Synbiotics in Metabolic Health
Transforming Therapy for Obesity, Diabetes, and Dyslipidemia
Dr. Neeraj Mishra, Professor, Amity Institute of Pharmacy, Amity University Madhya Pradesh, (Corresponding author)
Devyani Rajput, Assistant Professor, Amity Institute of Pharmacy, Amity University Madhya Pradesh
Synbiotics combining probiotics and prebiotics, are promising in metabolic disorder management by modulating gut microbiota, enhancing bioavailability, and supporting metabolic health. They optimise gut composition, improve glucose homeostasis, reduce inflammation, and positively influence lipid profiles, offering a potential adjunct therapy for conditions like obesity, diabetes, and dyslipidemia.
1. Introduction
Metabolic disorders have become a widespread epidemic globally, posing one of the most significant public health challenges of the twenty-first century. The incidence rate ranges between 20 to 45 percent (Ramesh et al., 2023). The World Health Organization (WHO) projects that by 2025, around 300 million individuals worldwide will develop metabolic disorders along with their associated complications (van Hoogstraten et al., 2023). The primary metabolic disorders observed are complex conditions characterised by interconnected metabolic abnormalities such as obesity, hyperlipidemia, inflammation, and nonalcoholic fatty liver disease as shown in Fig 1. Numerous lifestyle and dietary elements contribute to these issues. Given the growing health concerns, it is crucial to seek effective strategies for prevention and treatment (Sharma et al., 2024). One preventive strategy that has emerged to combat increasing healthcare expenses is the development of innovative synbiotic products. Synbiotics involve the combined effects of probiotics and prebiotics, which offer various therapeutic advantages and have been utilised for the prevention and treatment of human illnesses over the last decade (Kaushik et al.; Pandey et al., 2015).
Elevated blood glucose levels and insulin resistance (IR) are critical concerns in patients with metabolic disorders, potentially leading to cardiovascular diseases (CVDs) and type 2 diabetic mellitus (T2DM) if left uncontrolled and untreated (Zhao et al., 2023). Moreover, a significant and robust correlation exists between metabolic problems and nonalcoholic fatty liver disease (NAFLD). When combined with elevated plasma low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC), lipid abnormalities—which include elevated triglycerides and decreased HDL-C—define metabolic abnormalities that significantly leads to the development of cardiovascular diseases (CVDs) (Højlund, 2014; Muzurović et al., 2021).
Fig 1: Mechanisms of synbiotics on metabolic diseases targeting gut microbiota.
Synbiotics which are prebiotic foods mixed with probiotic strains—can have a major effect on metabolic activities. Current research identifies three primary pathways via which synbiotics affect metabolic diseases: alterations in gut microbiota composition, modification of gut microbial metabolites, and augmentation of intestinal barrier function; these will be elaborated upon subsequently (Oniszczuk et al., 2021; Santos-Marcos et al., 2019).
2.1 By modulation of Gut Microbiota Composition
Synbiotics have been recognised as a viable approach for obesity prevention. The amalgamation of omega-3 fatty acids and live probiotics, including Bifidobacterium, Lactobacillus, Lactococcus, and Propionibacterium, has demonstrated superior efficacy in diminishing liver fat and lipid buildup compared to the usage of probiotics in isolation (Yang et al., 2024). Additionally, oral supplements containing xylo-oligosaccharides and Bacillus licheniformis have shown enhanced weight management and lipid metabolism in obese rats, as well as a decrease in the populations of Desulfovibrionaceae and Ruminococcaceae (Li et al., 2021). The combination of Lactobacillus plantarum PMO 08 and chia seeds in murine models has demonstrated a synergistic effect on adiposity, thereby improving the intestinal environment that is conducive to the proliferation of Lactobacillus plantarum (Pires et al., 2024). Alterations in gut microbial composition were associated with increased activation of the IRS1-Akt-GLUT2 and SIRT1-AMPK-PPARα-CPR1α signaling pathways, as well as decreased ACE mRNA, bile salt hydrolase activity, and hepatic cholesterol 7-alpha hydroxylase expression (Li et al., 2021).
