Gut health benefit and application of postbiotics in animal production
Journal of Animal Science and Biotechnology volume 13, Article number: 38 (2022)
Gut homeostasis is of importance to host health and imbalance of the gut usually leads to disorders or diseases for both human and animal. Postbiotics have been applied in manipulating of gut health, and utilization of postbiotics threads new lights into the host health. Compared with the application of probiotics, the characteristics such as stability and safety of postbiotics make it a potential alternative to probiotics. Studies have reported the beneficial effects of components derived from postbiotics, mainly through the mechanisms including inhibition of pathogens, strengthen gut barrier, and/or regulation of immunity of the host. In this review, we summarized the characteristics of postbiotics, main compounds of postbiotics, potential mechanisms in gut health, and their application in animal production.
Gut homeostasis has been demonstrated to be with importance in maintaining human and animal health [1, 2], and there is mounting evidence that gut microbiota plays a vital role in this function [3, 4]. Although it remains challenging, modulation of complex interactions between gut microbes and host health shows a promise in growth , fertility , aging , disease . It is well established that supplementary probiotics can benefit the host, including specific strains from Lactobacillus , Bifidobacterium , and Akkermansia . The term of probiotics, “Live microorganisms which when administered in adequate amounts, confer a health benefit on the host,”  has been widely accepted. The probiotics improve host health via supporting a healthy digestive tract and/or a healthy immune system , mainly through producing useful metabolites or enzymes [14, 15]. Since probiotics were defined as live microorganisms and probiotic products have been widely applied, large numbers of dead and injured microorganisms existed [16, 17], still maintaining the influence on host health while having little attention. The beneficial effects of components and end-products from non-viable microorganisms were also observed, such as bacterial lysates , lactic acid , short-chain fatty acids (SCFAs) , bioactive peptides . Moreover, appropriate applications of probiotics remain uncertain because they are alive when administered. The safety of probiotics [22, 23] and complex interactions between gut microbiota  have not been totally illustrated yet. Postbiotics were proposed and bring new inspiration for the modulation of gut health due to their advantages. Here, we provided a review of the postbiotics, including their definition, potential mechanisms, and application in animal production.
Postbiotics and its advantages in utilization
Several terms of postbiotics have existed and used, for example, ‘Tyndallized probiotics’ , ‘Heat-killed probiotics’ , ‘Paraprobiotics’ , and ‘Bacterial lysates’ . Although studies and publications of “postbiotics” are increasing steadily , the precise definition of “postbiotics” remains under discussion . The term of “postbiotics” was first coined by Tsilingiri et al., which are metabolic products derived from probiotics that exert beneficial effects on the host via direct or indirect way [31, 32]. In 2019, definition of ‘postbiotic’ was proposed as “preparation of inanimate microorganisms and/or their components that confers a health benefit on the host” by International Scientific Association of Probiotics and Prebiotics (ISAPP) .
The safety of probiotics is associated with their further utilization. Although few studies have reported on this issue, potential risks of probiotics existed, including genetic stability, infectivity, or in situ toxin production [34, 35]. Postbiotics are inanimate microorganisms or their product those lose the capacity to replicate or produce and are free from the concerns above. However, a lower risk of postbiotics does not mean that there is no risk. Specific toxic metabolites or substrates might be released from dead bacteria , which still need to be further assessed.
The rate of live microorganisms in probiotics is uncertain at the end of shelf life due to the death of live microorganisms during different storage conditions . Therefore, probiotics is commonly included in excess of dose to avoid the loss of live microorganisms during the production . In contrast, the potential effects of dead microorganisms in the probiotic products were usually ignored. Postbiotics can maintain stability during industrial process and storage in long shelf life, making it more potentialities in application than probiotics . Thus, it is with possibility to control the precision amount of postbiotics in the products during processing.
Components of postbiotics
Diverse components and molecules derived from microorganisms still exist in postbiotics after processing, contributing to host health in different ways. To discover the beneficial effects and mechanisms of components in postbiotics, they were purified and administrated in both in vivo and in vitro studies. In this part, we summarize the potentially probiotic components as postbiotics reported in previous studies, and these components includes exopolysaccharides, wall polysaccharides, teichoic acids (wall teichoic acids and lipoteichoic acids), surface layer proteins and bacterial DNA and metabolites and so on (Fig. 1).
Exopolysaccharides (EPS) are extracellular carbohydrate polymers with high molecular weight compounds produced and secreted by microorganisms , which attracted attention due to the therapeutic potential in medical applications and the food industry during the past decades . EPS can be found abundantly in lactic acid bacteria (LAB), including Lactobacillus, Lactococcus, Bifidobacterium, Leuconostoc, Pediococcus, Streptococcus, and Weissella [41, 42]. EPS such as xanthan, sphingan, alginate, cellulose show the capability in water-binding, water-retention water, and immense swelling and gelation, which could act as a protective barrier via promoting biofilm formation on the bacterial cell surfaces [43, 44]. Beneficial effects of EPS to gut health were observed, including antimicrobial , immunomodulatory , and anti-inflammatory activities . An in vitro study revealed the EPS produced by Lactobacillus rhamnosus isolated from human breast milk showed substantial antibacterial activity against the pathogens Salmonella enterica serovar Typhimurium and Escherichia coli . The previous study showed pretreatment of IPEC-J2 cells with EPS isolated from L. rhamnosus GG (LGG) could attenuate LPS-induced MAPK and NF-κB as well as alleviate the inflammatory cytokines and TLR activation at mRNA level . Moreover, EPS could prevent bacterial adhesion to the epithelium and contribute to the epithelial barrier integrity in the gut . An in vivo studies showed EPS derived from Bifidobacterium breve UCC2003 could prevent bacterial adhesion to the intestinal epithelium . Transepithelial electrical resistance (TEER) is often used to assess epithelial cell barrier function . Exopolysaccharides from Lactobacillus plantarum NCU116 induce apoptosis via TLR2 in mouse intestinal epithelial cancer cells, which demonstrated that EPS116/TLR2/MyD88 signaling activated c-Jun N-terminal kinase (JNK) and promoted c-Jun phosphorylation to promote upregulation of Fas/Fasl and to trigger apoptotic signaling .
Cellular wall fragments
Most of the probiotics to date, including Lactobacillus and Bifidobacterium, are gram-positive . The cell wall of gram-positive bacteria is a complex assemblage of peptidoglycan, teichoic acids, polysaccharides, and proteins  which are considered beneficial components to the host.
Peptidoglycan consists of β-1,4-linked N-acetylglucosamine and N-acetylmuramic disaccharide units and accounts for approximately 90% of the weight of the cell wall in gram-positive bacteria . Previous studies have revealed that peptidoglycan derived from probiotics or commensal LAB might play a positive role in maintaining the immune balance of the gut. The peptidoglycan of heat-killed L. casei, L. johnsonii JCM 2012T, and L. plantarum ATCC 14917T could inhibit the production of IL-12 through Toll-like receptor 2 (TLR2) in the gut, which further maintains homeostasis in the host . The protective capacity of purified peptidoglycan from L. salivarius Ls33 was observed in IL-10 dependent pathway through induction of regulatory CD103+ DCs and regulatory T cells in the gut of mice .
Teichoic acids are anionic polymers made of alditol-phosphate repeating units and can be classified into wall teichoic acids (WTAs) and lipoteichoic acids (LTAs) . The function of teichoic acids in regulation of cell physiology remains to be investigated, but the importance of teichoic acids has been highlighted in host-cell adhesion, inflammation, and immune activation . The immunostimulatory effects of LTAs were observed via binding to TLR2 and activating cytokine release . LTAs purified from L. casei YIT 9029 and L. fermentum YIT 0159 could induce TNF-α secretion from murine macrophages via a TLR2-mediated strain-dependent mechanism . The structures of WTA are more diverse than those of LTA, and the immune signaling of WTA is still debated [63, 64]. A previous study showed that the purified WTAs of L. plantarum strains did not induce the secretion of any cytokines when applied in human dendritic cells . Apart from the beneficial effects of teichoic acid, the safety of teichoic acid still needs to be tested since the excessive inflammatory response might be triggered .
