Therapeutic Potential of a Synbiotic to Improve Mental Health in Subjects With Obesity.

Obesity is one of the most widespread chronic diseases globally, resulting from a complex interaction between dietary habits and environmental and genetic factors. According to the statistics from the World Health Organization, more than 1.9 billion adults are overweight, and approximately 650 million people suffer from obesity. Moreover, these individuals are at a higher risk of developing numerous metabolic disorders, such as type 2 diabetes, atherosclerosis, cardiovascular diseases, non-alcoholic fatty liver disease, reproductive issues, and some forms of cancer. Lifestyle and pharmacological interventions are two of the most important strategies for treating obesity. However, strict lifestyle changes are often only accepted by a limited number of individuals, and anti-obesity drugs can have some adverse effects, while their efficacy is often diminished after prolonged use. Therefore, a significant unmet need is the lack of convenient and effective adjunctive therapies for treating obesity.

There is a bidirectional association between obesity and mood disorders such as depression and anxiety. Obesity also has a negative effect on health and quality of life, as well as on self-esteem. Specifically, it is estimated that approximately 50% of individuals with obesity develop depressive and anxious traits, which are more common in females and more frequent as the degree of obesity increases. Furthermore, people with obesity often suffer a considerable emotional burden, increasing stress, daily worries, and even experiencing difficulties in performing daily life activities. Added to the stigma of the disease, which has a negative impact on self-esteem and body image, this worsens the quality of life and emotional state of these individuals. Therefore, mental health is closely interconnected with obesity, and addressing both the physical and emotional aspects is crucial for promoting overall well-being. It is important to adopt a holistic approach that includes interventions in diet, physical exercise, and emotional and psychological support for those struggling to maintain a healthy weight and adequate mental health.

The gut-brain axis is a bidirectional communication network between the gut and the central nervous system, functioning through neuroimmune and neuroendocrine processes. Its involvement in the onset of depression has been postulated and is mediated by molecules such as short-chain fatty acids, gamma-aminobutyric acid (GABA), and tryptophan metabolites originating from the gut microbiota. In situations of dysbiosis or alterations in microbiota homeostasis, the gut-brain pathways can be found deregulated and are associated with neuroinflammation and altered blood-brain barrier permeability. Moreover, alterations in the gut microbiota may contribute to a depressive state by directly affecting the release of neurotransmitters such as serotonin and dopamine, influencing the stress response and the hypothalamic-pituitary-adrenal (HPA) axis, affecting brain-derived neurotrophic factor (BDNF) levels, and triggering the release of inflammatory cytokines. For example, depression is associated with an increased release of C-reactive protein (CRP) and cytokines such as IL-1, IL-2, IL-6, IFN-y, and IL-1ß.

Obesity also causes inflammation at the intestinal level, insulin resistance, and body fat deposits. Research in this field suggests that there is a bidirectional relationship between the composition of the gut microbiota, obesity, and insulin resistance. It has been observed that people with obesity have a different microbial composition compared to those with a healthy weight. It is believed that this alteration in the gut microbiota could further contribute to the progression of obesity by increasing the ability to extract energy from food, promoting low-grade inflammation, increasing lipogenesis, decreasing fatty acid oxidation, and increasing triglyceride accumulation at the hepatic level, among other mechanisms.

Considering the role of the gut microbiota in regulating the immune system and inflammation, it can be observed that chronic inflammation is linked to both obesity and psychological disorders, including depression and anxiety. These changes in the gut microbiota may contribute to systemic inflammation and immune dysfunction, which in turn could affect both obesity and psychological disorders. Some gut bacteria can produce neurotransmitters that are absorbable at the intestinal level, such as serotonin or GABA, which are important for regulating mood and anxiety. It is believed that changes in the composition of the gut microbiota could affect the production of these neurotransmitters, and therefore, influence mental health.

Although lifestyle modifications, such as caloric restriction and physical exercise, are considered the best therapies for weight loss, there are other adjunctive options, such as the modulation of the gut microbiota, that could be useful for people with obesity. Studies in which prebiotics, probiotics, and synbiotics were administered to individuals with obesity have shown their beneficial effects on weight reduction and other metabolic parameters through the modulation of the gut microbiota. Due to the emerging evidence implicating the gut-brain axis in obesity and its relation to psychological disorders, there has been increased interest in the development of these treatments as therapies for restoring the gut microbiota.

Prebiotics are functional foods, given their beneficial role in promoting health and preventing disease. An example is tannins, considered bioactive compounds due to their ability to modulate metabolic processes and promote health. Much of the tannins ingested reach the large intestine, where the gut microbiota converts them into metabolites, including short-chain fatty acids such as acetate, propionate, and butyrate. These short-chain fatty acids are important metabolites that can have various beneficial effects on the host's intestinal and overall health. They also exert a potential antidiabetic effect through the following mechanisms: (i) Improvement of insulin and proinsulin levels in the blood: the affinity of tannins for binding to polysaccharides causes a delay and a decrease in the availability of glucose in the gastrointestinal tract. Additionally, several studies have reported the potential for inhibiting the activities of α-amylase and α-glucosidase through hydrolyzable tannins and condensed tannins, respectively. (ii) Insulin-like effect on insulin-sensitive tissues: procyanidins may act on specific components of the intracellular insulin signaling pathway. (iii) Regulation of the antioxidant environment of pancreatic cells: oxidative stress is believed to play a role in insulin resistance as it determines pancreatic cell apoptosis. Additionally, the expression of genes related to antioxidant enzymes in the pancreas is low. The high antioxidant capacity of tannins can counteract the pathogenesis of insulin resistance, along with their anti-inflammatory properties (they decrease TNFα, IL-1, IL-6 levels, etc.) and cardioprotective properties (they increase superoxide dismutase, decrease ROS, etc.).