2.2 By the regulation of Gut Microbial Metabolites
The number of metabolites made after the synbiotic action was changed by gut bacteria. Adding Bifidobacterium lactis, Lactobacillus paracasei DSM 4633, and oat β-glucan together helped obese mice lose weight and improved metabolic conditions by balancing the levels of acetate, propionate, and butyrate in their stools and lowering the levels of bile acid (Uusitupa et al., 2020). Also, synbiotics comprising Clostridium butyricum and corn bran markedly decreased pathogen populations and promoted the growth of acetate-producing bacteria, resulting in increased concentrations of acetate and isovalerate (Russell et al., 2011). In addition, synbiotics such as Lactobacillus paracasei N1115 and fructo-oligosaccharides improved NAFLD in mice by promoting lipid metabolism through the downregulation of relevant molecular targets, such as TLR4 and NF-κB, and the reduction of LPS production (Li et al., 2021). In addition, synbiotics including Bifidobacterium bifidum V, Lactobacillus plantarum X, and polysaccharides sourced from Salvia miltiorrhiza shown markedly improved effectiveness in alleviating NAFLD and diminishing LPS generation compared to the individual constituents. Synbiotics affect metabolic disorders by enhancing the synthesis of beneficial bacterial metabolites, including acetate, propionate, butyrate, isovalerate, lactic acid, and palmitoylethanolamide (Kaufmann et al., 2023; Moszak et al., 2021). The levels of LPS and TMAO in production were reduced, which was associated with a decrease in bile acid concentrations. Synbiotics activated various signaling pathways such as AMPK, ERK, GPR43, IRF4, NOD2, and TLR2, thereby promoting the conversion of tryptophan to serotonin, while also inhibiting pathways linked to TLR4, NF-κB, NOD1, and TNF-α (Kaufmanna et al.; Pires et al., 2024).
2.3 By the improvement of Intestinal Barrier Function
The functionality of the intestinal barrier is significantly influenced by the flora that lives in the gut. A poor diet might encourage the growth of bacteria that produce lipopolysaccharides (LPS), such as Enterobacteriaceae. This can potentially cause LPS to breach a weaker intestinal barrier, which can lead to a variety of health problems, including dyslipidemia, insulin resistance, systemic inflammation, and immunological reactions (Di Lorenzo et al., 2019; Gnauck et al., 2016).
3. Synbiotics in the Management of Metabolic disorders
The application of synbiotics to treat metabolic disorders has garnered interest as a viable treatment due to their established safety and accessibility. Despite promising results from certain laboratory and animal studies, there remains a paucity of clinical trials demonstrating the benefits of synbiotic nutrition in persons with Metabolic disorders, with some data even presenting contradictions (Pires et al., 2024). Synbiotics comprising Lactobacillus paracasei HII01 and xylo-oligosaccharides considerably enhanced metabolic disorders and fortified the intestinal barrier in obese rats by mitigating metabolic endotoxemia, reducing the Firmicutes to Bacteroidetes ratio, and decreasing Enterobacteriaceae levels, as evidenced by an in vivo study (Santos-Marcos et al., 2019). Also, synbiotics such as Lactobacillus paracasei N1115 and fructo-oligosaccharides have shown effectiveness in reducing hepatic steatosis, decelerating the advancement of cirrhosis, and enhancing the intestinal barrier in mouse models of non-alcoholic fatty liver disease (NAFLD) (Li et al., 2021). This treatment resulted in the activation of the p38 MAPK pathway and the production of tight junction proteins, including occludin 1 and claudin 1, which resulted in enhanced lipid profiles, reduced fasting blood glucose and insulin levels, and reduced TNF-α levels (Kaminsky et al., 2021). Synbiotics may mitigate metabolic issues by improving the integrity of the intestinal barrier. This is achieved by enhancing the activation of signaling pathways including GLUT4, GPR43, NLCR3, p38 MAPK, and TRAF6, alongside the expression of claudin 1, GLP1, IL-10, occludin 1, and ZO-1 (Singh et al., 2010). At the exact period that they decrease TNF-α expression and circulating endotoxin levels, synthbiotics have the potential to alter the make-up of Allobaculum, Akkermansia, Bifidobacterium, Coprococcus, Enterobacteria, Lactobacilli, Oscillospira, and Prevotellaceae (Malesza et al., 2021).