Bacterial wall polysaccharides can be divided into three groups, including exopolysaccharides (EPS), capsular polysaccharides (CPS), and cell wall polysaccharides (WPS). Unlike EPSs loosely associated with the cell surface, the CPSs are permanently attached to the cell, and WPS may or may not be covalently attached to the cell wall but do not form a capsule . Since EPS has been discussed above, the beneficial effects of CPS and WPS were discussed here. CPS is a highly hydrated molecule that contains over 95% water, protecting cells from desiccation in adverse conditions . In addition, the CPS was considered to be immunomodulating molecules and has been reported to be important virulence factors in pathogenic bacteria [67, 68]. For LAB, WPS plays a role in cell division and morphology, protection against phagocytosis , adhesion, and biofilm formation in bacterial physiology , while the beneficial effects of purified WPS remain to be investigated in the future.
The proteinaceous surface layer (S-layer) are the basic components of gram-positive and gram-negative bacteria and provide important functional properties . Proteins in S-layer, known as S-layer proteins (SLPs), represent one of the most abundant cellular proteins and interact with the host and its immune system . The SLPs of probiotics could contribute to the adhesion to epithelial cells and extracellular matrix proteins, thus inhibiting the pathogens’ infections and further benefiting the host . Indeed, SLPs in Lactobacillus strains isolated from pig intestine play an important role in adhesion and competitive exclusion of E. coli and Salmonella enteritidis in Caco-2 cells . Spent culture supernatants of L. kefir with significant amounts of SLPs could inhibition the invasion of Salmonella in Caco-2/TC-7 cells . SLPs isolated from L. acidophilus could block the viral infection via binding DC-specific intercellular adhesion molecule 3-grabbing non-integrin in 3 T3 cells .
The bacterial DNA can be recognized by the vertebrate immune system, especially unmethylated cytosine-guanine dinucleotide (CpG motifs) in particular base contexts . Unmethylated CpG motifs are prevalent in bacterial but are heavily suppressed and methylated in vertebrate genomic DNAs, which could play an immunomodulatory effect via the TLR9-MyD88-NF-κB signaling pathway . For example, a high frequency of CpG motifs was identified in the DNA of B. longum NCC2705, which might be one of the reasons that they play an important role in the immunostimulatory properties . The synthetic oligodeoxynucleotides (ONDs) contain CpG motifs were found to be effective immunotherapy in several diseases, including the treatment of kidney, skin, breast, uterine, and immune malignancies . Furthermore, CpG-ONDs derived from LGG could attenuate inflammatory cytokine TNF-α and IL-6 production in LPS-stimulated cells, which exerted an anti-inflammation effect on epithelial cells . Apart from the unmethylated GpG motifs, the probiotic DNA was also found to possess immune modulation effects. Purified genomic DNA from the mixture of LGG and B. longum BB536 could enhance the intestinal barrier function and preventing food allergic response in rats . Moreover, pure DNA of Bifidobacterium, which was isolated from feces, also showed an anti-inflammatory effect in peripheral blood mononuclear cells, including the decrease of IL-1β and increase of IL-10 .
Probiotics could interact with the host via metabolites, including indole, SCFAs, vitamins, and other metabolites. Cell-free supernatants (CFS) contain metabolites derived from probiotics were investigated in several previous studies. CFS of L. reuteri AN417, the strain isolated from porcine small intestine, showed greater antimicrobial activity against oral pathogenic bacteria than other Lactobacillus strains such as KCTC 3594 and KETC 3678. The carbohydrates and/or fatty acid metabolites in the CFS of L. reuteri AN417 might be the main antimicrobial factors in reducing biofilm’s integrity and suppressing the expression of genes involved in biofilm formation . Previously study showed that culture supernatant from probiotics isolated from breast milk-fed infants, including L. paracasei CNCM I-4034, B. breve CNCM I-4035, and L. rhamnosus CNCM I-4036 inhibits the growth of enterotoxigenic and enteropathogenic bacteria . L. reuteri ZJ617 isolated from piglets showed probiotic attributes , ZJ617 culture supernatant attenuated liver injury induced by LPS via suppression of hepatic TLR4/MAPK/NF-κB activation, apoptosis, and autophagy in mice . The culture supernatant of L. paracasei CNCM I-4034 could modulate the Salmonella-induced inflammation of human intestinal-like dendritic and Caco-2 cells . CFS of cultures originated from sixteen strains of Lactobacilli and Bifidobacteria prevented E. coli from entering into small and large intestine in human colonic adenocarcinoma cell lines, T84 and Caco2 cells .
Beneficial of postbiotics on gut health
Protective effects against pathogens
Disturbance of gut microbiota, such as the colonization of pathogens and overgrowth of indigenous pathobionts, leads to the damage of gut health and diseases. Postbiotics can be used as a therapeutic approach to inhibit pathogens mainly via the components and competition for adhesion to mucosa and epithelium in the gut . Metabolites such as lactic acids, bacteriocins, and SCFAs in postbiotics were observed to have a role in protecting from invasion by pathogens via diffusion across the bacterial membrane and reducing pH value in the gut . Studies showed lactic acid and bacteriocins from lactic acid bacteria have antimicrobial activity and might be the alternatives to antibiotics [91, 92]. Moreover, extensive studies revealed the beneficial effects of SCFAs against the pathogens in the gut, including acetate, propionate, butyrate. Acetate derived in the gut could protect against respiratory syncytial virus infection via activation of GPR43 in pulmonary epithelial cells and promotion IFN-β response in mice . An in vitro study revealed that propionate directly inhibited S. typhimurium growth by disrupting intracellular pH homeostasis and mediated the colonization resistance to S. typhimurium infection in the gut . Single-cell RNA-sequencing showed the butyrate could imprints potent antimicrobial activity in macrophage differentiation through HDAC3 function . Bacteriocins are small antimicrobial peptides that exhibit inhibitory activity against pathogens and can be a potential candidate for antimicrobial agents in the application of food and pharmaceutics [96, 97]. For example, a purified bacteriocin from L. helveticus PJ4 isolated from Wistar Rat showed a bactericidal mode of action against E. coli and E. faecalis DT48 . The metabolites in postbiotics inhibit pathogens directly but also contribute to cross-feeding on micronutrients in the gut bacteria .
In addition to direct antimicrobial activity, postbiotics could modulate the gut microbiota and inhibit the pathogens, possibly via quorum sensing and adhesion. Quorum sensing is a process of cell-cell communication that allows bacteria to sense population density and regulate their behavior collectively . The block of quorum sensing, called quorum quenching, can be applied in the control of bacterial infections and biofilm formation . Enzymes from bacterial with quorum quenching activity, including lactonases and acylases, showed the ability to degrade the N-Acyl homoserine lactones (AHLs), which led to the inhibition of biofilm formation of Pseudomonas aeruginosa PAO1 . Although the approaches targeting quorum sensing were reported as a therapy for pathogens , the efficiency and mechanisms of quorum quenching still remain debate which require further investigation . The adhesion ability of probiotics also plays a potential protective role against pathogens through competition for the binding sites in the epithelium . High adherence ability to Caco-2 cells was observed in heat-killed L. acidophilus strain LB (Lactobacillus Boucard), which exerted the inhibition effect of different diarrheagenic bacteria, including enterotoxigenic and enteropathogenic E.coli , suggesting the adherence ability still existed in postbiotics.
Benefits for gut barrier function
The gut barrier strongly interacts with the gut bacteria, which could regulate the absorption of nutrients, electrolytes, and water from the lumen into the circulation and prevent toxic entities and pathogens . Beneficial effects of postbiotics on the gut barrier were observed by eliminating the risk of intestinal translocation or local inflammation . Pretreatment of SLP from L. acidophilus NCFM improved integrity and permeability, restored ZO-1 and occludin protein expression in Caco-2 cells. Moreover, SLP also attenuated the cell apoptosis and inhibited TNF-α by suppressing the activation of NF-κB . Similar protective effects on Caco-2 cells were observed in purified SLPs from L. plantarum by increasing the transepithelial resistance and down-regulating permeability . Metabolites such as SCFAs exist in postbiotics could also contribute to the gut barrier function improvement . A study on mice revealed propionate could improve the tight junction through the AKT signaling pathway . Studies showed that administration of acetate, propionate, butyrate alone or in combination boosted transepithelial resistance and stimulated the formation of tight junction in both in vitro and in vivo [113, 114]. Besides, mucin MUC2 expression and secretion can be stimulated by butyrate in goblet cells, which prevents pathogens from destroying enterocytes . Moreover, proteins p40 secreted from LGG could modulate the intestinal epithelial cell homeostasis through the activation of estimated glomerular filtration rate (EGFR) in young adult mouse colon epithelial cells and human colonic epithelial cell line, and T84 cells . An in vitro study showed that protein HM0539 purified from LGG could enhance mucin expression and prevent LPS or TNF-α from inducing gut barrier injury. In mice study, it was verified that HM0539 could promote the development of neonatal intestinal defense and prevent the infection of E. coli K1 .
