Postbiotic metabolites and Antimicrobial peptides

Postbiotic Metabolites

“Postbiotics” are herein considered the metabolites produced in the anaerobic fermentation of non-digestible dietary components, or even digestible ones (e.g., complex carbohydrates, proteins, and lipids), and those released by bacterial metabolism in the GI tract.

Available Postbiotic Metabolites:

  • Short-Chain Fatty Acids (SCFAs)

  • Exopolysaccharides (EPS)

  • Bacteriocins

  • Teichoic and lipoteichoic acids

  • Polyamines

  • Glutathione: synthesized by Lactobacillus fermentum ME3

  • Organic acids

Mechanism of Action

Short-chain fatty acids - SCFAs (acetate, butyrate, and propionate):

  • SCFAs participate in the modulation of immune signaling by activating inflammasomes and increasing the synthesis of mucins (butyrate).

  • Regulate intestinal epithelial cell energy metabolism and preserve mucosal immunity.

  • Increase the number of Tregs cells and their regulatory function in the large intestine through epigenetic regulation.

  • Inhibit stem cell proliferation by acting as a histone deacetylase inhibitor (HDAC).

  • Improve protection against infections.

  • Activate GPR43 and GPR109a in the intestinal cell.

Exopolysaccharides:

  • Exopolysaccharides produced by lactic acid bacteria have biofunctional properties, such as antioxidant effects by the scavenging of free radicals, immunomodulatory effects, the regulation of intestinal microbiota, and cholesterol-lowering activity by binding to free cholesterol.

  • Exopolysaccharides from Lactobacillus plantarum L-14 extract inhibit adipogenesis through TLR2 and AMP-activated protein kinase (AMPK) signaling pathways, and oral intake of L. plantarum L-14 extract ameliorates obesity.

Bacteriocins:

  • Bacteriocins are a group of antimicrobial peptides produced by Gram-positive and Gram-negative bacteria with a broad spectrum of effects.

  • Nisin, a bacteriocin class I has anti-microbial activity against both Gram-positive and Gram-negative disease-associated pathogens.

  • Plantaricin EF (PlnEF), a bacteriocin class II, produced by Lactobacillus plantarum, exhibits anti-inflammatory activity against 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced inflammatory bowel disease.

Teichoic and lipoteichoic acids:

  • Teichoic acids (TA), in particular lipoteichoic acid (LTA), are important immunomodulatory structures found in Gram-positive bacteria.

  • Bacterial LTA activates the immune system through toll-like receptor (TLR) interactions.

  • The interaction between mononuclear cells and LTA was found to be of great importance to the host.

Polyamines (putrescine, spermine, and spermidine):

  • They can act as secondary messengers, mediating the effects of hormones and growth factors, and support high proliferation of intestinal epithelial cells.

  • The activation of the NLRP6 inflammasome is influenced by the microbiota-modulated metabolites taurine, histamine, and spermine.

Glutathione: synthesized by Lactobacillus fermentum ME3:

  • Glutathione is a powerful antioxidant that plays a critical role in protecting cells from oxidative stress, detoxifying harmful substances, and supporting the immune system.

  • Glutathione functions in the detoxification of hydrogen peroxide, other peroxides and free radicals.

Organic acids:

  • Organic acids are substances that are suitable for use as antibacterial agents.

  • Organic acids act as an acidifier, reducing the pH of the surrounding environment and the ability of infections that are not acid-tolerant to survive.

  • Acetic and lactic acids are created to encourage the development of producer cells during the generation of postbiotics by L. plantarum.

  • Organic acids may prevent pathogens’ enzymes from working properly, making the bacterial cell expend all its energy to release extra proton H+, which causes the bacteria to die.

Antimicrobial Peptides

  • Antimicrobial peptides (AMPs) are groups of effectors with the ability to inactivate microorganisms by membranolytic effects as well as by interacting with specific molecular targets through the nonlytic pathway.

  • Play a crucial role in the innate immunity of the host.

  • Bacteriocins are a group of antimicrobial peptides produced by Gram-positive and Gram-negative bacteria with a broad spectrum of effects.

Mechanism of Action

  • The direct bactericidal mechanism of AMPs is performed through interacting with negatively charged membranes, resulting in increased membrane permeability, cell membrane lysis, or release of intracellular contents, which ultimately leads to cell death.

  • There are four main models of membrane-pore formation, namely barrel-stave model, toroidal-pore model, carpet model and aggregate model.

  • After AMPs penetrate into the phospholipid membrane, their hydrophobic regions combine with the internal hydrophobic regions of the phospholipid bilayer, while their hydrophilic regions are exposed to the outside.

  • Another bactericidal mechanism is that AMPs penetrate into the cytoplasm and interact with intracellular substances, such as inhibiting DNA, RNA and protein synthesis, inhibiting protein folding, inhibiting enzyme activity and cell wall synthesis, and promoting the release of lyases to destroy cell structures.
  • AMPs also modulate host immunity by recruiting/activating immunocytes or by influencing Toll-like receptor (TLR) recognition of microbial products and nucleic acids released upon tissue damage.

Antiviral activity:

  • Antimicrobial peptide-13 effectively inhibits the viral proliferation by disruption of the viral protein synthesis and the viral gene expression in transmissible gastroenteritis virus.

  • The inhibitory effect of LL-37 on a variety of the enveloped viruses, including human immunodeficiency virus (HIV), influenza A virus (IAV), vaccinia virus (VV), HSV, dengue virus (DENV) and Zika virus (ZIKV) is achieved by destroying the viral membrane and inhibiting DNA replication.

Antifungal Peptides (AFPs):

  • Antifungal peptides can kill fungi by targeting either the cell wall or intracellular components. However, bacterial membrane and fungi cell wall.

  • Cell wall targeting-antifungal AMPs kill the target cells by disrupting the integrity of fungal membranes.

References:

  • Peluzio MD, Martinez JA, Milagro FI. Postbiotics: Metabolites and mechanisms involved in microbiota-host interactions. Trends in Food Science & Technology. 2021 Feb 1;108:11-26.

  • Hijová E. Postbiotics as Metabolites and Their Biotherapeutic Potential. International Journal of Molecular Sciences. 2024 May 16;25(10):5441.

  • Prajapati N, Patel J, Singh S, Yadav VK, Joshi C, Patani A, Prajapati D, Sahoo DK, Patel A. Postbiotic production: harnessing the power of microbial metabolites for health applications. Frontiers in Microbiology. 2023 Dec 19;14:1306192.

  • Zhang QY, Yan ZB, Meng YM, Hong XY, Shao G, Ma JJ, Cheng XR, Liu J, Kang J, Fu CY. Antimicrobial peptides: mechanism of action, activity and clinical potential. Military Medical Research. 2021 Dec;8:1-25.

  • Bahar AA, Ren D. Antimicrobial peptides. Pharmaceuticals. 2013 Nov 28;6(12):1543-75.