3.1 Synbiotics in the Management of Obesity
The study by Westfall et al. investigated into a new synbiotic formulation that combines the probiotics B. longum spp. infantis NCIMB 702255, L. fermentum NCIMB 5221, and L. plantarum NCIMB 8826 with Triphala, an Ayurvedic herb that is high in polyphenols, to examine how it affects metabolic markers and obesity on a systemic level (Westfall & Pasinetti, 2019). The researchers investigated the therapeutic advantages of this synbiotic combination in aging Drosophila and discovered that it produced significantly superior outcomes collectively compared to the individual components, resulting in a remarkable 60% increase in lifespan and a reduction in metabolic markers, including overall weight, total glucose, and total triglycerides (Kerry et al., 2022). The synbiotic formulation reduced age-related increases in inflammation and oxidative stress. A unique synbiotic formulation containing L. acidophilus, B. lactis, B. longum, B. bifidum, and a prebiotic GOS blend positively impacted gut microbiota in individuals following a low-carbohydrate, high-protein, calorie-restricted diet, increasing levels of Lactobacillus and Bifidobacterium while enhancing microbial diversity, without changes in body composition (Chlebicz-Wójcik & Śliżewska, 2021). Clinical research demonstrates that specific synbiotic combinations can augment the growth of beneficial gut bacteria and promote general health in obese or elderly individuals. The administration of a synbiotic, especially B. lactis and fructo-oligosaccharides, led to diminished systemic inflammation and advantageous outcomes on body weight in obese women (Pandey et al., 2015). Furthermore, synbiotic therapy may alleviate overall gastrointestinal symptoms in children with IBS, exceeding prebiotics alone. However, similar to other biological therapies, there is a significant lack of clinical data. Further investigation is necessary to assess the effectiveness of prebiotics and synbiotics in addressing issues related to obesity and aging (Abdul Kalam Saleena et al., 2024; de Alba et al.).
3.2 Synbiotics and Diabetes
The consumption of synbiotics may diminish the risk of cardiovascular disease in individuals with prediabetes and Type 2 Diabetes Mellitus (T2DM) by lowering levels of CRP, TNF-α, and MDA, while elevating TAC, GSH, and NO levels; however, no significant alterations in IL-6, adiponectin, and leptin are observed compared to a control group (Naseri et al., 2023). Individuals with Type 2 Diabetes Mellitus appear to derive greater advantages from this method compared to those with prediabetes. Furthermore, probiotic or synbiotic products have exhibited beneficial antioxidant effects in persons with type 2 diabetes mellitus and prediabetes who are overweight or obese. Extensive randomised controlled trials (RCTs) with extended follow-up durations are crucial for assessing the long-term impacts of these supplements in individuals with prediabetes and type 2 diabetic mellitus (T2DM) (Corb Aron et al., 2021; Paul et al., 2022).
3.3 Role of Synbiotics in Dyslipidemia
These drugs have demonstrated efficacy in enhancing metabolic parameters, especially in instances of lipid dysregulation. A three-week investigation by Rousseaux et al. assessed the impact of prebiotic xylo-oligosaccharides (XOS), both alone and in combination with Bifidobacterium animalis lactis, on gut microbiota composition, immunological responses, and blood lipid levels (Rousseaux et al., 2023). The findings indicated an augmentation of Bifidobacteria with XOS supplementation, notable enhancements in fasting HDL levels, and an increase in Th1 responses coupled with a reduction in Th2 responses (Rastall & Gibson, 2015). Over the course of six weeks, the levels of blood triglycerides and very low-density lipoprotein were significantly reduced when inulin was mixed with Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum. Bacillus licheniformis, in conjunction with Bifidobacterium and Lactobacillus, has been investigated using XOS to evaluate its synergistic impact on intestinal dysbiosis in rats subjected to a high-fat diet (Saville & Saville, 2018). The combination of XOS and Bacillus licheniformis led to lower serum LPS levels, a decreased F/B ratio, reduced body weight, and a decline in total serum cholesterol. The incorporation of prebiotics and probiotics can effect alterations in gut microbiota that assist in alleviating dyslipidemia (Mohr et al., 2020; Palaniappan et al., 2021).