Specifically, high molecular weight tannins reach the gut microbiota in the colon showing a prebiotic effect. In this case, the compounds are metabolized by microorganisms, producing metabolites with different bioavailability, activity, or functional effects compared to the original molecule. Finally, tannins can modulate the composition and function of the gut microbiota, selectively inhibiting pathogens and promoting the growth of beneficial bacteria.

Probiotics are preparations of microorganisms that, when administered in appropriate conditions and amounts, improve the microbial balance of the gut. These microorganisms have been shown to suppress inflammation and modulate the immune system by preventing the induction of the IL-8 cytokine in the human colon epithelium, as well as reducing intestinal permeability, inhibiting endotoxemia. Probiotic interventions can contribute to the treatment of obesity and associated complications by improving the abundance and function of the gut microbiota. Therefore, the combination of prebiotic and probiotic interventions (synbiotics) can provide a synergistic and effective therapy for metabolic disorders. Additionally, the positive role of synbiotic supplementation in mental illnesses such as major depressive disorder has been documented. In this case, synbiotics could improve depression symptoms by enhancing tryptophan metabolism and decreasing dopamine metabolite concentrations in the amygdaloid cortex.

It has been suggested that synbiotics could help improve the type and functionality of the microbiota, reduce intestinal inflammation, and promote satiety through increased production of hormones that have this effect on the body. Therefore, this could be beneficial in managing obesity. Synbiotics may play a crucial role in modulating macronutrient metabolism by producing short-chain fatty acids, which bind to G-protein-coupled receptors and increase the secretion of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) from enteroendocrine L cells. These bindings can trigger insulin production by pancreatic β-cells, inhibit glucagon secretion, decrease hepatic gluconeogenesis, and increase insulin sensitivity. Synbiotics also improve intestinal function, elevate mucin production, and reduce the number of pathogenic gram-negative bacteria in the colon. These changes reduce the transmission of lipopolysaccharides (LPS) across the mucosal wall and metabolic endotoxemia, which may ultimately lead to improvements in insulin receptor function and lower insulin levels. Previous studies have shown that their administration is beneficial for both obesity and typical psychological symptoms of depression or anxiety, among others. A 6-week intervention with synbiotics can significantly reduce depression symptoms compared to a placebo. In this field, a 2017 meta-analysis suggested that probiotics can reduce psychological symptoms, including anxiety, depression, and perceived stress in healthy adult volunteers. The gut microbiota can directly produce neurotransmitters like serotonin and influence its production. It also has immunomodulatory functions and is capable of activating the hypothalamic-pituitary axis through the production of proinflammatory cytokines IL-1 and IL-6.

In this context, an intervention with a synbiotic composed of tannins and beneficial intestinal strains in individuals with obesity could have beneficial effects on health by increasing antioxidant capacity and short-chain fatty acid production, modulating the production of neurotransmitters involved in satiety and mood, and promoting gut microbiota balance, mucosal protection, and improved intestinal permeability.

Therefore, combining synbiotic interventions could provide a synergistic and effective therapy for both metabolic and psychological disorders. Addressing obesity comprehensively, including medical treatment, psychological support for mental health, and synbiotic treatment, could improve emotional state, obesity, and psychological disorders. Ultimately, it could enhance the quality of life for affected individuals. While research in this area is still ongoing and more evidence is needed to understand these interactions underfully, there is growing evidence suggesting that gut microbiota health can influence both physical and mental health in complex and significant ways. Promoting a healthy gut microbiota through a balanced diet, intake of fiber-rich foods and probiotics, as well as stress reduction, may be beneficial for addressing both obesity and psychological disorders, even synergistically with other treatments.

Therefore, our goal is to determine whether the intake of a synbiotic composed of lactic acid bacteria, bifidobacteria, and tannin-based phytocomplexes, is capable of improving an

• Evaluate significant changes in body fat mass percentage after the synbiotic intake. [Time frame: 3 years]
• Assess significant changes in high-sensitivity C-reactive protein (hs-CRP) as an inflammatory parameter after the synbiotic intake [Time frame: 3 years]
• Evaluate significant changes in C3 protein as an inflammatory parameter after the synbiotic intake. [Time frame: 3 years]
• Assess significant changes in plasmatic homocysteine as an inflammatory parameter after the synbiotic intake. [Time frame: 3 years]
• Evaluate significant changes in interleukin 1-beta (IL-1B) levels as a pro-inflammatory molecule after the synbiotic intake [Time frame: 3 years]
• Evaluate significant changes in interleukin 6 (IL-6) levels as a pro-inflammatory molecule after the synbiotic intake. [Time frame: 3 years]
• Evaluate significant changes in tumor necrosis factor alpha (TNF-alpha) levels as a pro-inflammatory molecule after the synbiotic intake. [Time frame: 3 years]
• Assess significant changes in superoxide dismutase (SOD) levels after the synbiotic intake. [Time frame: 3 years]
• Evaluate if there is a significant reduction after the synbiotic intake in total ROS levels. [Time frame: 3 years]
• Assess if there is a significant reduction after the synbiotic intake in glutathione levels. [Time frame: 3 years]
• Analyze if there is a significant change after the synbiotic intake in total free radicals and superoxide levels. [Time frame: 3 years]
• Analyze if there is a significant reduction after the synbiotic intake in mitochondrial ROS production. [Time frame: 3 years]