CUR is a powerful and adaptable substance with a broad range of therapeutic applications, and its remarkable effects go beyond conventional medical interventions. It is well-known for its excellent ability to alleviate inflammation, combat free radicals, support the body’s natural defense mechanisms against cancer, and protect against various cardiovascular ailments, thus being a valuable ally in modern medicine (Mondal et al., 2024; Mayo et al., 2024). Obesity is associated with increased levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). CUR’s anti-inflammatory action is typically linked to one or more of the following mechanisms: acting on receptors and signaling pathways, controlling how the target tissue reacts to inflammatory mediators, reversing the effects of media on the target tissue, or generating anti-inflammatory mediators (Medzhitov, 2008). CUR has anti-inflammatory properties as it regulates inflammatory signaling pathways and inhibits the synthesis of inflammatory mediators (Peng et al., 2021). CUR has been shown to inhibit the growth of cancer cells in many cancers. Prostate cancer originates from or affects the male prostate epithelium. Considerable research has investigated the anti-cancer influence of CUR on androgen-sensitive prostate cancer cells. For example, a study by Dorai found that the proliferation rate of LNCaP cells decreased to 20%–30% of untreated cells, with a maximal half-maximal inhibitory concentration (IC50) of CUR being 10–20 μM (Dorai et al., 2000). Under the same condition, the level of Bcl-2 binding X (Bax) remained unchanged, but there was significant inhibition on the levels of Bcl-2 and Bcl-xL, showing a higher Bax/Bcl-2 ratio compared to untreated cells. Another example is NF-κB, a pro-inflammatory transcription factor crucial for breast cancer cell growth. It controls the expression of proteins involved in cell signaling pathways and over 500 different genes related to cancer and inflammation. By inhibiting NF-κB interactions, CUR may be useful in cancer treatment. Specifically, by downregulating the NF-κB-inducing gene, CUR can prevent breast cancer cells from proliferating and invading (Liu et al., 2009; Kim et al., 2012).

CUR, a potent and multifaceted compound derived from the yellow spice turmeric, has been extensively studied not only for its culinary properties but also for its potential health benefits. Its ability to be consumed in various forms such as tea, food, and supplements has made it a popular ingredient in many cuisines worldwide. The United States Food and Drug Administration (FDA) has declared that CUR is a safe substance, and there are no significant risks associated with its use (Cheng et al., 2001; Prasad et al., 2014; Rahimnia et al., 2015).

The wide range of suggested dosages for CUR indicates the need for caution when using this natural compound in daily life. There are numerous dosage recommendations depending on factors such as individual tolerance, intended use, and the particular ailment being treated. In one clinical trial involving healthy individuals who were administered up to 8,000 mg of CUR daily, only negligible amounts of CUR were detected in the blood after a period of regular dosing (Kocaadam and Şanlier, 2017). In contrast, when two separate groups of subjects were given either 10,000 mg or 12,000 mg of CUR respectively, a much more significant concentration was found in their blood serum. Based on these findings, a daily dose of 12,000 mg of CUR is considered safe for healthy individuals since no adverse effects have been observed (Lao et al., 2006; Vareed et al., 2008). However, despite the lack of evidence of harm, further exploration regarding the bioavailability of CUR and the optimal formulation for enhanced absorption and efficacy is still needed.

Prebiotics, as a type of food supplement, serve as the “nutrition” for probiotics. They are inactive and not affected by human digestive enzymes or gastric acid. Prebiotics can directly reach the stomach and intestines, promote the growth of probiotics in the gut, and inhibit the growth of pathogens. Well-known prebiotics include fructooligosaccharides, galactooligosaccharides, and inulin. Probiotics are various microorganisms that are beneficial to the human body and possess biological activity. They are naturally present in the human body but can also be taken orally. However, the number of living bacteria will be reduced to a certain extent after passing through the mouth, stomach, and small intestine. The most commonly used probiotics are Bifidobacteria, Lactobacillus, and Subtilis. The former two are the main probiotic ingredients in probiotic oral fluids and drinks. Escherichia coli is a bacterium that is commonly part of the normal gut microbiota in humans and animals, but some strains can be harmful and serve as important pathogens of childhood diarrhea, often leading to watery stools (Masiga et al., 2022). Pseudomonas aeruginosa is another harmful bacterium that often causes clinical symptoms such as pyogenic enteritis, abdominal pain, and diarrhea, which may lead to severe toxicity and infection (Jacobson et al., 2020). Therefore, we should focus on healthy eating to maintain the balance of bacteria in our body and stay healthy.

