Draft:Probiotics

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Postbiotics (from Ancient Greek post — after and βίος — life) are inactivated microbial cells, their structural components, or metabolites that have a defined chemical nature and exert physiological effects on the host organism.[1]

Active Metabolites

Postbiotics are capable of modulating immune function, supporting intestinal barrier integrity, regulating metabolism, and exerting anti-inflammatory effects. They are regarded as a new generation of microbiota-related agents and represent a logical progression of the probiotic concept: from the use of live microorganisms to the application of safe, standardized, and stable compounds with predictable effects.[2]

General characteristics

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A pure organic postbiotic is a product obtained through controlled fermentation of multiple strains of bifidobacteria, lactobacilli, and enterococci. The microorganisms are cultivated in groups and subsequently combined into a single symbiotic system. Joint fermentation allows each strain to enhance the activity of the others, leading to the production of highly effective metabolites.

The bioactive compounds formed during this process are preserved in their original state and constitute the basis of the final product. Unlike probiotics, postbiotics do not require colonization of the intestine by live bacteria: their effect is mediated by metabolites and structural components of microbial cells. This ensures predictable outcomes and a high level of safety.

Metabolites of beneficial bacteria stimulate the growth of the host’s own symbiotic microbiota, suppress the proliferation of pathogenic microorganisms, and modulate immune functions. Bacterial cell material, interacting with intestinal immune tissues, contributes to the restoration of the body’s defenses and the reduction of inflammatory processes.

The product exerts a complex physiological action: it improves digestion, supports intestinal barrier function, promotes nutrient absorption, and is characterized by stability during storage as well as compatibility with human physiology.

Strains used

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  • Bifidobacterium longum — 2 strains
  • Bifidobacterium adolescentis — 2 strains
  • Bifidobacterium bifidum — 1 strain
  • Bifidobacterium breve — 1 strain
  • Bifidobacterium infantis — 1 strain
  • Enterococcus faecium — 5 strains
  • Enterococcus faecalis — 1 strain
  • Enterococcus durans — 3 strains
  • Lactobacillus ss. casei — 2 strains
  • Lactobacillus bulgaricus — 1 strain
  • Lactobacillus lactis — 1 strain
  • Lactobacillus casei — 4 strains
  • Lactobacillus brevis — 1 strain
  • Lactobacillus acidophilus — 3 strains
  • Lactobacillus gasseri — 2 strains
  • Lactobacillus delbrueckii — 1 strain
LAB Fermented Extract

Indications and Research on Efficacy

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Postbiotics have been investigated across a wide range of clinical and pre-clinical settings. Their potential applications include gastrointestinal, infectious, immunological, dermatological, metabolic, neurological, oncological, gynecological, pediatric, and geriatric conditions.

Gastrointestinal disorders

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  • Constipation and motility disorders — postbiotic supplementation improves bowel regularity and stool consistency.[3]
  • Irritable bowel syndrome (IBS) — heat-inactivated *Bifidobacterium bifidum* MIMBb75 reduced IBS symptoms in multicenter RCTs.[4]
  • Diarrheal diseases — pediatric trials showed reduced severity and duration of acute diarrhea with heat-killed *Lactobacillus acidophilus* LB.[5]
  • Inflammatory bowel disease (IBD) — postbiotics reduce colitis severity in animal models via immunomodulation and barrier protection.[6]

Infectious diseases

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  • Respiratory tract infections — heat-killed *Lactobacillus plantarum* L-137 reduced URTI incidence and improved immune response.[7]
  • Helicobacter pylori — inactivated *Lactobacillus acidophilus* increased eradication rates with standard therapy.[8]
  • Pediatric infections— fermented milk with postbiotic activity reduced incidence of common infections in children.[9]

Immune and allergic conditions

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  • Allergic rhinitis — heat-killed strains improved symptoms and IgA secretion.[10]
  • Food allergy and atopy — experimental data support reduced allergic sensitization and inflammation.[11]
  • Autoimmune diseases — SCFAs regulate T-cell activity and suppress inflammatory cytokines.[12]

Dermatological conditions

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  • Acne vulgaris — topical postbiotics reduced lesion counts in randomized trials.[13]
  • Alopecia areata — PRP-like formulations with postbiotics stimulated hair regrowth.[14]
  • Atopic dermatitis — postbiotics demonstrated anti-inflammatory and skin barrier–restoring properties.[15]

