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Why do dead bacteria still have health benefits? A detailed explanation of the five mechanisms of postbiotics.

Editor's Note:

In 2013, Spanish researcher Katerina Tsilingiri officially proposed the concept of 'postbiotics'. Since then, different researchers have assigned various names and definitions to postbiotics. Until May 2021, the International Scientific Association for Probiotics and Prebiotics (ISAPP) released a consensus statement on postbiotics, clarifying the definition and scope of postbiotics. So, how do postbiotics, which we commonly refer to as 'dead bacteria', actually work?

Today, we focus on postbiotics. This article will interpret the mechanisms of action of postbiotics based on the consensus statement published by ISAPP. We hope this article can provide some inspiration and assistance to relevant industry professionals and readers.

Mechanisms of Action of Postbiotics

Postbiotics refer to preparations of non-living microorganisms and/or other components that are beneficial to host health. Due to the 'non-living' characteristics of postbiotics, they have great application prospects. Therefore, although postbiotics are far behind probiotics in terms of both the starting time and the number of studies, both academia and industry are still fascinated by them, with the industry viewing postbiotics as the fourth generation of microecological products following probiotics, prebiotics, and synbiotics.

However, any successful microecological product relies on sufficient scientific research. So, how do postbiotics actually work? Why can dead microorganisms still have health benefits?

In fact, the health benefits provided by postbiotics may be driven by many different mechanisms. In some cases, these mechanisms may be similar to the known mechanisms of action of probiotics.

These mechanisms can act independently or in combination, mainly including the following five: (1) beneficial modulation of the microbiome; (2) enhancement of epithelial barrier function; (3) modulation of immune responses; (4) regulation of systemic metabolism; (5) signaling through the nervous system.

So, how do these mechanisms specifically affect the health of the body? Which postbiotics are involved? Below, this article will elaborate on each one.

Figure. Potential mechanisms of action of postbiotics and examples of utilizing these mechanisms. Image source:Nature Reviews Gastroenterology & Hematology

Mechanism 1

Beneficial Modulation of the Microbiome

Although the impact of postbiotics on the microbiome may be temporary, they may still play an important role. In vivo studies have shown that molecules in postbiotics, such as lactic acid and bacteriocins, have antibacterial activity.

Postbiotics can also indirectly modulate the microbiome. For example, there may be quorum sensing and quorum quenching molecules in postbiotics; certain microorganisms in the gut can utilize lactic acid carried by postbiotics to produce beneficial short-chain fatty acids (SCFAs) and butyrate.

If, after processing, postbiotics still contain intact adhesins (such as fimbriae and lectins), then postbiotics can also compete with resident microorganisms for adhesion sites.

Mechanism 2

Enhancement of Epithelial Barrier Function

Secreted proteins can mediate the enhancement of epithelial barrier function, such as the major secreted proteins Msp1/p75 and Msp1/p40, or the protein HM0539 from the probiotic Lactobacillus rhamnosus GG. Additionally, for example, extracellular polysaccharides extracted from bifidobacteria can reduce inflammation through unclear signaling mechanisms to promote barrier function.

Increasing evidence suggests that specific bifidobacteria can activate signaling pathways, such as MAPK and AKT signaling pathways, to promote tight junction function through autophagy and calcium signaling pathways.

If SCFAs in postbiotics reach sufficient levels, they may also alter epithelial barrier function and resist lipopolysaccharide-induced damage. For example, in Caco-2 cells, butyrate can activate lipoxygenase through histone acetylation to alter the permeability of tight junctions.

Mechanism 3

Modulation of Immune Responses

Local and systemic immune regulatory activities are typically mediated by the interaction of microbe-associated molecular patterns with specific pattern recognition receptors on immune cells, leading to the expression of various cytokines and immune regulators.