Having established the typical composition of gut microbiota, we next explore how dysbiosis—shifts in microbial balance—contributes to the pathogenesis of obesity, focusing on underlying molecular and physiological mechanisms. The accumulation of fat in the body is harmful to health so obesity is a complex, multi-factorial disease. Obesity is a disease that has emerged rapidly and shows no clear signs of disappearing soon. A higher body mass index (BMI) is a risk factor for non-communicable diseases (NCDs), including diabetes, cardiovascular, and musculoskeletal disorders, which can lead to a lower quality of life and reduced longevity (Litwin and Kułaga, 2021).

A persistent energy imbalance between calories consumed and calories expended is one of the main causes of obesity. The mechanism of obesity is complex and involves many aspects, such as heredity, environment, physiology, psychology, and society. Genetic factors play a significant role in obesity. Some genes have been found to be important in weight control, appetite control, and energy metabolism. A person is at a higher risk of becoming obese if there is a family history of obesity. Research on the tissue-specific effects of epigenetic factors in metabolic organs, combined with the latest advances in sequencing techniques, has greatly enhanced our understanding of the mechanisms involved in energy metabolism in obesity. The epigenome, which includes RNA-mediated processes, DNA methylation, and histone modification, is characterized by changes in gene function during mitosis or meiosis without changes in DNA sequences (Gao et al., 2021). High-calorie, HF, and high-carbohydrate diets are major reasons for obesity as they lead to excessive energy consumption. Insufficient physical activity and a sedentary lifestyle are also significant factors contributing to obesity. Moreover, the fast-paced modern life means that many people lack sufficient time or motivation to exercise regularly, resulting in lower energy consumption.

Against the backdrop of obesity mechanisms driven by gut microbiota dysbiosis, we now turn to the positive regulatory role of gut microbiota in lipid metabolism and weight control—key processes that CUR may modulate. The gut microbiota plays a crucial role in regulating body weight and fat content. The microbiota initially convert indigestible carbohydrates into short-chain fatty acids (SCFAs). Subsequently, these SCFAs are either excreted as feces or absorbed via the gut mucosa. What is more, gut microbiota and the brain interact in intricate ways through immunological, endocrine, and neurological processes (Cryan et al., 2019). By means of the “brain-gut axis,” gut microorganisms can impact the host’s CNS, and the CNS in turn influences the composition and structure of gut microbes. Furthermore, the regulation of food intake by the host’s gut microbial population might impact brain function. Subsequent research has demonstrated that gut bacteria may affect a host’s circadian rhythms in relation to nutrition. Increased adiposity may result from disruptions to the circadian rhythm.

These results emphasize how crucial gut microorganisms are for preserving a healthy weight and metabolic balance. Comprehending their role in an individual’s body metabolism might not only improve our understanding of the processes involved in energy expenditure and nutrient intake, but it may also offer suggestions for novel therapeutic approaches. Scientists aim to improve human well-being by investigating the roles of gut microorganisms to learn more about the relationship between nutrition, lifestyle, and illness (Figure 1).

In the present study, the potential remedial role of CUR in reducing insulin resistance and metabolic disturbance in the obese and type 2 diabetic male albino Wistar rat model was investigated. Also, its effect on the expression levels of brain glucose transporter 1 protein (GLUT1) and femoral muscle glucose transporter 4 protein (GLUT4) was examined. It was found that a low dose of streptozotocin (STZ) combined with a HF diet could induce diabetes. CUR was administered intragastrically at a dose of 80 mg/kg BW/day for 8 weeks (Al-Saud, 2020).