Metabolic and systemic disorders

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  • Obesity and metabolic syndrome — postbiotics improved glucose homeostasis and reduced adiposity.[16]
  • Cardiovascular disease and dyslipidemia — inactivated bifidobacteria reduced cholesterol levels.[17]
  • Telomere protection and aging — in vitro studies suggest postbiotics delay telomere shortening.[18]

Neurological and psychiatric conditions

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  • Depression and anxiety — microbial metabolites such as SCFAs influence the gut–brain axis and mood.[19]
  • Autism spectrum disorders (ASD) — studies suggest postbiotics may regulate gut-derived metabolites implicated in ASD symptoms.[20]
  • Dementia and Alzheimer’s disease — butyrate and other postbiotics demonstrate neuroprotective effects.[21]
  • Cognitive decline and neurodegeneration — supplementation slowed age-related impairment in experimental models.[22]

Oncological applications

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  • Cancer prevention and therapy support — postbiotic metabolites such as butyrate act as tumor suppressors by regulating apoptosis.[23]
  • Colorectal cancer — SCFAs protect against carcinogenesis in experimental models.[24]
  • Adjuvant therapy — postbiotics reduce chemotherapy-related toxicity by maintaining gut barrier integrity.[25]

Gynecology, proctology, and reproductive health

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  • Bacterial vaginosis and vaginal dysbiosis — postbiotics maintain acidic pH and inhibit pathogens.[26]
  • Endometriosis and pelvic inflammation — SCFAs reduce systemic inflammation and improve hormonal balance.[27]
  • Proctology — postbiotics support mucosal healing in anorectal conditions (pilot studies).[28]
  • Reproductive medicine — postbiotics may modulate vaginal and endometrial microbiota to enhance fertility.[29]

Pediatrics

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  • Neonatal and infant health — postbiotics may reduce risk of necrotizing enterocolitis (NEC).[30]
  • Early-life nutrition — inclusion of postbiotic metabolites in infant formula supports immune maturation.[31]

Geriatrics and healthy aging

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  • Elderly immune support — inactivated *Lactobacillus pentosus* enhanced salivary IgA secretion and reduced infections.[32]
  • Frailty and immunosenescence — postbiotics are safe tools to support host defense in aging.[33]

Indications and Research on Efficacy

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Recent studies indicate that postbiotics may prevent putrefactive processes in the intestine, improve nutrient absorption, and enhance overall resilience to internal and external stressors. Their action is mediated by metabolites and microbial cell components, making the effect more predictable and safe compared to traditional probiotics.

Constipation and Gastrointestinal Health

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In 2025, a randomized, double-blind, placebo-controlled clinical trial in patients with chronic constipation (Rome IV criteria) demonstrated that supplementation with the postbiotic Probio-Eco significantly improved symptoms: increased spontaneous bowel movements, improved stool consistency, and reduced straining. Analysis of the gut microbiota and metabolites revealed involvement of succinate, 5-hydroxytryptophan, and 3-indoleacrylic acid, which enhanced mucin-2 secretion, regulated intestinal hormones, and exerted anti-inflammatory effects. The effect was also confirmed in a corresponding animal model.[34]

Athletic Performance and Recovery

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A 2024 systematic review including 477 participants showed that postbiotics may reduce fatigue, support mood, and improve readiness for training. Positive effects were noted on endurance, strength recovery, and reductions in biomarkers of inflammation and oxidative stress.[35] Another review from the same year emphasized the potential of "microecologic" approaches (including postbiotics) to improve sports performance by influencing energy metabolism, immune responses, and recovery processes.[36]

Pregnancy and Gastrointestinal Health

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Direct clinical data on postbiotics in pregnant women remain limited, but probiotic studies provide useful context. A 2024 randomized trial demonstrated that probiotics reduced constipation severity and improved stool characteristics in pregnant women, while restoring gut microbial diversity.[37] Other studies also reported reductions in nausea, vomiting, and constipation, as well as improvements in quality of life during early pregnancy when probiotics were administered.[38][39] These data suggest potential efficacy of postbiotics in this population, which requires further direct investigation.