Immunomodulatory effects on gut
Increasing evidence suggested that substances in postbiotics could interact with the gut immune system and show the potential of immunomodulatory and pharmaceutical effects in individuals [29, 118]. Pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs), nucleotide-binding oligomerization domain-like receptors (NLRs), C-Type lectin-like receptors (CTLRs), and G-protein-coupled receptors (GPCRs) in the gut could recognize components in postbiotics and further induce downstream signaling cascades for beneficial function on the host [65, 119]. The immune functions can be activated by SCFAs through GPCRs, like GPR41, GPR43, and GPR109A, which have shown therapeutic potential in inflammatory bowel diseases . SLP of L. helveticus SBT2171 induced the expression of human β-defensin by activating JNK signaling through TLR2 in Caco-2 cells . SLP-8348 from L. kefiri increased the expression of IL-6 and IL-10 at both transcription and protein levels, and further improved the murine macrophages’ response to LPS in a Ca2+-dependent manner . Furthermore, a study on mice revealed that SLP-8348 exerts immunostimulatory activity through the interactions with mincle . Proteins secreted from probiotics were also observed to have immunomodulatory effects, such as p40 and p75 identified from Lactobacilli species . Proteins p40 and p75 produced from LGG can ameliorate the epithelial barrier disruption by a PKC- and MAP kinase-dependent manner . Unmethylated CpG DNA in postbiotics could be recognized by TLR9 and lead to the recruitment of adapter protein MyD88 and activation of NF-κB, which initiate a cascade of innate and adaptive immune responses in the host [126, 127]. Since postbiotics consist of a wide range of molecules, the immunomodulatory effects of postbiotics might not perform by only one single factor. An in vitro study showed expression of prostaglandin E2 and IL-8 was downregulated by CFS of L. acidophilus, L. casei, L. lactis, L. reuteri, and Saccharomyces boulardii in human colon epithelial HT-29 cells. In addition, peculiar anti-inflammatory effects of supernatants from probiotics were also observed in the modulation of IL-1β, IL-6, TNF-α, and IL-10 production in human macrophages . Heat-killed probiotic bacteria have also been shown to have an immunomodulatory effect in the gut, which are similar to live bacteria . Previous study showed heat-killed lactic acid bacteria such as L. paracasei could induce IL-12 secretion that enhances the innate immunity in mice . The addition of heat-inactivated probiotic B. bifidum OLB6378 exerts beneficial effects on the mucosal immune system by upregulation of polymeric immunoglobulin receptor mRNA expression in mouse intestinal explant model .
Application of postbiotics in animal production
Apart from the therapeutic effects in mice and human health, postbiotics have been applied in animal production as potential alternatives for antibiotics . We summarized the application of postbiotics in swine, poultry, and ruminants reported in previous studies (Table 1).
Beneficial effects of postbiotics were observed in swine for the growth promoter and regulation of the immune system. Strains from L. rhamnosus isolated from pigs were cultured and processed by heating at 80 °C for 30 min. Dietary inclusion 1 × 109 CFU/g of this kind of product could improve production performance, including growth rate, feed efficiency, and apparent total tract digestibility of dry matter in weaned pig. What’s more, pigs fed postbiotics showed reduced post-weaning diarrhea rate together with lower TNF-α, transforming growth factor-β1, and cortisol in serum than that in control group [132, 133]. Feeding of 0.5% metabolites combination from strains of L. plantarum TL1, RG14, and RS5 isolated from Malaysian foods in the piglet diet could improve average daily gain and daily feed intake, as well as reduce diarrhea incidence in the postweaning piglets. What’s more, lower Enterobacteriaceae (ENT), higher LAB counts and SCFA levels in the gut of piglets were observed . Similar results were observed in weaned piglets fed with liquid metabolite combinations derived from strains including L. plantarum TL1, RG11, RG14, RS5 and RI11. In addition to the improvement of growth performance, metabolite combinations derived from L. plantarum strains could contribute to higher villus height of duodenum, suggesting the application of postbiotics could benefit the gut morphology in piglets . Since early weaning usually induced atrophy of villous, oral administration of heat-killed and dried cell preparation of Enterococcus faecalis strain EC-12 led to the higher villous of jejunum in piglets weaned at 21-day-old, suggesting the postbiotics could protect the gut health and relief weaning stress in piglets . Also, immunomodulatory ability of postbiotics in weaned piglets was also observed. Oral administration of heat-killed E. faecium strain NHRD IHARA led to the increase in serum IgA production in weaned piglets, which showed similar effects with the administration of live cells . On the other hand, heat-killed strain E. faecium strain NHRD IHARA also showed beneficial effects on growth performance in pigs . Daily intake of heat-killed L. plantarum L-137 induced higher levels of IFN-β and gene expression in the whole blood cells of pigs, which might subsequently augment host defense against the virus infection . However, Busanello et al. showed treatment with inactivated probiotics cells including L. spp. and L. plantarum showed no significant effects on blood parameters and microbiological counts in the gut of piglets during lactation . Sprat-dried L. plantarum strain 22F, 25F, Pediococcus acidilactici 72 N isolated from pig feces exhibited beneficial effects in the nursery-finishing pigs, including a better feed conversion ratio, increase of Lactobacilli counts, decrease of Enterobacterial counts in the gut, which demonstrated the feasibility of substitute for antibiotics .
Postbiotics has been applied in poultry as well. For instance, as mentioned above, heat-killed Enterococcus faecalis strain EC-12 also applied in newly hatched broilers from age of 3 to 14. Supplement with heat-killed Enterococcus faecalis strain EC-12 increased total IgA in the cecal digesta and total IgG in the serum, and reduced vancomycin-resistant enterococci (VRE) colonization in the intestine, suggesting this kind of postbiotics could stimulate the gut immune system and reinforce the immune reaction against the VRE challenge to accelerate its defecation in chicken . The addition of metabolite combination of L. plantarum RS5, RI11, RG14, and RG11 strains could increase fecal lactic acid bacteria counts, villus height, and volatile fatty acids in broiler chickens . What’s more, chicks fed with CFS of L. plantarum RI11 showed improvement of growth performance, including higher final body weight, total weight gain and average daily gain than other groups, suggesting the L. plantarum RI11 could be used as an alternative antibiotic growth promoter. Also, supplementation of postbiotics improved the gut morphology, lowered ENT and E. coli counts and caecal pH value in the gut but showed limited effect on plasma IgA level [145, 146]. Anti-stress effects of postbiotics L. plantarum RI11 were also observed via regulation of antioxidant enzyme activity, gut barrier genes, and cytokine, acute phase proteins in broilers [147, 148]. In addition, postbiotic metabolite combinations derived from L. plantarum strains RI11 also reduced fecal ENT levels, improved egg quality and increase hen-day egg production in laying hens . Apart from strains from Lactobacillus, postbiotics from Bacillus subtilis also showed beneficial effects in laying hens and broilers, including feed efficiency, egg quality, and immune response [150, 151]. Postbiotics product from a cocktail containing Pediococcus acidilactici, L. reuteri, Enterococcus faecium, and L. acidophilus could improve weight gain and alleviate the proinflammatory responses after the challenge of Clostridium perfringens in broilers .
In ruminants, an in vitro study revealed the alteration of rumen fermentation and bacteria composition after supplementary of postbiotics from L. plantarum RG14, including elevated ruminal volatile fatty acid (VFA) and population of total bacteria, cellulolytic bacteria, and total protozoa . When the same postbiotics were applied in postweaning lambs for 60 d, improvement of rumen epithelium and intestinal barrier function was observed, including the increase of ruminal papillae growth and upregulation of tight junction protein-1, Claudin-1, and Claudin-4 mRNA levels. Lambs fed with postbiotics from L. plantarum RG14 also showed increase of IL-6 mRNA and decrease of mRNA of IL-1β, IL-10, TNF in the jejunum, suggesting the immunomodulation effects of postbiotics in ruminants [152,153,154].
The utilization of postbiotics has shown great potential and can be an alternative to antibiotics in animal production (Fig. 1). However, despite the fact that the inanimate of postbiotics makes it more stable and safer than probiotics, the exact composition in postbiotics remains to be identified in the future, which would make it more capable and convinced in the application. Moreover, although studies have investigated the mechanism of a single factor in postbiotics, the complex interaction between diverse compounds and host can exist. Therefore, as an integration of various compounds, the exact mechanism of the postbiotics is needed to be further illustrated in future studies.