In the HF-diet group, obesity, hyperglycemia, hyperinsulinemia, decreased hepatic glycogen content, and severe dyslipidemia were all observed. In the diabetic control group, as measured by the high calculated homeostasis model assessment (HOMA-IR-index score), hyperglycemia and insulin resistance were prominent. Additionally, liver and muscle glycogen contents were reduced, dyslipidemia was present, and liver and pancreatic malondialdehyde levels were significantly elevated. In the control groups with diabetes and obesity, the levels of GLUT1 and GLUT4 were decreasing respectively.

Compared with the diabetic control group, CUR showed a glucose-lowering effect, reduced insulin resistance, dyslipidemia, and malondialdehyde levels in both tissues, and increased the glycogen amounts in the liver and muscles. Moreover, when compared to the diabetic control group, CUR significantly increased GLUT4 gene expression (Al-Saud, 2020).

As is widely known, gut microbiota plays a crucial role in human physiology, and their composition is influenced by a variety of environmental and lifestyle factors (Flandroy et al., 2018; Gentile and Weir, 2018; Rothschild et al., 2018). Any disruption in the gut microbiota spectrum, known as dysbiosis, is significant for disease development. Interestingly, CUR and its metabolites have been demonstrated to have an impact on gut microbiota (Feng et al., 2017; Cotillard et al., 2013). It is important to note that the interaction between CUR and gut microbiota gives rise to two distinct phenomena: CUR directly modulates the gut microbiota, and CUR is transformed by the gut microbiota to generate active metabolites (Lou et al., 2015; Sun et al., 2020). These two effects appear to be essential for CUR’s activity. Based on 16S rRNA sequencing of gut microbiota, the addition of CUR may increase the abundance of Bacteroides in the gut microbiota (Yi et al., 2025). Consequently, it is hypothesized that CUR alleviates oxidative damage to the liver by regulating the abundance of the gut microbiota. Specifically, when combined with HF diets, CUR has been shown to significantly reduce the abundance of many previously known inflammatory and diabetic-related species, such as Ruminococcus (Lamichhane et al., 2024). Moreover, CUR has successfully decreased 36 potentially harmful bacterial strains that are positively associated with hepatic steatosis (Schneider et al., 2015). These data indicate that CUR could be used to treat fatty hepatic steatosis by targeting the gut microbiota. These findings strongly suggest that the protective effect of CUR is likely due to its capacity to promote a significant shift from pathogenic to beneficial bacteria in the gut. CUR can also promote the transformation of anaerobes, such as Exiguobacterium, Helicobacter, Pseudomonas, Serratia, and Shewanella. This is partly reversed by the lack of estrogen following oophorectomy (Zhang et al., 2017).

Building on CUR’s ability to reshape gut microbiota, we now examine how these microbial changes translate into tangible anti-obesity effects, particularly in the context of weight loss and lipid reduction. There is mounting evidence that CUR treatment can alleviate the altered secretion of proinflammatory mediators associated with obesity and related pathologies. This section compiles and summarizes data from six trials conducted in overweight and obese patients using CUR. CUR (1 g/day) over 8 weeks decreased TNF-α, IL-6, and MCP-1 in male and female patients diagnosed with metabolic syndrome (MS) (Panahi et al., 2016). In a randomized placebo-controlled trial of 60 adolescent girls on a 10-week moderate weight loss diet, the intake of CUR (500 mg/day) resulted in significantly lower levels of hs-CRP and IL-6 compared to the placebo (Saraf-Bank et al., 2019). Additionally, it was demonstrated that CUR could regulate the circulating IL-1β level in 30 volunteers randomly assigned to either CUR (1 g/day) or a placebo for 4 weeks. Treatment with CUR showed a significantly lower level of IL-1β, whereas there was no significant difference in IL-6 and MCP-1 concentrations (Ganjali et al., 2014). In conclusion, CUR supplementation (300 mg/day) for 3 months in type 2 diabetes (T2D) patients led to significantly lower circulating free fatty acid (FFA) levels, which are believed to be a major contributor to obesity and inflammation (Na et al., 2013). CUR exerts notable effects on adipose tissue biology, as demonstrated in key preclinical studies. This study reports that CUR intervention reduces macrophage infiltration in WAT, shifts macrophage polarity toward a more anti-inflammatory profile (evidenced by a higher M2/M1 ratio), and lowers levels of proinflammatory factors such as TNF-α and IL-6 (Song et al., 2018). Additionally, CUR enhances thermogenesis, upregulates UCP1, via PPAR-dependent and -independent mechanisms, latter less characterized. CUR combined with white pepper (0.1% CUR + 0.01% white pepper) in high-fat diet mice for 4 weeks showed no significant changes in body weight or core metabolic markers, but reduced proinflammatory cytokines in subcutaneous adipose tissue with tetrahydrocurcumin accumulation. White pepper may enhance CUR solubility and tissue uptake via piperine, amplifying its adipose actions (Neyrinck et al., 2013) (Table 1).