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A 2025 multi-omics study demonstrated that a hawthorn-probiotic–derived postbiotic alleviated age-related constipation in laboratory animals. The findings included restoration of intestinal barrier function, reduction of inflammation, normalization of water and sodium metabolism, and restoration of gut microflora structure.[40]

Other Potential Effects

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Reviews and meta-analyses suggest that paraprobiotics and postbiotics may be beneficial in a broad range of conditions, including gastrointestinal disorders, atopic dermatitis, inflammatory diseases, and respiratory tract infections.[41]

Summary of Research

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Focus Key Findings Source
Constipation Improvement in symptoms, modulation of metabolites and gut microbiota; confirmed in humans and animals PMC12147849
Athletic performance Reduced fatigue, improved mood and recovery, positive impact on endurance and biomarkers PMC10933997; MDPI
Pregnancy Reduction of gastrointestinal symptoms, nausea, and constipation; improved quality of life (probiotic data) PubMed 38955353; MDPI; UC Davis
Age-related constipation Improved intestinal barrier, reduced inflammation, alleviation of constipation in animal models Frontiers in Nutrition
Broader applications Gastrointestinal, dermatological, inflammatory, and respiratory conditions Wikipedia

Mechanism of Action and Advantages

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Mechanism of Action

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  • Support of beneficial microbiota — postbiotics create favorable conditions for the growth and activity of the host’s own symbiotic gut microbiota.
  • Suppression of pathogens — metabolites and cellular components of postbiotics can inhibit the growth of pathogenic microorganisms, helping maintain microbial balance.
  • Protection of the intestinal barrier — postbiotics strengthen the mucosal layer and tight junctions, reducing intestinal permeability and preventing toxins and pathogens from entering the bloodstream.
  • Immunomodulation — interaction of postbiotic cell structures with intestinal immune tissues enhances both innate and adaptive immune responses, strengthening the body’s natural defense.

Key Advantages Compared to Probiotics and Prebiotics

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  • Long-term effect — the positive action of postbiotics may persist even after supplementation ends, due to stabilization of the microbiota and immune mechanisms.
  • High stability — unlike live microorganisms, postbiotics are resistant to gastric acid, temperature fluctuations, and storage conditions.
  • Safety of use — the absence of live bacteria eliminates the risk of excessive microbial growth or dysbiosis.
  • Rapid onset of action — postbiotics begin to act immediately upon ingestion, as they do not require time to colonize the intestine.
  • Broad spectrum of physiological activity — postbiotics not only support beneficial microbiota but also exert anti-inflammatory, immunomodulatory, and antimicrobial effects.

History of Postbiotics in Japan

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Élie Metchnikoff and His Influence

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Élie Metchnikoff (1845–1916), a Russian scientist, Nobel laureate in Physiology or Medicine (1908), and one of the founders of immunology, had a significant influence on the development of concepts related to the microbiota and human health. Metchnikoff discovered the phenomenon of phagocytosis and proposed a new concept of innate immunity. Later in his career, he focused on aging and the role of the intestinal flora in this process. He hypothesized that premature aging was caused by chronic self-intoxication of the body by toxins produced by putrefactive gut bacteria. As a preventive measure, he recommended the consumption of fermented dairy products, particularly those containing the Bulgarian lactic acid bacterium (Lactobacillus delbrueckii subsp. bulgaricus), which he believed could suppress harmful microbes and contribute to longevity.[42]

These ideas laid the groundwork for the later development of probiotics and, eventually, postbiotics.

Kakutaro Masagaki and the First Yogurt in Japan

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In the early 20th century, Metchnikoff’s writings became widely known in Japan. Inspired by his ideas on intestinal flora, Japanese physician Kakutaro Masagaki established the first yogurt production in Kyoto in 1905. He regarded fermented dairy products as a means of preventing gastrointestinal disorders and strengthening overall health. The popularization of yogurt played an important role in the advancement of microbiological research in Japan and marked the starting point of the country’s long-standing interest in microbiota-related products.[43]

From Live Bacteria to Metabolites

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By the mid-20th century, Japanese researchers observed that live bacteria contained in yogurt did not always survive passage through the stomach and could not guarantee colonization of the gut. Moreover, since every individual’s microbiome is unique, foreign strains often failed to establish themselves. This shifted the focus of research from live microorganisms to their metabolites — such as organic acids, peptides, enzymes, polysaccharides, and signaling molecules.