Availability of data and materials
N-Acyl homoserine lactones
- CpG motifs:
Cytosine-guanine dinucleotide in particular base contexts
C-Type lectin-like receptors
Estimated glomerular filtration rate
International Scientific Association of Probiotics and Prebiotics
c-Jun N-terminal kinase
Lactic acid bacteria
Lactobacillus rhamnosus GG
Nucleotide-binding oligomerization domain-like receptors
Pattern recognition receptors
Short-chain fatty acids
Surface layer proteins
Transepithelial electrical resistance
Wall teichoic acids
Garrett WS, Gordon JI, Glimcher LH. Homeostasis and inflammation in the intestine. Cell. 2010;140(6):859–70. https://doi.org/10.1016/j.cell.2010.01.023.
Lallès J-P. Microbiota-host interplay at the gut epithelial level, health and nutrition. J Anim Sci Biotechnol. 2016;7:66.
Fan Y, Pedersen O. Gut microbiota in human metabolic health and disease. Nat Rev Microbiol. 2021;19(1):55–71. https://doi.org/10.1038/s41579-020-0433-9.
Wang X, Yang S, Li S, Zhao L, Hao Y, Qin J, et al. Aberrant gut microbiota alters host metabolome and impacts renal failure in humans and rodents. Gut. 2020;69(12):2131–42. https://doi.org/10.1136/gutjnl-2019-319766.
Wang H, Xu R, Zhang H, Su Y, Zhu W. Swine gut microbiota and its interaction with host nutrient metabolism. Anim Nutr. 2020;6(4):410–20. https://doi.org/10.1016/j.aninu.2020.10.002.
Qi X, Yun C, Sun L, Xia J, Wu Q, Wang Y, et al. Gut microbiota–bile acid–interleukin-22 axis orchestrates polycystic ovary syndrome. Nat Med. 2019;25:1225–33.
Wilmanski T, Diener C, Rappaport N, Patwardhan S, Wiedrick J, Lapidus J, et al. Gut microbiome pattern reflects healthy ageing and predicts survival in humans. Nat Metab. 2021;3:274–86.
Zmora N, Suez J, Elinav E. You are what you eat: diet, health and the gut microbiota. Nat Rev Gastroenterol Hepatol. 2019;16:35–56.
Zheng J, Wittouck S, Salvetti E, Franz C, Harris HMB, Mattarelli P, et al. A taxonomic note on the genus Lactobacillus: description of 23 novel genera, emended description of the genus Lactobacillus Beijerinck 1901, and union of Lactobacillaceae and Leuconostocaceae. Int J Syst Evol Microbiol. 2020;70(4):2782–858. https://doi.org/10.1099/ijsem.0.004107.
Picard C, Fioramonti J, Francois A, Robinson T, Neant F, Matuchansky C. Review article: bifidobacteria as probiotic agents-physiological effects and clinical benefits. Aliment Pharmacol Ther. 2005;22(6):495–512. https://doi.org/10.1111/j.1365-2036.2005.02615.x.
Xu Y, Wang N, Tan H-Y, Li S, Zhang C, Feng Y. Function of Akkermansia muciniphila in obesity: interactions with lipid metabolism, immune response and gut systems. Front Microbiol. 2020;11:219. https://doi.org/10.3389/fmicb.2020.00219.
FAO/WHO. Health and nutritional properties of probiotics in food including powder milk with live lactic acid bacteria. Córdoba, Argentina: Reports of The Joint FAO/WHO Expert Consultation; 2001.
Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. Expert consensus document. The international scientific association for probiotics and prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014;11(8):506–14. https://doi.org/10.1038/nrgastro.2014.66.
Kumar M, Nagpal R, Verma V, Kumar A, Kaur N, Hemalatha R, et al. Probiotic metabolites as epigenetic targets in the prevention of colon cancer. Nutr Rev. 2013;71(1):23–34. https://doi.org/10.1111/j.1753-4887.2012.00542.x.
Matthews C, Crispie F, Lewis E, Reid M, O'Toole PW, Cotter PD. The rumen microbiome: a crucial consideration when optimising milk and meat production and nitrogen utilisation efficiency. Gut Microbes. 2019;10(2):115–32. https://doi.org/10.1080/19490976.2018.1505176.
Fiore W, Arioli S, Guglielmetti S. The neglected microbial components of commercial probiotic formulations. Microorganisms. 2020;8(8):1177–85. https://doi.org/10.3390/microorganisms8081177.
Holmes E, Kinross J, Gibson GR, Burcelin R, Jia W, Pettersson S, et al. Therapeutic modulation of microbiota-host metabolic interactions. Sci Transl Med. 2012;4(137):137rv6. https://doi.org/10.1126/scitranslmed.3004244.
Esposito S, Soto-Martinez ME, Feleszko W, Jones MH, Shen KL, Schaad UB. Nonspecific immunomodulators for recurrent respiratory tract infections, wheezing and asthma in children: a systematic review of mechanistic and clinical evidence. Curr Opin Allergy Clin Immunol. 2018;18(3):198–209. https://doi.org/10.1097/ACI.0000000000000433.
Pessione E. Lactic acid bacteria contribution to gut microbiota complexity: lights and shadows. Front Cell Infect Microbiol. 2012;2:1–15. https://doi.org/10.3389/fcimb.2012.00086.
Nagpal R, Wang S, Ahmadi S, Hayes J, Gagliano J, Subashchandrabose S, et al. Human-origin probiotic cocktail increases short-chain fatty acid production via modulation of mice and human gut microbiome. Sci Rep. 2018;8:12649–64.
Zielińska D, Kolożyn-Krajewska D. Food-origin lactic acid bacteria may exhibit probiotic properties: review. Biomed Res Int. 2018;2018:5063185–200. https://doi.org/10.1155/2018/5063185.
Žuntar I, Petric Z, Bursać Kovačević D, Putnik P. Safety of probiotics: functional fruit beverages and nutraceuticals. Foods. 2020;9:947–66.
Snydman DR. The safety of probiotics. Clin Infect Dis. 2008;46(s2):S104–S11. https://doi.org/10.1086/523331.
Nayfach S, Shi ZJ, Seshadri R, Pollard KS, Kyrpides NC. New insights from uncultivated genomes of the global human gut microbiome. Nature. 2019;568:505–10.
Piqué N, Berlanga M, Miñana-Galbis D. Health benefits of heat-killed (Tyndallized) probiotics: an overview. Int J Mol Sci. 2019;20(10):2534–64. https://doi.org/10.3390/ijms20102534.
Li N, Russell WM, Douglas-escobar M, Hauser N, Lopez M, Neu J. Live and heat-killed Lactobacillus rhamnosus GG: effects on proinflammatory and anti-inflammatory cytokines/chemokines in gastrostomy-fed infant rats. Pediatr Res. 2009;66(2):203–7. https://doi.org/10.1203/PDR.0b013e3181aabd4f.
Taverniti V, Guglielmetti S. The immunomodulatory properties of probiotic microorganisms beyond their viability (ghost probiotics: proposal of paraprobiotic concept). Genes Nutr. 2011;6(3):261–74. https://doi.org/10.1007/s12263-011-0218-x.
Jurkiewicz D, Zielnik-Jurkiewicz B. Bacterial lysates in the prevention of respiratory tract infections. Otolaryngol Pol. 2018;72(5):1–8. https://doi.org/10.5604/01.3001.0012.7216.
Wegh CAM, Geerlings SY, Knol J, Roeselers G, Belzer C. Postbiotics and their potential applications in early life nutrition and beyond. Int J Mol Sci. 2019;20:4673–96.
Żółkiewicz J, Marzec A, Ruszczyński M, Feleszko W. Postbiotics-a step beyond pre- and probiotics. Nutrients. 2020;12(8):2189–206. https://doi.org/10.3390/nu12082189.
Tsilingiri K, Rescigno M. Postbiotics: what else? Benef Microbes. 2013;4:101–7.
Tsilingiri K, Barbosa T, Penna G, Caprioli F, Sonzogni A, Viale G, et al. Probiotic and postbiotic activity in health and disease: comparison on a novel polarised ex-vivo organ culture model. Gut. 2012;61(7):1007–15. https://doi.org/10.1136/gutjnl-2011-300971.
Swanson KS, Gibson GR, Hutkins R, Reimer RA, Reid G, Verbeke K, et al. The international scientific association for probiotics and prebiotics (ISAPP) consensus statement on the definition and scope of synbiotics. Nat Rev Gastroenterol Hepatol. 2020;17(11):687–701. https://doi.org/10.1038/s41575-020-0344-2.
