation” have demonstrated impaired differentiation toward anti-inflammatory phenotypes[30]. This deficiency contributes to the chronic inflammatory processes characteristic of GI inflammatory disorders such as IBD, Crohn’s disease, and ulcerative colitis, and may represent a similar mechanism operative in obesity. Indeed, leukocyte accumulation has been documented in the stomach, duodenum, and colon of individuals with obesity. Importantly, macrophage differentiation is not fixed and can be modulated by dietary factors, including saturated fatty acids and omega-3 fatty acids. A key mechanism linking increased BMI to GI inflammation is the triggering of innate immune signaling pathways, especially the TLR4/NF-κB axis and the NLRP3 inflammasome (Figure 5).
Upstream, these pathways are primarily triggered by metabolic endotoxemia. Increased intestinal permeability promotes LPS translocation into the systemic circulation. LPS is a component of Gram-negative bacteria that binds to TLR4 on intestinal epithelial cells, macrophages, and Kupffer cells. This process begins intracellular signaling through adaptor proteins such as MyD88. This signaling pathway triggers the IκB kinase complex, leading to IκB degradation and nuclear translocation of NF-κB. Once triggered, NF-κB promotes transcription of multiple pro-inflammatory genes, including TNF-α, IL-6, and pro-IL-1β, thereby establishing a pro-inflammatory milieu. Importantly, NF-κB signaling also provides the main signal required for the NLRP3 inflammasome triggering. This multiprotein complex is subsequently activated by secondary stimuli associated with obesity, including ROS, mitochondrial dysfunction, and intracellular lipid accumulation. Upon activation, NLRP3 recruits and activates caspase-1, which cleaves pro-IL-1β and pro-IL-18 into their mature, biologically active forms[40]. The crosstalk between these pathways starts a self-amplifying inflammatory loop. TLR4/NF-κB signaling enhances inflammasome priming, while IL-1β and IL-18 released from NLRP3 activation further amplify NF-κB-driven transcription and immune cell recruitment. This interaction maintains chronic low-grade inflammation (metainflammation) and contributes to epithelial barrier disruption, immune cell infiltration, and systemic metabolic dysregulation[41].
Another important process involves dysregulated Ca2+-mediated pathways implicated in adipogenesis and subsequent inflammation. Abnormally stimulated, immune responses in the GI mucosa trigger TNF-α, IL-6, IL-12/23, and IFN-γ, ultimately leading to tissue damage. These findings may develop a vicious circle in which the affected GI barrier and creeping fat magnify injury mechanisms. Therefore, adipose-induced inflammation weakens intestinal integrity[43]. A critical observation is that this inflammatory process is dynamic rather than static, advancing as obesity increases. Adipocyte death driven by hypoxia, together with excess free fatty acids, acts as a danger signal to the immune system, thereby amplifying systemic inflammation[50]. This combination disrupts metabolic homeostasis, impairs insulin signalling, and preserves a self-sustaining inflammatory-metabolic cycle that directly affects both the GI tract and the liver[42].
Collectively, evidence shows that nearly all GI organs react adversely to the chronic inflammatory environment generated by adipose tissue. Immune tolerance is compromised, epithelial barriers become increasingly susceptible to injury, and the gut microbiota works as an amplifier of inflammation. Excess adiposity, systemic inflammation, and increased intestinal permeability comprise the fundamental pathophysiological basis for heightened GI vulnerability in individuals with a high BMI[42,50-52].