This line of inquiry gave rise to the concept of “next-generation biotics,” emphasizing the health-promoting properties of microbial metabolites regardless of bacterial viability.

The Concept of Biogenics

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In the 1970s and 1980s, the concept of "biogenics" (biogenics) emerged in Japan. This term referred to substances produced during microbial fermentation that exerted beneficial effects on human health. Unlike probiotics and prebiotics, the focus was placed specifically on the actions of bacterial metabolites, rather than on the presence of live organisms.[44]

Modern Research in Japan

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By the late 20th and early 21st centuries, Japanese universities and research centers were actively conducting clinical trials of fermented products containing inactivated microbial cells and their metabolites. These studies demonstrated that postbiotics could:

  • strengthen the intestinal barrier,
  • regulate immune responses,
  • reduce inflammation,
  • improve metabolic indicators,
  • and support healthy aging.

Examples of clinical research included:

  • studies on the effects of fermented products on constipation symptoms in pregnant women,
  • clinical trials in endurance athletes, showing improved gut microbiota composition and reduced fatigue,
  • research into aging processes and the maintenance of telomere stability in cells.[45][46]

The Significance of the Japanese School

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Thus, the Japanese school of microbiology and nutritional science played a key role in shaping the concept of postbiotics. While the European tradition traces its roots to the work of Élie Metchnikoff, in Japan it was the combination of ideas about the benefits of fermented foods with subsequent biotechnological advances that led to the emergence of the modern concept of postbiotics. Today, Japan remains one of the leading countries in microbiota and functional nutrition research.

Production of Postbiotics

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Postbiotics are obtained through multistage fermentation using several dozen strains of probiotic microorganisms cultivated on a plant-based medium, such as soy milk. The production process is based on the principles of molecular microbiology, biochemistry, and enzymatic hydrolysis technology.

Fermentation typically lasts 18 to 24 months and is carried out under strictly controlled conditions. Particular attention is given to maintaining stable environmental parameters such as pH, temperature, enzyme activity, and time intervals. A two-stage cultivation scheme is often applied: 1. a stage of active bacterial colony growth, 2. a stage of growth limitation with modulation of environmental conditions (temperature, oxygen or light exposure, concentration of metabolites).

Cell disruption is performed using enzymatic hydrolysis. Unlike acid or alkaline methods, this approach preserves bioactive compounds such as amino acids, short-chain peptides, antioxidants, and enzymes. It also minimizes the risk of producing toxic byproducts or racemization of amino acids.

Soy milk is commonly used as a substrate, derived from organically grown soybeans without pesticides or mineral fertilizers. Soy protein is highly digestible and provides a favorable profile for bacterial growth compared to cow’s milk casein, which may have allergenic properties.

Strain Management and Quality Control

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Microorganisms used in production are classified according to physiological and biochemical properties, capacity for symbiotic growth, and metabolic activity. At each stage, metabolites and cell fragments (peptidoglycans, cytoplasmic fractions, low-molecular compounds) are monitored.

To evaluate the biological activity of components, artificial models of the human intestine are employed. These systems reproduce physiological conditions, including: temperature (37 °C), a pH gradient from 5.5 to 7.4, aerobic and anaerobic zones, peristaltic motion, and metabolite secretion. Such models allow researchers to simulate the behavior of postbiotic substances under conditions close to those in vivo.

Epigenetic Regulation During Fermentation

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During fermentation, directed regulatory methods are applied: amino acid, sugar, ionic, and light signals serve as chemotriggers to modulate gene expression in bacteria. This approach helps optimize the synthesis of desired metabolites (e.g., short-chain fatty acids, γ-aminobutyric acid, serotonin) while suppressing unwanted biochemical pathways.

Composition of the Final Product

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As a result of long-term fermentation and hydrolysis, the final complex contains:

  • free amino acids,
  • short-chain peptides,
  • monosaccharides (glucose, galactose),
  • volatile fatty acids,
  • vitamins (B-group, C, PP),
  • minerals (potassium, magnesium, zinc, phosphorus),
  • cellular fragments (lysates).