Sanders ME, Akkermans LM, Haller D, Hammerman C, Heimbach J, Hörmannsperger G, et al. Safety assessment of probiotics for human use. Gut Microbes. 2010;1(3):164–85. https://doi.org/10.4161/gmic.1.3.12127.
Guo P, Zhang K, Ma X, He P. Clostridium species as probiotics: potentials and challenges. J Anim Sci Biotechnol. 2020;11:24.
Periti P, Mazzei T. Antibiotic-induced release of bacterial cell wall components in the pathogenesis of sepsis and septic shock: a review. J Chemother. 1998;10(6):427–48. https://doi.org/10.1179/joc.1918.104.22.1687.
Fenster K, Freeburg B, Hollard C, Wong C, Rønhave Laursen R, Ouwehand AC. The production and delivery of probiotics: a review of a practical approach. Microorganisms. 2019;7:83–100.
Sreeja V, Prajapati JB. Probiotic formulations: application and status as pharmaceuticals-a review. Probiotics Antimicrob Proteins. 2013;5:81–91.
Ghrairi T, Jaraud S, Alves A, Fleury Y, El Salabi A, Chouchani C. New insights into and updates on antimicrobial agents from natural products. Biomed Res Int. 2019;2019:7079864–7. https://doi.org/10.1155/2019/7079864.
Moscovici M. Present and future medical applications of microbial exopolysaccharides. Front Microbiol. 2015;6:1012.
Ruas-Madiedo P, de los Reyes-Gavilán CG. Invited review: Methods for the screening, isolation, and characterization of exopolysaccharides produced by lactic acid bacteria. J Dairy Sci. 2005;88:843–56.
Nguyen PT, Nguyen TT, Bui DC, Hong PT, Hoang QK, Nguyen HT. Exopolysaccharide production by lactic acid bacteria: the manipulation of environmental stresses for industrial applications. AIMS Microbiol. 2020;6(4):451–69. https://doi.org/10.3934/microbiol.2020027.
Kodali VP, Das S, Sen R. An exopolysaccharide from a probiotic: biosynthesis dynamics, composition and emulsifying activity. Food Res Int. 2009;42:695–9.
Majee SB, Avlani D, Biswas GR. Rheological behavior and pharmaceutical applications of bacterial exopolysaccharides. J Appl Pharm Sci. 2017;7:224–32.
Abdalla AK, Ayyash MM, Olaimat AN, Osaili TM, Al-Nabulsi AA, Shah NP, et al. Exopolysaccharides as antimicrobial agents: mechanism and spectrum of activity. Front Microbiol. 2021;12:1182. https://doi.org/10.3389/fmicb.2021.664395.
Górska S, Sandstrőm C, Wojas-Turek J, Rossowska J, Pajtasz-Piasecka E, Brzozowska E, et al. Structural and immunomodulatory differences among lactobacilli exopolysaccharides isolated from intestines of mice with experimentally induced inflammatory bowel disease. Sci Rep. 2016;6(1):37613–29. https://doi.org/10.1038/srep37613.
Angelin J, Kavitha M. Exopolysaccharides from probiotic bacteria and their health potential. Int J Biol Macromol. 2020;162:853–65. https://doi.org/10.1016/j.ijbiomac.2020.06.190.
Riaz Rajoka MS, Jin M, Haobin Z, Li Q, Shao D, Jiang C, et al. Functional characterization and biotechnological potential of exopolysaccharide produced by Lactobacillus rhamnosus strains isolated from human breast milk. LWT. 2018;89:638–47.
Gao K, Wang C, Liu L, Dou X, Liu J, Yuan L, et al. Immunomodulation and signaling mechanism of Lactobacillus rhamnosus GG and its components on porcine intestinal epithelial cells stimulated by lipopolysaccharide. J Microbiol Immunol Infect. 2017;50(5):700–13. https://doi.org/10.1016/j.jmii.2015.05.002.
Oerlemans MMP, Akkerman R, Ferrari M, Walvoort MTC, de Vos P. Benefits of bacteria-derived exopolysaccharides on gastrointestinal microbiota, immunity and health. J Funct Foods. 2021;76:104289. https://doi.org/10.1016/j.jff.2020.104289.
Fanning S, Hall LJ, Cronin M, Zomer A, MacSharry J, Goulding D, et al. Bifidobacterial surface-exopolysaccharide facilitates commensal-host interaction through immune modulation and pathogen protection. Proc Natl Acad Sci U S A. 2012;109(6):2108–13. https://doi.org/10.1073/pnas.1115621109.
Srinivasan B, Kolli AR, Esch MB, Abaci HE, Shuler ML, Hickman JJ. TEER measurement techniques for in vitro barrier model systems. J Lab Autom. 2015;20:107–26.
Zhou X, Hong T, Yu Q, Nie S, Gong D, Xiong T, et al. Exopolysaccharides from Lactobacillus plantarum NCU116 induce c-Jun dependent Fas/Fasl-mediated apoptosis via TLR2 in mouse intestinal epithelial cancer cells. Sci Rep. 2017;7(1):14247–60. https://doi.org/10.1038/s41598-017-14178-2.
Marco ML, Pavan S, Kleerebezem M. Towards understanding molecular modes of probiotic action. Curr Opin Biotechnol. 2006;17(2):204–10. https://doi.org/10.1016/j.copbio.2006.02.005.
Chapot-Chartier MP, Kulakauskas S. Cell wall structure and function in lactic acid bacteria. Microb Cell Factories. 2014;13(Suppl 1):S9–32.
Dziarski R. Recognition of bacterial peptidoglycan by the innate immune system. Cell Mol Life Sci. 2003;60(9):1793–804. https://doi.org/10.1007/s00018-003-3019-6.
Shida K, Kiyoshima-Shibata J, Kaji R, Nagaoka M, Nanno M. Peptidoglycan from lactobacilli inhibits interleukin-12 production by macrophages induced by Lactobacillus casei through toll-like receptor 2-dependent and independent mechanisms. Immunology. 2009;128(1pt2):e858–69. https://doi.org/10.1111/j.1365-2567.2009.03095.x.
Macho Fernandez E, Valenti V, Rockel C, Hermann C, Pot B, Boneca IG, et al. Anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptide. Gut. 2011;60(8):1050–9. https://doi.org/10.1136/gut.2010.232918.
Weidenmaier C, Peschel A. Teichoic acids and related cell-wall glycopolymers in gram-positive physiology and host interactions. Nat Rev Microbiol. 2008;6(4):276–87. https://doi.org/10.1038/nrmicro1861.
Swoboda JG, Campbell J, Meredith TC, Walker S. Wall teichoic acid function, biosynthesis, and inhibition. Chembiochem. 2010;11:35–45.
Wells JM, Brummer RJ, Derrien M, MacDonald TT, Troost F, Cani PD, et al. Homeostasis of the gut barrier and potential biomarkers. Am J Physiol Gastrointest Liver Physiol. 2017;312(3):G171–93. https://doi.org/10.1152/ajpgi.00048.2015.
Matsuguchi T, Takagi A, Matsuzaki T, Nagaoka M, Ishikawa K, Yokokura T, et al. Lipoteichoic acids from Lactobacillus strains elicit strong tumor necrosis factor alpha-inducing activities in macrophages through toll-like receptor 2. Clin Diagn Lab Immunol. 2003;10(2):259–66. https://doi.org/10.1128/CDLI.10.2.259-266.2003.
Bron PA, van Baarlen P, Kleerebezem M. Emerging molecular insights into the interaction between probiotics and the host intestinal mucosa. Nat Rev Microbiol. 2012;10(1):66–78. https://doi.org/10.1038/nrmicro2690.
Rockel C, Hartung T, Hermann C. Different Staphylococcus aureus whole bacteria mutated in putative pro-inflammatory membrane components have similar cytokine inducing activity. Immunobiology. 2011;216(3):316–21. https://doi.org/10.1016/j.imbio.2010.08.001.
Bron PA, Tomita S, van Swam II, Remus DM, Meijerink M, Wels M, et al. Lactobacillus plantarum possesses the capability for wall teichoic acid backbone alditol switching. Microb Cell Factories. 2012;11(1):123–38. https://doi.org/10.1186/1475-2859-11-123.
Madigan MT, Martinko JM, Bender KS, Buckley DH, Stahl DA. Brock biology of microorganisms. In: Prentice hall upper Saddle River. Pearson Education: NJ; 2011.
Azurmendi HF, Veeramachineni V, Freese S, Lichaa F, Freedberg DI, Vann WF. Chemical structure and genetic organization of the E. coli O6:K15 capsular polysaccharide. Sci Rep. 2020;10:12608–20.