Currently, through studies of molecular interactions and validation in animal models, multiple microbe-associated molecular patterns and their interactions with specific immune receptors have been identified:

• Lipoteichoic acid interacts with TLR2 or TLR6;

• Peptidoglycan or its derived peptides interact with NOD2;

• Fimbriae and pili can modulate TLR2 signaling;

• Flagella primarily interact with TLR5;

• CpG-DNA interacts with TLR9;

• Certain postbiotic lipopolysaccharides derived from Gram-negative bacteria (such as Escherichia coli Nissle) primarily interact with TLR4 and sometimes with TLR2;

• β-glucans in yeast (such as Saccharomyces cerevisiae) interact with TLR2 and lectin immune receptors;

• Lipoproteins primarily interact with TLR2.

If not destroyed or altered by the inactivation process, these microbe-associated molecular patterns may also exist in postbiotics. Studies have shown that some lysates from Gram-positive and Gram-negative bacteria can interact with TLR4 and TLR2.

Additionally, it has been reported that metabolites such as lactic acid can mediate immune responses through GPR31-dependent dendritic protrusions in intestinal CX3CR1+ cells. Similarly, tryptophan derivatives produced by Lactobacillus reuteri—indole—can activate the aryl hydrocarbon receptor in CD4+ T cells in the mouse gut, inducing their differentiation into CD4+CD8αα+ double-positive intraepithelial lymphocytes.

There may also be other immune-regulating microbial metabolites in postbiotics, including: histamine, branched-chain fatty acids, and SCFA (which have been shown to affect many immune responses, including the inhibition of NF-κB).

Mechanism 4

Regulating systemic metabolism

The impact of postbiotics on systemic metabolic responses can be directly mediated by the metabolites or enzymes from inactivated microbes, both inside and on their surfaces.

One example is bile salt hydrolase (BSH). This microbial enzyme is responsible for the deconjugation of bile acids, allowing microbes to undergo further biotransformation and diversifying the pool of bile acids circulating in the system.

BSH is primarily expressed in the cytoplasm of microbes, but extracellular forms have also been observed, and its activity has been confirmed in the supernatant of probiotics, specifically Lactobacillus reuteri. Moreover, studies have shown that the loss of BSH makes individuals more susceptible to recurrent Clostridium difficile infections, while restoring the activity of this enzyme through fecal microbiota transplantation has been proven to help treat this infection.

Another example is succinate (an intermediate product of bacterial carbohydrate fermentation). Succinate is a substrate for gluconeogenesis in the intestine and has been found to improve blood glucose regulation in mice.

Other known host metabolic regulators include microbial-derived vitamins and SCFA. Propionate can improve insulin sensitivity, glucose tolerance, and lipid metabolism; butyrate can upregulate the antioxidant glutathione and has beneficial effects on oxidative stress in the colons of healthy individuals.

Mechanism 5

Signaling through the nervous system

Microbes can produce various neuroactive substances that can act on the gut and central nervous system, potentially regulating behavior and cognitive functions in animals and humans. These substances include several neurotransmitters (such as serotonin, dopamine, acetylcholine, and γ-aminobutyric acid), as well as various compounds that can bind to receptors expressed in the brain (such as indole and bile acids).

Microbial enzymes can also metabolize nutrients for the synthesis of host neurotransmitters (for example, tryptophan for serotonin synthesis, tyrosine for dopamine synthesis), thereby reducing the bioavailability of nutrients.

Additionally, microbial metabolites may also play a role, such as SCFA. SCFA can stimulate enterochromaffin cells to produce 5-hydroxytryptamine; in human intervention studies, SCFA have been shown to improve eating behavior by stimulating the release of anorexigenic hormones; mouse experiments indicate that acetate produced in the gut can enter the brain and regulate appetite through central metabolic mechanisms. However, whether the SCFA contained in processed postbiotics still retain the aforementioned benefits requires further research.