Postbiotics contain no live microbial cells, do not require intestinal colonization, and do not cause sensitization. Their effects are mediated by modulation of the host’s native microbiota through signaling molecules and enzymatic metabolites.

Production Cycle

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The full production cycle generally includes:

  • cultivation of plant raw materials (e.g., soy),
  • preparation of microbial strains,
  • fermentation systems and bioreactors,
  • hydrolysis and purification systems,
  • quality control and product standardization.

This technology integrates molecular microbiology, biochemistry, and engineering solutions, enabling the production of postbiotics with high stability, reproducibility, and confirmed physiological potential.

Probiotics, Prebiotics, Synbiotics and Postbiotics

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Modern strategies for modulating the intestinal microbiota involve several distinct categories of biotic agents. For proper clinical use, it is important to clearly distinguish between probiotics, prebiotics, synbiotics, and postbiotics, as well as to understand their mechanisms of action.

Probiotics

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Probiotics are defined as live microorganisms which, when administered in adequate amounts, confer a health benefit on the host.[47]

Mechanisms of action:

  • strengthening of the intestinal barrier,
  • competitive inhibition of pathogens,
  • modulation of the immune response.

Common strains: 

Lactobacillus, Bifidobacterium.

Limitations:

  • sensitivity to storage and transportation conditions,
  • inactivation in the acidic environment of the stomach,
  • variability in survival and colonization of the intestine.

Prebiotics

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Prebiotics are food substrates, typically indigestible fibers, that selectively stimulate the growth and/or activity of beneficial gut microorganisms.[48]

Common compounds: inulin, fructooligosaccharides (FOS), galactooligosaccharides (GOS).

Advantages:

  • do not require the presence of live bacteria,
  • compatible with probiotic supplementation,
  • metabolized by microbiota into SCFAs and other bioactive metabolites.

Synbiotics

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Synbiotics are combinations of probiotics and prebiotics designed to provide synergistic effects. The prebiotic component enhances the survival of probiotic strains and increases their colonization potential.[49]

Applications:

  • restoration of the microbiota after antibiotic therapy,
  • management of gastrointestinal dysbiosis,
  • enhancement of probiotic efficacy.

Postbiotics

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Postbiotics are preparations of inactivated (non-viable) microbial cells, their structural components, and/or metabolites with demonstrated biological activity.[50]

Key components:

  • short-chain fatty acids (SCFAs: butyrate, acetate, propionate),
  • lactic acid and D-lactate,
  • peptidoglycans, lipopolysaccharides,
  • cell wall fragments and bacterial exometabolites.

Advantages:

  • no risk of translocation or systemic infection,
  • high stability during storage,
  • reproducibility of effects,
  • evidence of efficacy in conditions involving intestinal barrier dysfunction, inflammatory diseases, allergies, and autoimmune disorders.

Summary

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  • Probiotics — live microorganisms.
  • Prebiotics — substrates that nourish beneficial bacteria.
  • Synbiotics — combinations of probiotics and prebiotics.
  • Postbiotics — microbial products that act independently of live bacteria.

Postbiotics are increasingly regarded as a promising direction in biotherapy with a strong safety profile, particularly relevant in pediatrics, gerontology, and immunology, as well as in the treatment of functional and inflammatory intestinal disorders.

Modern Perspectives on the Role of the Microbiome and Postbiotics

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Current scientific evidence increasingly confirms that human health largely depends on the state of the gut. The microbiome is considered not merely a collection of microorganisms but a complex regulatory system influencing immunity, metabolism, skin health, and the risk of oncological and autoimmune disorders.[51]

Postbiotics, which include inactivated microorganisms and their metabolites, are being studied as promising agents for systemic health support. Research indicates their potential effects in several areas:

  • modulation of the immune system and enhancement of cellular defense,
  • normalization of intestinal motility and reduction of toxic load,
  • improvement of skin condition through microbiota restoration,
  • preventive influence on tumor development via immune modulation,
  • reduction of metabolic toxins in chronic and stress-related conditions.[52]

Unlike pharmacological agents, the action of postbiotics is based on physiological interaction with the body’s natural mechanisms. They are regarded as a safe and gentle option for long-term nutritional support, particularly during recovery, aging, and in preventive medicine programs.[53]

In a clinical context, postbiotics are considered one of the key directions in the development of preventive and personalized medicine.