Beyond its direct role in weight regulation, CUR exerts broader physiological effects that complement its anti-obesity properties. These include anti-inflammatory, antioxidant, and metabolic regulatory functions that synergize with its gut microbiota-mediated effects. Polyphenols (PP), which are natural bioactive ingredients in fruits and vegetables, are among the richest antioxidants in the human diet. Research has shown that PP may contribute to the improvement of MS, which may be helpful in preventing many chronic conditions, including diabetes, obesity, hypertension, and colon cancer. PP has structural diversity, which affects its bioavailability as it accumulates in the large intestine and is extensively metabolized by the gut microbiota. The gut microbiota converts PP into its metabolites, making them biologically active. Interestingly, gut microbiota not only metabolizes PP but also regulates the composition of the gut microbiota. Thus, a shift from pathogenic to beneficial microbiota can contribute to the improvement of gut health and related diseases (Shabbir et al., 2021). The good news is that CUR is a polyphenolic compound, so it can improve MS, prevent many chronic diseases, and also have beneficial effects on the gut. When administered orally, CUR enters the gut and influences the genetic diversity, richness, and composition of the gut microbiota (He et al., 2024). Shen et al. (2017) has found that CUR has a significant effect on the families of Bacteroidetes, Rikenellaceae, and Prevotellaceae. Another study showed that CUR had a significant effect on weight loss in ovariectomized rats (Zhang et al., 2017). In a recent Al-Saud (2020) study, the administration of CUR (8 weeks, 80 mg/kg/day) demonstrated anti-obesity and anti-diabetes effects in obese Wistar rats while increasing the expression of glucose transporter type 4 (GLUT4). Hepatic and pancreatic glucose-lowering effects, dyslipidemia, decreased insulin resistance, and decreased malondialdehyde were all features of CUR. Koboziev et al. (2020) added CUR to mice susceptible to diet-induced metabolic dysfunction on a HF diet. They found that the animals were protected against osteoarthritis (OA) and obesity, and there was no change in glucose clearance, the size of white adipose cells, or the integrity of the knee. CUR has also been shown to improve gut barrier function through the regulation of intracellular signaling and tight junctions. For example, it reduces the rate at which bacteria spread into the blood, liver, kidney, and spleen (Wang et al., 2017). In one study, it was discovered that CUR could improve the gut barrier and decrease the serum LPS induced by a Western diet (Ghosh et al., 2014) (Figure 3).

Mechanistically, three shared pathways emerge from current research: first, CUR improves the microbial habitat by inhibiting intestinal inflammatory factors (e.g., TNF-α and IL-6); second, its metabolites (e.g., tetrahydrocurcumin) directly regulate the activity of microbial metabolic enzymes; third, it indirectly influences microbiota-host energy metabolism crosstalk via activating the AMPK signaling pathway (Cheng et al., 2023). Notably, the validation of these mechanisms varies across species—for example, the AMPK pathway is well-studied in rodents but lacks sufficient clinical data in humans (He et al., 2024; Xiao et al., 2023; Table 2).