NUTRITIONAL PREVENTIVE STRATEGIES
Emerging evidence suggests that prevention-focused strategies may play a critical role in mitigating GI and systemic inflammation associated with increased adiposity. Accordingly, restricting excessive adiposity and preserving gut homeostasis are key preventive strategies. Once metabolic dysfunction has been established, early interventions targeting weight control, dietary patterns, physical activity, and gut microbiota modulation represent promising approaches to attenuate the biomolecular pathways linking obesity to chronic inflammation. Sustained weight control remains a cornerstone preventive strategy. It has been demonstrated that even moderate body weight loss is associated with significant improvements in obesity-related inflammatory biomarkers. Hence, reductions in adipose tissue directly decrease the production of pro-inflammatory adipokines such as TNF-α, IL-6, and leptin, while restoring adiponectin levels, thereby partially reversing the chronic low-grade inflammatory state. Remarkably, achieving a weight loss of at least 10% has been associated with consistent improvements in these inflammatory markers, supporting a dose-dependent relationship between adiposity reduction and immunometabolic recovery[53]. Dietary and lifestyle modifications act as key upstream modulators of GI inflammation by directly affecting the mechanisms previously described. Limiting adherence to Western-type diets may inhibit metabolic dysregulation, gut microbiota dysbiosis, and increased intestinal permeability. Diets high in saturated fats and ultra-processed foods encourage LPS translocation and TLR4/NF-κB activation[54], thereby maintaining systemic inflammation. In contrast, dietary patterns rich in fiber, fruits, and plant-based foods enhance SCFAs production, particularly butyrate. Accordingly, SCFA strengthen intestinal barrier integrity by upregulating tight junction proteins, such as ZO-1, and lower endotoxemia. These effects directly counteract the barrier dysfunction and microbial translocation described in obesity-related GI inflammation[55-58].
Regular physical activity plays a key role in preventive strategies by improving gut motility, reducing intra-abdominal pressure, and enhancing metabolic efficiency. Therefore, physical activity attenuates inflammatory signaling pathways associated with obesity. Additionally, modulation of the gut microbiota represents a central therapeutic target. Prebiotics and probiotics, particularly Lactobacillus and Bifidobacterium species, encourage microbial diversity, enhance SCFA production, and improve intestinal barrier integrity[59]. These effects are associated with reduced translocation of LPS and attenuation of TLR4-mediated inflammatory signaling, thereby contributing to lower systemic and intestinal inflammation[60,61]. It has been demonstrated that strategies aimed at preserving microbial metabolic activities (such as SCFA production, bile acid metabolism, and micronutrient synthesis) may provide long-term protection against obesity-associated GI inflammation. By directly targeting these connected biomolecular mechanisms, preventive approaches can interfere with the feed-forward cycle of dysbiosis, endotoxemia, and immune activation. Accordingly, evolution towards metabolic and immune-mediated GI comorbidities associated with increased adiposity is reduced[62].
MECHANISM-TARGETED NUTRITIONAL INTERVENTIONS
Beyond general recommendations such as weight loss, diet, and physical activity, targeted nutritional interventions have been shown to modulate molecular mechanisms involved in GI inflammation directly. Human data analysis demonstrates that prebiotic fibers, especially inulin-type fructans, improve intestinal barrier integrity by increasing SCFA production. In turn, SCFA strengthen tight junction protein expression, including ZO-1, and reduce endotoxemia[63,64]. These outcomes are further reinforced by the key role of SCFAs in regulating epithelial integrity and inflammatory signaling pathways, as described by Nogal et al[65]. In addition, SCFA supplementation, particularly butyrate, has barrier-protective effects independent of microbial fermentation by promoting antimicrobial peptide production and strengthening tight junction structure[63]. Probiotic interventions, especially Lactobacillus and Bifidobacterium strains, further contribute to this process. They modulate gut microbiota composition, lower LPS production, and suppress pro-inflammatory pathways such as NF-κB. At the same time, they are improving the expression of tight junction proteins. These findings are consistently supported by both experimental and clinical evidence[66]. Additionally, omega-3 PUFAs have been shown to support intestinal barrier function by promoting beneficial microbial populations and reducing systemic inflammation, thereby improving SCFA production and gut homeostasis[67]. Collectively, these findings suggest that dietary composition and microbiota-directed interventions, rather than weight loss alone, play a critical role in modulating gut barrier integrity and inflammatory pathways associated with obesity-related GI dysfunction.