Bentley SD, Aanensen DM, Mavroidi A, Saunders D, Rabbinowitsch E, Collins M, et al. Genetic analysis of the capsular biosynthetic locus from all 90 pneumococcal serotypes. PLoS Genet. 2006;2:262–9.
Chapot-Chartier MP, Vinogradov E, Sadovskaya I, Andre G, Mistou MY, Trieu-Cuot P, et al. Cell surface of Lactococcus lactis is covered by a protective polysaccharide pellicle. J Biol Chem. 2010;285(14):10464–71. https://doi.org/10.1074/jbc.M109.082958.
Lebeer S, Verhoeven TL, Francius G, Schoofs G, Lambrichts I, Dufrêne Y, et al. Identification of a gene cluster for the biosynthesis of a long, galactose-rich exopolysaccharide in Lactobacillus rhamnosus GG and functional analysis of the priming glycosyltransferase. Appl Environ Microbiol. 2009;75(11):3554–63. https://doi.org/10.1128/AEM.02919-08.
Fagan RP, Fairweather NF. Biogenesis and functions of bacterial S-layers. Nat Rev Microbiol. 2014;12:211–22.
Sára M, Sleytr UB. S-layer proteins. J Bacteriol. 2000;182(4):859–68. https://doi.org/10.1128/JB.182.4.859-868.2000.
do Carmo FLR, Rabah H, De Oliveira Carvalho RD, Gaucher F, Cordeiro BF, da Silva SH, et al. Extractable bacterial surface proteins in probiotic–host interaction. Front Microbiol. 2018;9:645.
Zhang W, Wang H, Liu J, Zhao Y, Gao K, Zhang J. Adhesive ability means inhibition activities for lactobacillus against pathogens and S-layer protein plays an important role in adhesion. Anaerobe. 2013;22:97–103. https://doi.org/10.1016/j.anaerobe.2013.06.005.
Golowczyc MA, Mobili P, Garrote GL, Abraham AG, De Antoni GL. Protective action of Lactobacillus kefir carrying S-layer protein against Salmonella enterica serovar Enteritidis. Int J Food Microbiol. 2007;118:264–73.
Prado Acosta M, Geoghegan EM, Lepenies B, Ruzal S, Kielian M, Martinez MG. Surface (S) layer proteins of Lactobacillus acidophilus block virus infection via DC-SIGN interaction. Front Microbiol. 2019;10:810. https://doi.org/10.3389/fmicb.2019.00810.
Hartmann G, Krieg AM. Mechanism and function of a newly identified CpG DNA motif in human primary B cells. J Immunol. 2000;164:944–53.
Krieg AM. CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol. 2002;20(1):709–60. https://doi.org/10.1146/annurev.immunol.20.100301.064842.
Ménard O, Gafa V, Kapel N, Rodriguez B, Butel M-J, Waligora-Dupriet A-J. Characterization of immunostimulatory CpG-rich sequences from different Bifidobacterium species. Appl Environ Microbiol. 2010;76:2846–55.
Klinman DM. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol. 2004;4(4):249–58. https://doi.org/10.1038/nri1329.
Qi SR, Cui YJ, Liu JX, Luo X, Wang HF. Lactobacillus rhamnosus GG components, SLP, gDNA and CpG, exert protective effects on mouse macrophages upon lipopolysaccharide challenge. Lett Appl Microbiol. 2020;70:118–27.
Zhong Y, Huang J, Tang W, Chen B, Cai W. Effects of probiotics, probiotic DNA and the CpG oligodeoxynucleotides on ovalbumin-sensitized Brown-Norway rats via TLR9/NF-κB pathway. FEMS Immunol Med Microbiol. 2012;66:71–82.
Lammers KM, Brigidi P, Vitali B, Gionchetti P, Rizzello F, Caramelli E, et al. Immunomodulatory effects of probiotic bacteria DNA: IL-1 and IL-10 response in human peripheral blood mononuclear cells. FEMS Immunol Med Microbiol. 2003;38(2):165–72. https://doi.org/10.1016/S0928-8244(03)00144-5.
Yang KM, Kim J-S, Kim H-S, Kim Y-Y, Oh J-K, Jung H-W, et al. Lactobacillus reuteri AN417 cell-free culture supernatant as a novel antibacterial agent targeting oral pathogenic bacteria. Sci Rep. 2021;11(1):1631–47. https://doi.org/10.1038/s41598-020-80921-x.
Muñoz-Quezada S, Bermudez-Brito M, Chenoll E, Genovés S, Gomez-Llorente C, Plaza-Diaz J, et al. Competitive inhibition of three novel bacteria isolated from faeces of breast milk-fed infants against selected enteropathogens. Br J Nutr. 2013;109(S2):S63–9. https://doi.org/10.1017/S0007114512005600.
Cui Y, Qi S, Zhang W, Mao J, Tang R, Wang C, et al. Lactobacillus reuteri ZJ617 culture supernatant attenuates acute liver injury induced in mice by lipopolysaccharide. J Nutr. 2019;149(11):2046–55. https://doi.org/10.1093/jn/nxz088.
Bermudez-Brito M, Muñoz-Quezada S, Gómez-Llorente C, Matencio E, Romero F, Gil A. Lactobacillus paracasei CNCM I-4034 and its culture supernatant modulate Salmonella-induced inflammation in a novel transwell co-culture of human intestinal-like dendritic and Caco-2 cells. BMC Microbiol. 2015;15:79–94.
Khodaii Z, Ghaderian SMH, Natanzi MM. Probiotic bacteria and their supernatants protect enterocyte cell lines from enteroinvasive Escherichia coli (EIEC) invasion. Int J Mol Cell Med. 2017;6:183–9.
Mantziari A, Salminen S, Szajewska H, Malagón-Rojas JN. Postbiotics against pathogens commonly involved in pediatric infectious diseases. Microorganisms. 2020;8:1510–32.
Lamas A, Regal P, Vázquez B, Cepeda A, Franco CM. Short chain fatty acids commonly produced by gut microbiota influence Salmonella enterica motility, biofilm formation, and gene expression. Antibiotics. 2019;8:265–78.
Sun Z, Harris HMB, McCann A, Guo C, Argimón S, Zhang W, et al. Expanding the biotechnology potential of lactobacilli through comparative genomics of 213 strains and associated genera. Nat Commun. 2015;6(1):8322–35. https://doi.org/10.1038/ncomms9322.
Corr SC, Li Y, Riedel CU, O’Toole PW, Hill C, Gahan CG. Bacteriocin production as a mechanism for the antiinfective activity of Lactobacillus salivarius UCC118. Proc Natl Acad Sci U S A. 2007;104(18):7617–21. https://doi.org/10.1073/pnas.0700440104.
Antunes KH, Fachi JL, de Paula R, da Silva EF, Pral LP, dos Santos AÁ, et al. Microbiota-derived acetate protects against respiratory syncytial virus infection through a GPR43-type 1 interferon response. Nat Commun. 2019;10(1):3273–90. https://doi.org/10.1038/s41467-019-11152-6.
Jacobson A, Lam L, Rajendram M, Tamburini F, Honeycutt J, Pham T, et al. A gut commensal-produced metabolite mediates colonization resistance to Salmonella infection. Cell Host Microbe. 2018;24(2):296–307. https://doi.org/10.1016/j.chom.2018.07.002.
Schulthess J, Pandey S, Capitani M, Rue-Albrecht KC, Arnold I, Franchini F, et al. The short chain fatty acid butyrate imprints an antimicrobial program in macrophages. Immunity. 2019;50:432–45.
Simons A, Alhanout K, Duval RE. Bacteriocins, antimicrobial peptides from bacterial origin: overview of their biology and their impact against multidrug-resistant bacteria. Microorganisms. 2020;8(5):639–70. https://doi.org/10.3390/microorganisms8050639.
Yang S-C, Lin C-H, Sung CT, Fang J-Y. Antibacterial activities of bacteriocins: application in foods and pharmaceuticals. Front Microbiol. 2014;5:241.
Jena PK, Trivedi D, Chaudhary H, Sahoo TK, Seshadri S. Bacteriocin PJ4 active against enteric pathogen produced by Lactobacillus helveticus PJ4 isolated from gut microflora of wistar rat (Rattus norvegicus): partial purification and characterization of bacteriocin. Appl Biochem Biotechnol. 2013;169(7):2088–100. https://doi.org/10.1007/s12010-012-0044-7.