Vitamins synthesized by bacteria, such as B vitamins (riboflavin, folate, and cobalamin), are also present in probiotic products, so postbiotics may also retain these vitamins. Vitamin B plays an important beneficial role in the function of the central nervous system. However, there is currently no detailed report on how many of these neuroactive molecules can be retained in postbiotics.

The era of postbiotics is leading a new age of gut health.

As the academic and industrial communities increasingly focus on postbiotics, we will undoubtedly gain a deeper understanding of postbiotics and the mechanisms by which they operate. Research on these mechanisms will further promotethe application of postbiotics, helping postbiotics become more effective and safer probiotic functional solutions.

The era of postbiotics has quietly arrived. Are you ready?

References:

Salminen, S., Collado, M.C., Endo, A. et al. The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics. Nat Rev Gastroenterol Hepatol 18, 649–667 (2021).

Source: Gut Industry WeChat Official Account, authorized for reproduction.

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2024-12-23

In December 2024, Tianjin Chuangyuan Biotechnology Co., Ltd. and Haihe Dairy jointly held a series of themed activities titled "Party Building Mutual Visits and Learning" to further promote the deep integration of both parties' party building work and business development. During the event, both sides will conduct company visits and on-site discussions. Recently, Haihe Dairy made an initial visit and, after gaining a deep understanding of Chuangyuan Biotech's products, expressed high recognition and close attention, laying a solid foundation for future cooperation. Subsequently, both parties engaged in detailed communication on the core topics of "exchange of party building experiences and sharing of business resources," discussing standardized construction of party branches, distinctive party building measures, and the promotion of party-business integration. They also conducted in-depth exchanges on aspects such as corporate cooperation, product intercommunication, and information sharing, jointly exploring new paths for the development of the health industry under the guidance of party building, providing more possibilities for further establishing a "symbiotic, mutually promoting, and win-win" cooperative relationship. Both parties hope to achieve industrial resonance through party building leadership and contribute to the development of the health industry in the Binhai New Area.

Strength crowned, Chuangyuan Biotechnology won two Science and Technology Awards from the China Food Industry Association.

2024-12-17

On December 16, 2024, the 22nd China Food Safety Conference and the 2024 National Food Industry Science and Technology Progress Conference, themed "Implementing Food Safety Strategy to Support the Construction of a Healthy China," was grandly held in Beijing. During the conference, the award ceremony for the 2024 National Food Industry Science and Technology Progress Conference was also held. Tianjin Chuangyuan Biotechnology Co., Ltd. won the second prize for scientific and technological progress in the "2023 China Food Industry Association Science and Technology Award" for two projects: "Key Technology Breakthrough and Industrial Application of New Postbiotics Segmented Solid-State Fermentation" and "Development and Application of Key Technologies and Equipment for Plant Polysaccharide Efficacy Verification and Extraction."

Chuangyuan Biotech's lactic acid bacteria IOB701 post-fermentation probiotic powder has been granted a national invention patent.

2024-12-13

On December 13, 2024, Tianjin Chuangyuan Biotechnology Co., Ltd. received an invention patent certificate from the National Intellectual Property Administration for its independently developed and filed method and application for the preparation of Lactobacillus plantarum IOB701 fermented postbiotics powder (Patent No.: ZL 202411354886.X). This invention provides a method and application for the preparation of Lactobacillus plantarum IOB701 fermented postbiotics powder, which relates to the field of microbiology. The Lactobacillus plantarum IOB701 was preserved on July 10, 2018, at the General Microbial Culture Collection Center of the China Microbial Strain Preservation Management Committee, abbreviated as CGMCC, with the preservation address at No. 3, Courtyard 1, Beichen West Road, Chaoyang District, Beijing, and the preservation number CGMCC No. 16077. Using grains or legumes treated with low oxygen stress as the fermentation substrate, the Lactobacillus plantarum IOB701 fermentation resulted in postbiotics powder, which, according to animal experiments, has been shown to improve chronic unpredictable mild stress-induced depressive-like behavior in mice.

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