As indicated earlier, while BMI is commonly used to explore the relationship between obesity and GI inflammation, its limitations significantly affect the interpretation of underlying mechanistic pathways. BMI does not account for fat distribution, particularly visceral adiposity, which is a key driver of inflammation through its role in cytokine production, metabolic endotoxemia, and intestinal barrier dysfunction[68]. As a result, BMI-based analyses may either underestimate or hide associations between adiposity and inflammatory processes. Current evidence suggests that measures displaying visceral fat provide a more accurate illustration of inflammatory risk. Anthropometrically predicted visceral adipose tissue has been shown to explain a greater proportion of the variability in inflammatory biomarkers than BMI alone[69]. This is particularly relevant in the context of GI mechanisms, as intestinal permeability has been directly associated with visceral fat accumulation, but not with overall adiposity[70]. Similarly, WC demonstrates stronger associations with multiple inflammatory cytokines than BMI, further supporting the importance of fat distribution in shaping inflammatory profiles[71]. Moreover, BMI may wrongly categorize individuals across the adiposity spectrum, as seen in normal-weight obesity. That is, individuals with normal BMI but elevated body fat show increased systemic inflammation that would not be identified using BMI alone. Despite these limitations, BMI remains a useful epidemiological tool due to its simplicity and consistent correlation with overall adiposity in the general population. However, analysis in mechanistic studies should be carefully approached, recognizing that it works as an indirect measure that may not fully identify the biological processes driving GI inflammation.
CONCLUSION
Although BMI remains a widely used anthropometric tool because of its simplicity, it still lacks the capacity to fully cover the complex biological processes underlying obesity-associated GI inflammation. Our review supports the perspective that excess adiposity should not be interpreted as a quantitative increase in body mass alone, but as part of a dynamic immunometabolic state characterized by chronic low-grade inflammation, barrier dysfunction, and microbiota-driven signaling disturbances. It is important to note that the relationship between BMI and GI inflammation is neither linear nor uniform. It is possible that individuals with the same BMI values could exhibit markedly different inflammatory responses. This suggests that BMI alone does not involve the heterogeneity of adipose tissue distribution, immune activation, and gut microbiota composition. This underscores the need to move beyond conventional anthropometric stratification toward more integrative tools or models that include metabolic, immunological, and microbiome-related parameters. Current evidence highlights an important and central pathophysiological axis involving intestinal barrier disruption, dysbiosis, and adipose tissue-derived inflammatory signaling. Accordingly, intestinal permeability and metabolic endotoxemia act as key amplifiers of systemic and local inflammation, strengthening the cycle that contributes to GI dysfunction and metabolic disease. Although our understanding of this mechanism is still in progress, current research is focused on transforming these findings into clinically applicable tools. Future research should prioritize the identification of reproducible biomarkers that reveal GI inflammatory stress and intestinal barrier integrity. It would also be useful for the development of clinically relevant obesity subtypes based on immunometabolic phenotypes rather than using BMI alone. This kind of stratification could allow more precise risk assessment and lead the way towards targeted therapeutic strategies for each type of patient. Interventions aimed at modulating the gut microbiota, restoring epithelial barrier function, and selectively targeting inflammatory pathways. So, all of these could represent an innovative approach for treatment. Integrating BMI with functional, metabolic, and inflammatory markers may improve both preventive and therapeutic decision-making. At the end, redefining obesity as a heterogeneous immunometabolic disorder, rather than just an anthropometric condition, may facilitate the transition to personalized clinical approaches in the management of GI inflammation and associated comorbidities.
Peer review: Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: Mexico
Peer-review report’s classification
Scientific quality: Grade A, Grade B, Grade B
Novelty: Grade A, Grade B, Grade C
Creativity or innovation: Grade A, Grade B, Grade C
Scientific significance: Grade A, Grade A, Grade B
P-Reviewer: Ji KK, MD, PhD, China; Wang XD, MD, PhD, Researcher, China S-Editor: Liu H L-Editor: A P-Editor: Lei YY