The course of a drug in the body determines its fate. Proper absorption, distribution, metabolism, and excretion of the drug are required for it to produce therapeutic effects in the body. The bioavailability of CUR is limited by its low solubility, poor absorption, rapid elimination, and metabolism. CUR has low solubility in water, and its physicochemical properties are unstable. Only a small amount of CUR is dissolved in the gut tract, limiting its active ingredients. CUR is a highly hydrophobic compound with a solubility of about 11 ng/ml. CUR is very unstable in alkaline conditions, resulting in the degradation of ferulic acid, feruloyl methane, vanillin, and dicyclopentanedione (Vaughn et al., 2016).

Absorption is the process by which a drug enters the bloodstream from the administration site, and CUR is poorly absorbed from the gut tract. When a maximum safe dose of CUR of 12 g/day is administered orally, the terminal level of CUR is only approximately 10 ng/ml at this time (Simental-Mendía et al., 2019). This could be caused by the action of P-glycoprotein and the first-pass effect of the liver. CUR is a substrate of P-glycoprotein, a transmembrane ATP-dependent drug efflux pump, which facilitates the removal of CUR from the gut membrane, thus restricting its permeability. Furthermore, the first-pass effect of the liver results in the metabolism of some CUR in the gut and liver, leading to decreased absorption (Tsuda, 2018). One of the major reasons for low bioavailability is the rapid metabolism of CUR (Chen et al., 2020). After entering the bloodstream, CUR is rapidly metabolized into a stable substance. In phase I metabolism, CUR is reduced to dihydrocurcumin, tetrahydrocurcumin, hexahydrocurcumin, and octahydrocurcumin, and then in phase II, CUR and dimethylcurcumin are metabolized to glucuronide and sulfate, resulting in the formation of non-bioactive glucuronide and sulfate conjugates. Interestingly, 75% of unabsorbed CUR accumulates in the colon (50–200 μM), enabling direct modulation of gut microbiota, which may explain its local bioactivity despite low systemic bioavailability.

CUR research faces several notable limitations that hinder consistent interpretation and translation of findings. Firstly, study designs vary widely—ranging from in vitro experiments with isolated cells to animal models and human clinical trials—with little standardization in methodologies, making cross-study comparisons challenging (Singh et al., 2024; Shaban et al., 2025). Secondly, dose discrepancies are striking: animal studies often use extremely high doses to observe effects, which are far higher than the lower doses typically used in human trials, raising questions about translatability. For example, doses range from 1,000 mg/day in elderly populations to 1,600 mg/day in patients with ulcerative colitis, and even up to 4,000 mg/day in some trials (Erol Doğan et al., 2024; Sanmukhani et al., 2014). This heterogeneity hinders the establishment of a unified standard for effective and safe doses in humans. Current evidence suggests that a daily dose of 500–1,000 mg may be effective for metabolic disorders (e.g., non-alcoholic fatty liver disease), while higher doses (1,500–2,000 mg/day) have been used in inflammatory conditions with acceptable safety profiles (Wang et al., 2021). However, adverse effects such as gastrointestinal discomfort may occur at doses exceeding 8,000 mg/day (Qiu et al., 2016). Notably, the U.S. National Institutes of Health (NIH) recommends that daily intake should not exceed 1,500 mg to balance efficacy and safety, but further large-scale randomized controlled trials are needed to validate optimal doses for specific populations (e.g., obese individuals or patients with gut dysbiosis).

Delivery methods also differ significantly, including oral administration (with poor bioavailability due to low solubility), encapsulation in nanoparticles, or parenteral injection, each altering CUR’s absorption, distribution, and interaction with gut microbiota (Roy et al., 2025; Pandey et al., 2025; Olotu et al., 2020). Additionally, study populations exhibit marked heterogeneity, with variations in age, baseline health status, gut microbiota composition, and concurrent medications, all of which can influence CUR’s efficacy and mask consistent trends (Obeid et al., 2023). These inconsistencies underscore the need for more standardized protocols to enhance the reliability and clinical relevance of CUR research.