Conclusion
Metabolic diseases are intricately linked to dysbiosis in gut microbiota. On modifying the gut microbiota, synbiotics have shown promise in the treatment of metabolic diseases, such as obesity and type 2 diabetes mellitus. Given the beneficial impacts of synbiotics on metabolic disorders, researchers are diligently exploring several potential approaches to improve treatment efficacy, suggesting that the amalgamation of multiple viable bacterial strains may represent a realistic technique. Additionally, innovative food processing methods, like enzyme-modified prebiotics and probiotic-fermented natural foods, have been developed to enhance these advantageous effects. Also, the influence of synbiotics on metabolic disorders has been demonstrated in a multitude of clinical studies; however, additional research is necessary. It is imperative to execute a comprehensive evaluation of the specific effects of postbiotics on humans and optimal synbiotic formulations.
References
1. Abdul Kalam Saleena, L., Chang, S. K., Simarani, K., Arunachalam, K. D., Thammakulkrajang, R., How, Y. H., & Pui, L. P. J. C. R. i. M. (2024). A comprehensive review of Bifidobacterium spp: as a probiotic, application in the food and therapeutic, and forthcoming trends. 50(5), 581-597.
2. Chlebicz-Wójcik, A., & Śliżewska, K. J. B. (2021). Probiotics, prebiotics, and synbiotics in the irritable bowel syndrome treatment: a review. 11(8), 1154.
3. Corb Aron, R. A., Abid, A., Vesa, C. M., Nechifor, A. C., Behl, T., Ghitea, T. C., Toma, M. M. J. M. (2021). Recognizing the benefits of pre-/probiotics in metabolic syndrome and type 2 diabetes mellitus considering the influence of akkermansia muciniphila as a key gut bacterium. 9(3), 618.
4. de Alba, B. N. S., Andrews, H. E. J. P., & proteins, a. Benefits and Challenges of Encapsulating Bifidobacterium Probiotic Strains with Bifidogenic Prebiotics.
5. Di Lorenzo, F., De Castro, C., Silipo, A., & Molinaro, A. J. F. M. R. (2019). Lipopolysaccharide structures of Gram-negative populations in the gut microbiota and effects on host interactions. 43(3), 257-272.
6. Gnauck, A., Lentle, R. G., & Kruger, M. C. J. I. r. o. i. (2016). The characteristics and function of bacterial lipopolysaccharides and their endotoxic potential in humans. 35(3), 189-218.
7. Højlund, K. (2014). Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance.
8. Kaminsky, L. W., Al-Sadi, R., & Ma, T. Y. J. F. i. i. (2021). IL-1β and the intestinal epithelial tight junction barrier. 12, 767456.
9. Kaufmann, B., Seyfried, N., Hartmann, D., Hartmann, P. J. A. J. o. P.-G., & Physiology, L. (2023). Probiotics, prebiotics, and synbiotics in nonalcoholic fatty liver disease and alcohol-associated liver disease. 325(1), G42-G61.
10. Kaufmanna, B., Seyfrieda, N., Hartmanna, D., & Hartmannb, P. Probiotics, prebiotics and synbiotics in nonalcoholic fatty liver disease and alcohol-associated liver disease 2.
11. Kaushik, M., Madeswaraguptha, P., Vanangamudi, M., Surendran, V., Subramaniyan, N. K., & Kumar, A. J. S. i. M. D. Targeting Signaling Pathway and Mechanism of Prebiotics, Probiotics, and Synbiotics to Manage Metabolic Disorders. 10-38.