Seth EC, Taga ME. Nutrient cross-feeding in the microbial world. Front Microbiol. 2014;5:350.
Fuqua WC, Winans SC, Greenberg EP. Quorum sensing in bacteria: the LuxR-LuxI family of cell density-responsive transcriptional regulators. J Bacteriol. 1994;176(2):269–75. https://doi.org/10.1128/jb.176.2.269-275.1994.
Bzdrenga J, Daudé D, Rémy B, Jacquet P, Plener L, Elias M, et al. Biotechnological applications of quorum quenching enzymes. Chem Biol Interact. 2017;267:104–15. https://doi.org/10.1016/j.cbi.2016.05.028.
Rehman ZU, Leiknes T. Quorum-quenching bacteria isolated from red sea sediments reduce biofilm formation by Pseudomonas aeruginosa. Front Microbiol. 2018;9:1354.
LaSarre B, Federle MJ. Exploiting quorum sensing to confuse bacterial pathogens. Microbiol Mol Biol Rev. 2013;77:73–111.
Krzyżek P. Challenges and limitations of anti-quorum sensing therapies. Front Microbiol. 2019;10:2473. https://doi.org/10.3389/fmicb.2019.02473.
Monteagudo-Mera A, Rastall RA, Gibson GR, Charalampopoulos D, Chatzifragkou A. Adhesion mechanisms mediated by probiotics and prebiotics and their potential impact on human health. Appl Microbiol Biotechnol. 2019;103(16):6463–72. https://doi.org/10.1007/s00253-019-09978-7.
Liévin-Le MV. A gastrointestinal anti-infectious biotherapeutic agent: the heat-treated Lactobacillus LB. Ther Adv Gastroenterol. 2016;9:57–75.
König J, Wells J, Cani PD, García-Ródenas CL, MacDonald T, Mercenier A, et al. Human intestinal barrier function in health and disease. Clin Transl Gastroenterol. 2016;7(10):e196–209. https://doi.org/10.1038/ctg.2016.54.
Morniroli D, Vizzari G, Consales A, Mosca F, Giannì ML. Postbiotic supplementation for children and newborn’s health. Nutrients. 2021;13(3):781–92. https://doi.org/10.3390/nu13030781.
Wang H, Zhang Q, Niu Y, Zhang X, Lu R. Surface-layer protein from Lactobacillus acidophilus NCFM attenuates tumor necrosis factor-α-induced intestinal barrier dysfunction and inflammation. Int J Biol Macromol. 2019;136:27–34. https://doi.org/10.1016/j.ijbiomac.2019.06.041.
Li P-N, Herrmann J, Tolar BB, Poitevin F, Ramdasi R, Bargar JR, et al. Nutrient transport suggests an evolutionary basis for charged archaeal surface layer proteins. ISME J. 2018;12(10):2389–402. https://doi.org/10.1038/s41396-018-0191-0.
Liu P, Wang Y, Yang G, Zhang Q, Meng L, Xin Y, et al. The role of short-chain fatty acids in intestinal barrier function, inflammation, oxidative stress, and colonic carcinogenesis. Pharmacol Res. 2021;165:105420–31.
Huang T, Shi H, Xu Y, Ji L. The gut microbiota metabolite propionate ameliorates intestinal epithelial barrier dysfunction-mediated Parkinson’s disease via the AKT signaling pathway. Neuroreport. 2021;32(3):244–51. https://doi.org/10.1097/WNR.0000000000001585.
Feng Y, Wang Y, Wang P, Huang Y, Wang F. Short-chain fatty acids manifest stimulative and protective effects on intestinal barrier function through the inhibition of NLRP3 inflammasome and autophagy. Cell Physiol Biochem. 2018;49(1):190–205. https://doi.org/10.1159/000492853.
Liu H, Wang J, He T, Becker S, Zhang G, Li D, et al. Butyrate: a double-edged wword for health? Adv Nutr. 2018;9(1):21–9. https://doi.org/10.1093/advances/nmx009.
Burger-van Paassen N, Vincent A, Puiman PJ, van der Sluis M, Bouma J, Boehm G, et al. The regulation of intestinal mucin MUC2 expression by short-chain fatty acids: implications for epithelial protection. Biochem J. 2009;420:211–9.
Yan F, Liu L, Dempsey PJ, Tsai YH, Raines EW, Wilson CL, et al. A Lactobacillus rhamnosus GG-derived soluble protein, p40, stimulates ligand release from intestinal epithelial cells to transactivate epidermal growth factor receptor. J Biol Chem. 2013;288(42):30742–51. https://doi.org/10.1074/jbc.M113.492397.
Gao J, Li Y, Wan Y, Hu T, Liu L, Yang S, et al. A novel postbiotic from Lactobacillus rhamnosus GG with a beneficial effect on intestinal barrier function. Front Microbiol. 2019;10:477.
Akatsu H. Exploring the effect of probiotics, prebiotics, and postbiotics in strengthening immune activity in the elderly. Vaccines. 2021;9(2):136–47. https://doi.org/10.3390/vaccines9020136.
Teame T, Wang A, Xie M, Zhang Z, Yang Y, Ding Q, et al. Paraprobiotics and postbiotics of probiotic lactobacilli, their positive effects on the host and action mechanisms: a review. Front Nutr. 2020;7:191. https://doi.org/10.3389/fnut.2020.570344.
Parada Venegas D, De la Fuente MK, Landskron G, González MJ, Quera R, Dijkstra G, et al. Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front Immunol. 2019;10:277–93.
Kobatake E, Kabuki T. S-layer protein of Lactobacillus helveticus SBT2171 promotes human β-defensin 2 expression via TLR2-JNK signaling. Front Microbiol. 2019;10:2414. https://doi.org/10.3389/fmicb.2019.02414.
Malamud M, Carasi P, Freire T, Serradell MLA. S-layer glycoprotein from Lactobacillus kefiri CIDCA 8348 enhances macrophages response to LPS in a ca(+2)-dependent manner. Biochem Biophys Res Commun. 2018;495(1):1227–32. https://doi.org/10.1016/j.bbrc.2017.11.127.
Malamud M, Carasi P, Assandri MH, Freire T, Lepenies B, Serradell M. S-layer glycoprotein from Lactobacillus kefiri exerts its immunostimulatory activity through glycan recognition by mincle. Front Immunol. 2019;10:1422. https://doi.org/10.3389/fimmu.2019.01422.
Bäuerl C, Abitayeva G, Sosa-Carrillo S, Mencher-Beltrán A, Navarro-Lleó N, Coll-Marqués JM, et al. P40 and P75 are singular functional muramidases present in the Lactobacillus casei /paracasei/rhamnosus taxon. Front Microbiol. 2019;10:1420.
Seth A, Yan F, Polk DB, Rao RK. Probiotics ameliorate the hydrogen peroxide-induced epithelial barrier disruption by a PKC- and MAP kinase-dependent mechanism. Am J Physiol Gastrointest Liver Physiol. 2008;294:G1060–9.
Krieg AM. Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene. 2008;27(2):161–7. https://doi.org/10.1038/sj.onc.1210911.
Latz E, Verma A, Visintin A, Gong M, Sirois CM, Klein DC, et al. Ligand-induced conformational changes allosterically activate toll-like receptor 9. Nat Immunol. 2007;8(7):772–9. https://doi.org/10.1038/ni1479.
De Marco S, Sichetti M, Muradyan D, Piccioni M, Traina G, Pagiotti R, et al. Probiotic cell-free supernatants exhibited anti-inflammatory and antioxidant activity on human gut epithelial cells and macrophages stimulated with LPS. Evid Based Complement Altern Med. 2018;2018:1756308–20. https://doi.org/10.1155/2018/1756308.
Arai S, Iwabuchi N, Takahashi S, Xiao JZ, Abe F, Hachimura S. Orally administered heat-killed Lactobacillus paracasei MCC1849 enhances antigen-specific IgA secretion and induces follicular helper T cells in mice. PLoS One. 2018;13(6):e0199018–33. https://doi.org/10.1371/journal.pone.0199018.
Nakamura Y, Terahara M, Iwamoto T, Yamada K, Asano M, Kakuta S, et al. Upregulation of polymeric immunoglobulin receptor expression by the heat-inactivated potential probiotic Bifidobacterium bifidum OLB6378 in a mouse intestinal explant model. Scand J Immunol. 2012;75:176–83.
Vieco-Saiz N, Belguesmia Y, Raspoet R, Auclair E, Gancel F, Kempf I, et al. Benefits and inputs from lactic acid bacteria and their bacteriocins as alternatives to antibiotic growth promoters during food-animal production. Front Microbiol. 2019;10:57. https://doi.org/10.3389/fmicb.2019.00057.