Notes

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  1. ^ Salminen, S. et al. (2021). The ISAPP consensus statement on postbiotics: definition and scope. Nature Reviews Gastroenterology & Hepatology, 18(9), 649–667.
  2. ^ Aguilar-Toalá, J. E. et al. (2018). Postbiotics: An evolving term within the functional foods field. Trends in Food Science & Technology, 75, 105–114.
  3. ^ Clinical trial of Probio-Eco in chronic constipation
  4. ^ Andresen V. et al. Lancet Gastroenterol Hepatol. 2020;5(7):658–666. doi:10.1016/S2468-1253(20)30056-X
  5. ^ Salazar-Lindo E. et al. J Pediatr Gastroenterol Nutr. 2007;44(5):571–576. doi:10.1097/MPG.0b013e3180375594
  6. ^ Warda AK. et al. Front Microbiol. 2020;11:69. doi:10.3389/fmicb.2020.00069
  7. ^ Hirose Y. et al. J Nutr. 2006;136(12):3069–3073. doi:10.1093/jn/136.12.3069
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  25. ^ Ouwehand AC. et al. Lett Appl Microbiol. 2000;31(1):82–86. doi:10.1046/j.1472-765x.2000.00773.x
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  30. ^ Deshpande G. et al. Nutrients. 2018;10(7):871. doi:10.3390/nu10070871
  31. ^ Salminen S. et al. Nat Rev Gastroenterol Hepatol. 2021;18:649–667. doi:10.1038/s41575-021-00440-6
  32. ^ Shinkai S. et al. Br J Nutr. 2013;109(10):1856–1865. doi:10.1017/S0007114512003753
  33. ^ Wegh CAM. et al. Int J Mol Sci. 2019;20(19):4673. doi:10.3390/ijms20194673
  34. ^ Randomized clinical trial on the efficacy of the postbiotic Probio-Eco in chronic constipation
  35. ^ Review: Postbiotics and athletic performance
  36. ^ Microecologics in sports nutrition
  37. ^ Probiotics in pregnancy-related constipation
  38. ^ Probiotics improve gastrointestinal symptoms in pregnancy
  39. ^ UC Davis study on probiotics and nausea in pregnancy
  40. ^ Postbiotic alleviates age-related constipation in mice
  41. ^ General overview of postbiotic applications
  42. ^ Mechnikov, É. (1907). The Prolongation of Life: Optimistic Studies. New York: G.P. Putnam’s Sons.
  43. ^ Fukuda, S., & Ohno, H. (2014). Gut microbiome and metabolic diseases. Seminars in Immunopathology, 36, 103–114.
  44. ^ Yonezawa, Y. et al. (2015). Biogenics: A New Concept in Functional Foods. Japanese Journal of Clinical Nutrition, 36(2), 89–95.
  45. ^ Aguilar-Toalá, J. E. et al. (2018). Postbiotics: An evolving term within the functional foods field. Trends in Food Science & Technology, 75, 105–114.
  46. ^ Suez, J., & Elinav, E. (2017). The path towards microbiome-based metabolite treatment. Nature Microbiology, 2, 17075.
  47. ^ Hill, C. et al. (2014). The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nature Reviews Gastroenterology & Hepatology, 11, 506–514.
  48. ^ Gibson, G. R. et al. (2017). The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nature Reviews Gastroenterology & Hepatology, 14, 491–502.
  49. ^ Swanson, K. S. et al. (2020). The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus on synbiotics. Nature Reviews Gastroenterology & Hepatology, 17, 687–701.
  50. ^ Salminen, S. et al. (2021). The ISAPP consensus statement on postbiotics: definition and scope. Nature Reviews Gastroenterology & Hepatology, 18(9), 649–667.
  51. ^ Marchesi, J. R. et al. (2016). The gut microbiota and host health: a new clinical frontier. Gut, 65(2), 330–339.
  52. ^ Aguilar-Toalá, J. E. et al. (2018). Postbiotics: An evolving term within the functional foods field. Trends in Food Science & Technology, 75, 105–114.
  53. ^ Salminen, S. et al. (2021). The ISAPP consensus statement on postbiotics: definition and scope. Nature Reviews Gastroenterology & Hepatology, 18(9), 649–667.

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