12. Kerry, R. G., Das, G., Golla, U., del Pilar Rodriguez-Torres, M., Shin, H.-S., & Patra, J. K. J. C. P. B. (2022). Engineered probiotic and prebiotic nutraceutical supplementations in combating non-communicable disorders: A review. 23(1), 72-97.
13. Li, H.-Y., Zhou, D.-D., Gan, R.-Y., Huang, S.-Y., Zhao, C.-N., Shang, A., . . . Li, H.-B. J. N. (2021). Effects and mechanisms of probiotics, prebiotics, synbiotics, and postbiotics on metabolic diseases targeting gut microbiota: A narrative review. 13(9), 3211.
14. Malesza, I. J., Malesza, M., Walkowiak, J., Mussin, N., Walkowiak, D., Aringazina, R., . . . Mądry, E. J. C. (2021). High-fat, western-style diet, systemic inflammation, and gut microbiota: a narrative review. 10(11), 3164.
15. Mohr, A. E., Basile, A. J., Meli’sa, S. C., Sweazea, K. L., Carpenter, K. C. J. J. o. t. A. o. N., & Dietetics. (2020). Probiotic supplementation has a limited effect on circulating immune and inflammatory markers in healthy adults: A systematic review of randomized controlled trials. 120(4), 548-564.
16. Moszak, M., Szulińska, M., Walczak-Gałęzewska, M., Bogdański, P. J. I. J. o. E. R., & Health, P. (2021). Nutritional approach targeting gut microbiota in NAFLD—To date. 18(4), 1616.
17. Muzurović, E., Mikhailidis, D. P., & Mantzoros, C. J. M. (2021). Non-alcoholic fatty liver disease, insulin resistance, metabolic syndrome and their association with vascular risk. 119, 154770.
18. Naseri, K., Saadati, S., Ghaemi, F., Ashtary-Larky, D., Asbaghi, O., Sadeghi, A., . . . de Courten, B. J. E. j. o. n. (2023). The effects of probiotic and synbiotic supplementation on inflammation, oxidative stress, and circulating adiponectin and leptin concentration in subjects with prediabetes and type 2 diabetes mellitus: A GRADE-assessed systematic review, meta-analysis, and meta-regression of randomized clinical trials. 62(2), 543-561.
19. Oniszczuk, A., Oniszczuk, T., Gancarz, M., & Szymańska, J. J. M. (2021). Role of gut microbiota, probiotics and prebiotics in the cardiovascular diseases. 26(4), 1172.
20. Palaniappan, A., Antony, U., Emmambux, M. N. J. T. i. F. S., & Technology. (2021). Current status of xylooligosaccharides: Production, characterization, health benefits and food application. 111, 506-519.
21. Pandey, K. R., Naik, S. R., Vakil, B. V. J. J. o. f. s., & technology. (2015). Probiotics, prebiotics and synbiotics-a review. 52, 7577-7587.
22. Paul, P., Kaul, R., Abdellatif, B., Arabi, M., Upadhyay, R., Saliba, R., . . . Chaari, A. J. F. i. N. (2022). The promising role of microbiome therapy on biomarkers of inflammation and oxidative stress in type 2 diabetes: a systematic and narrative review. 9, 906243.
23. Pires, L., González-Paramás, A. M., Heleno, S. A., & Calhelha, R. C. J. A. (2024). Exploring therapeutic advances: a comprehensive review of intestinal microbiota modulators. 13(8), 720.
24. Ramesh, S., Kosalram, K. J. J. o. e., & promotion, h. (2023). The burden of non-communicable diseases: A scoping review focus on the context of India. 12(1), 41.
25. Rastall, R. A., & Gibson, G. R. J. C. o. i. b. (2015). Recent developments in prebiotics to selectively impact beneficial microbes and promote intestinal health. 32, 42-46.
26. Rousseaux, A., Brosseau, C., & Bodinier, M. J. N. (2023). Immunomodulation of B lymphocytes by prebiotics, probiotics and synbiotics: application in pathologies. 15(2), 269.