Kang J, Lee JJ, Cho JH, Choe J, Kyoung H, Kim SH, et al. Effects of dietary inactivated probiotics on growth performance and immune responses of weaned pigs. J Anim Sci Technol. 2021;63(3):520–30. https://doi.org/10.5187/jast.2021.e44.
Kang J, Chae JP, Kim S-H, Kim J-W, Park S, Mun D, et al. PSIV-B-42 late-breaking: effects of dietary inactivated probiotics on growth performance, nutrient digestibility, and immune responses of weaned pigs. J Anim Sci. 2019;97:327–8.
Thu TV, Loh TC, Foo HL, Yaakub H, Bejo MH. Effects of liquid metabolite combinations produced by Lactobacillus plantarum on growth performance, faeces characteristics, intestinal morphology and diarrhoea incidence in postweaning piglets. Trop Anim Health Prod. 2011;43:69–75.
Loh TC, Thu TV, Foo HL, Bejo MH. Effects of different levels of metabolite combination produced by Lactobacillus plantarum on growth performance, diarrhoea, gut environment and digestibility of postweaning piglets. J Appl Anim Res. 2013;41(2):200–7. https://doi.org/10.1080/09712119.2012.741046.
Tsukahara T, Yoshida Y, Tsushima T, Watanabe T, Matsubara N, Inoue R, et al. Evaluation of the heat-killed and dried cell preparation of enterococcus faecalis against villous atrophy in early-weaned mice and pigs. Anim Sci J. 2011;82(2):302–6. https://doi.org/10.1111/j.1740-0929.2010.00829.x.
Sukegawa S, Ihara Y, Yuge K, Rao S, Oka K, Arakawa F, et al. Effects of oral administration of heat-killed enterococcus faecium strain NHRD IHARA in post-weaning piglets. Anim Sci J. 2014;85(4):454–60. https://doi.org/10.1111/asj.12163.
Sato Y, Kuroki Y, Oka K, Takahashi M, Rao S, Sukegawa S, et al. Effects of dietary supplementation with enterococcus faecium and Clostridium butyricum, either alone or in combination, on growth and fecal microbiota composition of post-weaning pigs at a commercial farm. Front Vet Sci. 2019;6:26. https://doi.org/10.3389/fvets.2019.00026.
Arimori Y, Nakamura R, Hirose Y, Murosaki S, Yamamoto Y, Shidara O, et al. Daily intake of heat-killed Lactobacillus plantarum L-137 enhances type I interferon production in healthy humans and pigs. Immunopharmacol Immunotoxicol. 2012;34(6):937–43. https://doi.org/10.3109/08923973.2012.672425.
Busanello M, dos Santos MS, Pozza PC, Nunes RV, Chambo APS, Eckstein II. Probiotics: viable and inactivated cells on the performance, microflora and blood parameters of piglets. Rev Bras Saúde Prod Anim. 2015;16(2):387–96. https://doi.org/10.1590/S1519-99402015000200013.
Pupa P, Apiwatsiri P, Sirichokchatchawan W, Pirarat N, Maison T, Koontanatechanon A, et al. Use of Lactobacillus plantarum (strains 22F and 25F) and Pediococcus acidilactici (strain 72N) as replacements for antibiotic-growth promotants in pigs. Sci Rep. 2021;11(1):12028. https://doi.org/10.1038/s41598-021-91427-5.
Sakai Y, Tsukahara T, Bukawa W, Matsubara N, Ushida K. Cell preparation of enterococcus faecalis strain EC-12 prevents vancomycin-resistant enterococci colonization in the cecum of newly hatched chicks. Poult Sci. 2006;85(2):273–7. https://doi.org/10.1093/ps/85.2.273.
Thanh NT, Loh TC, Foo HL, Hair-Bejo M, Azhar BK. Effects of feeding metabolite combinations produced by Lactobacillus plantarum on growth performance, faecal microbial population, small intestine villus height and faecal volatile fatty acids in broilers. Br Poult Sci. 2009;50:298–306.
Loh TC, Choe DW, Foo HL, Sazili AQ, Bejo MH. Effects of feeding different postbiotic metabolite combinations produced by Lactobacillus plantarum strains on egg quality and production performance, faecal parameters and plasma cholesterol in laying hens. BMC Vet Res. 2014;10(1):149–58. https://doi.org/10.1186/1746-6148-10-149.
Humam AM, Loh TC, Foo HL, Samsudin AA, Mustapha NM, Zulkifli I, et al. Effects of feeding different postbiotics produced by Lactobacillus plantarum on growth performance, carcass yield, intestinal morphology, gut microbiota composition, immune status, and growth gene expression in broilers under heat stress. Animals (Basel). 2019;9:644–64.
Humam AM, Loh TC, Foo HL, Izuddin WI, Awad EA, Idrus Z, et al. Dietary supplementation of Postbiotics mitigates adverse impacts of heat stress on antioxidant enzyme activity, Total antioxidant, lipid peroxidation, physiological stress indicators, lipid profile and meat quality in broilers. Animals (Basel). 2020;10(6):982–1003. https://doi.org/10.3390/ani10060982.
Humam AM, Loh TC, Foo HL, Izuddin WI, Zulkifli I, Samsudin AA, et al. Supplementation of postbiotic RI11 improves antioxidant enzyme activity, upregulated gut barrier genes, and reduced cytokine, acute phase protein, and heat shock protein 70 gene expression levels in heat-stressed broilers. Poult Sci. 2021;100(3):100908–22. https://doi.org/10.1016/j.psj.2020.12.011.
Kareem KY, Loh TC, Foo HL, Akit H, Samsudin AA. Effects of dietary postbiotic and inulin on growth performance, IGF1 and GHR mRNA expression, faecal microbiota and volatile fatty acids in broilers. BMC Vet Res. 2016;12(1):163. https://doi.org/10.1186/s12917-016-0790-9.
Johnson CN, Kogut MH, Genovese K, He H, Kazemi S, Arsenault RJ. Administration of a postbiotic causes immunomodulatory responses in broiler gut and reduces disease pathogenesis following challenge. Microorganisms. 2019;7:268–87.
Zhu C, Gong L, Huang K, Li F, Tong D, Zhang H. Effect of heat-inactivated compound probiotics on growth performance, plasma biochemical indices, and Cecal microbiome in yellow-feathered broilers. Front Microbiol. 2020;11:585623. https://doi.org/10.3389/fmicb.2020.585623.
Zhang JL, Xie QM, Ji J, Yang WH, Wu YB, Li C, et al. Different combinations of probiotics improve the production performance, egg quality, and immune response of layer hens. Poult Sci. 2012;91(11):2755–60. https://doi.org/10.3382/ps.2012-02339.
Izuddin WI, Loh TC, Samsudin AA, Foo HL, Humam AM, Shazali N. Effects of postbiotic supplementation on growth performance, ruminal fermentation and microbial profile, blood metabolite and GHR, IGF-1 and MCT-1 gene expression in post-weaning lambs. BMC Vet Res. 2019;15:315–25.
Izuddin WI, Loh TC, Foo HL, Samsudin AA, Humam AM. Postbiotic L. plantarum RG14 improves ruminal epithelium growth, immune status and upregulates the intestinal barrier function in post-weaning lambs. Sci Rep. 2019;9:9938–48.
Izuddin WI, Humam AM, Loh TC, Foo HL, Samsudin AA. Dietary Postbiotic Lactobacillus plantarum improves serum and ruminal antioxidant activity and upregulates hepatic antioxidant enzymes and ruminal barrier function in post-weaning lambs. Antioxidants (Basel). 2020;9(3):250–63. https://doi.org/10.3390/antiox9030250.
Izuddin WI, Loh TC, Samsudin AA, Foo HL. In vitro study of postbiotics from Lactobacillus plantarum RG14 on rumen fermentation and microbial population. Revi Bras de Zootec. 2018;47:e20170255–63.
This study was supported by grants from the Key R&D Projects ofZhejiang Province (2022C04034), the Natural Science Foundation of Zhejiang Province (Z19C170001), the National Natural Science Foundation of China (31672430), the National Key Research and Development Program of China (2017YFD0500502) and the Funds of Ten Thousand People Plan.
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Zhong, Y., Wang, S., Di, H. et al. Gut health benefit and application of postbiotics in animal production. J Animal Sci Biotechnol 13, 38 (2022). https://doi.org/10.1186/s40104-022-00688-1