27. Russell, D., Ross, R., Fitzgerald, G., & Stanton, C. J. I. j. o. f. m. (2011). Metabolic activities and probiotic potential of bifidobacteria. 149(1), 88-105.
28. Santos-Marcos, J. A., Perez-Jimenez, F., & Camargo, A. J. T. J. o. n. b. (2019). The role of diet and intestinal microbiota in the development of metabolic syndrome. 70, 1-27.
29. Saville, B. A., & Saville, S. J. A. F. B. (2018). Xylooligosaccharidesand arabinoxylanoligosaccharides and their application as prebiotics. 5(3), 121-130.
30. Sharma, S., Chauhan, A., Ranjan, A., Mathkor, D. M., Haque, S., Ramniwas, S., . . . Yadav, V. J. F. i. M. (2024). Emerging challenges in antimicrobial resistance: implications for pathogenic microorganisms, novel antibiotics, and their impact on sustainability. 15, 1403168.
31. Singh, A. B., Sharma, A., & Dhawan, P. J. J. o. o. (2010). Claudin family of proteins and cancer: an overview. 2010(1), 541957.
32. Uusitupa, H.-M., Rasinkangas, P., Lehtinen, M. J., Mäkelä, S. M., Airaksinen, K., Anglenius, H., . . . Maukonen, J. J. N. (2020). Bifidobacterium animalis subsp. lactis 420 for Metabolic Health: Review of the Research. 12(4), 892.
33. van Hoogstraten, L. M., Vrieling, A., van der Heijden, A. G., Kogevinas, M., Richters, A., & Kiemeney, L. A. J. N. r. C. o. (2023). Global trends in the epidemiology of bladder cancer: challenges for public health and clinical practice. 20(5), 287-304.
34. Westfall, S., & Pasinetti, G. M. J. F. i. n. (2019). The gut microbiota links dietary polyphenols with management of psychiatric mood disorders. 13, 1196.
35. Yang, Y., Yang, L., Wu, J., Hu, J., Wan, M., Bie, J., . . . Yang, C. J. C. N. (2024). Optimal probiotic combinations for treating nonalcoholic fatty liver disease: A systematic review and network meta-analysis.
36. Zhao, X., An, X., Yang, C., Sun, W., Ji, H., & Lian, F. J. F. i. e. (2023). The crucial role and mechanism of insulin resistance in metabolic disease. 14, 1149239.
Dr. Neeraj Mishra is working as Professor and Head, Department of Pharmaceutics, in Amity Institute of Pharmacy, Gwalior since July 2019. He has around twenty years of teaching and research experience. He has more than 100 publications of International and National repute in recent concepts of novel drug delivery systems, localised drug delivery, targeted and controlled drug delivery of nanocarriers/ microparticles for the treatment of breast, colon cancer, and neurodegenerative disorders. Dr. Mishra more than 3700 citations with h- index 32. The total cumulative Impact Factor of his published papers is more than 300 (as per SCOPUS). He has also written 15 Books and 30 book chapters in Elsevier, Bentham, Springer and Wiley Publication etc. He has also been granted 3 international patents and 2 Indian patents. Dr. Mishra is recipient of “Distinguished Professor Award” 2019 from DST-NSTMIS, SPAICS, Indore, and M.P. in September 2019. Dr. Mishra has received the “Distinguished Professor Award '' 2021 from Indian Pharmaceutical Association, MP State Branch, Indore. Dr Mishra has received Best Academician Award in the Indian Pharmacy Graduate Association, M.P. State International Conference held on 06th May 2023 at DAVV Auditorium, Indore, India.
Dr. Devyani Rajput is working as an Assistant Professor, Department of Pharmacognosy, in Amity Institute of Pharmacy, Gwalior since Jan 2024. She has around seven years of research experience. Her expertise includes nanotechnology, phytomedicine, and advanced drug delivery systems, with notable contributions to cancer research. She has participated in various national and international conferences, published impactful research, and received prestigious awards, including the BEST SCHOLAR AWARD 2023. She has more than 150 citations with h- index 3. She has received the CSIR travel Grant in April 2024 for presenting her research work in Istanbul University.
