Anti-inflammatory and wound healing properties of lactic acid bacteria and its peptides

Because of their small dimensions and flexible surface chemistry, nanoparticulate (NP) drug delivery devices are of special interest among inflammation targeting methods in IBD. Recently, new drug delivery methods for IBD therapy that selectively targets the site of inflammation have been developed (Zhang et al. 2017 ). Nanoparticle-mediated drug delivery systems have been widely used to treat chronic inflammatory diseases such as IBD (Yang and Merlin  2019 ). A drug that is nanoparticle loaded may have the same/better efficacy at a smaller dose than the same drug rendered in a traditional formulation (Melero et al. 2017 ). Nanoparticles may enhance the pharmacokinetics of the drug particles, reducing toxicity and dosing frequency. The physiological changes indicated by the inflamed tissues are often the target approaches employed for NP-based drug delivery in the treatment of IBD (Dahan et al. 2010 ). These short peptide NPs are efficient in conquering several limitations associated with the conventional treatment methods by reducing adverse health effects and increasing drug accumulation at the tumor site (Saravanan and Barabadi 2021 ), thereby resulting in enhanced efficacy of the cancer therapeutics (Rayatpour and Javan 2021 ). Studies showed that Nisin was electro spun into nano fibers which then significantly reduced the S. aureus infections in murine models and also helped in accelerating the wound healing process (Jia et al. 2019 ). We have mainly discussed the potential examples of nano delivery systems of LAB-derived cyclic peptides in Table 3 . Table 3 Examples of bacteriocins formulated using nano technological approach with its applications Cyclic peptide Isolated strain Method of purification Nano-drug delivery system series Type of nanocarrier Application in nano-delivery system References Nisin Lactococcus lactis Capture method; Cation-exchange Chromatography Nanofiber electrospinning with metallic nanoparticles Silver nanoparticles—PEO 50–PDLLA 50 nano-fibers (i) Production of anti-microbial wound dressing material to target against S. aureus skin infections (Heunis et al. 2013 ) Enterocin FH-99 Enterococcus spp. Nanoencapsulation method Metallic nanoparticles Silver nanoparticles—Enterocin-capped-silver nanoparticles (EnSNPs) (i) Proinflammatory activities in burnt wounds, meshed skin grafts (ii) Activation of apoptosis in inflammatory cells of the dermis (Bhol and Schechter 2005 ; Fan and Bard 2002 ; Nadworny et al. 2008 ) (iii) Decline in the expression of IL-8 and Transforming Growth Factor (TGF)- β Plantaricin 432 Lactobacillus plantarum 432 Amberlite XAD 2, cation exchange chromatography, gel chromatography (i) Nanofiber electrospinning; metallic nanoparticles (i) Gold nanoparticles—solid lipid nanoparticles (SLNPs) (i) Bacterial inhibition of Lactococcus murei and E. coli (Gomashe and Dharmik  2012 ; Heunis et al. 2010 ) (ii) Polymeric nanoparticles (ii) Plantaricin encapsulated into polyethylene oxide (PEO) nanofibers (ii) Inhibition of Lactobacillus sakei Lacticin 3147 Lactococcus lactis DPC6577 Amberlite XAD 16 N resin, C18 solid phase extraction, reversed phase HPLC; confirmed by MALDI-TOF mass spectrometry Solid lipid nanoparticle delivery system (SLNPs) Microemulsion templating technique (i) Alternative for treating topical infected wounds (ii) Defend against bacterial infections in colon (Rea et al. 2007 ) (iii) Protection of LTNA1 and LTNA2 from digestive enzymes Bacteriocin produced by Lactobacillus acidophilic CH1 Lactobacillus gasseri Ammonium sulfate precipitation, sequential cation exchange on carboxymethylcellulose and reverse phase chromatography Metallic nanoparticles Gold nanoparticles Increased the anti-microsporidial effect without significant cell toxicity (Fahim et al. 2016 ; Mossallam et al. 2014 ) PEO  poly (ethylene oxide),  PDLLA  poly (D,L-lactide),  MALDI-TOF  matrix-assisted laser desorption /ionization-time of flight,  LTNA1 and LTNA2  lacticin A1 and lacticin A2 Examples of bacteriocins formulated using nano technological approach with its applications Capture method; Cation-exchange Chromatography (i) Proinflammatory activities in burnt wounds, meshed skin grafts (ii) Activation of apoptosis in inflammatory cells of the dermis (iii) Decline in the expression of IL-8 and Transforming Growth Factor (TGF)- β (i) Alternative for treating topical infected wounds (ii) Defend against bacterial infections in colon (iii) Protection of LTNA1 and LTNA2 from digestive enzymes PEO  poly (ethylene oxide),  PDLLA  poly (D,L-lactide),  MALDI-TOF  matrix-assisted laser desorption /ionization-time of flight,  LTNA1 and LTNA2  lacticin A1 and lacticin A2

Lactic acid bacteria are considered to be the most widely researched microorganisms over several years (Pasolli et al. 2020 ). Lactic acid bacteria are classified according to their morphological, metabolic, and physiological characteristics. Lactobacillus , Enterococcus , Lactococcus , Leuconostoc , Pediococcus , and Streptococcus comprise the core LAB group. Lactobacillus species are Gram positive, non-motile, non-spore forming, rod-shaped non-respiring (catalase negative), auxotrophic, aciduric, facultative anaerobes that release lactic acid as a major end product of carbohydrate fermentation (Bai and Ji 2017 ). They are widely used in the food industry for the production of fermented products and also as a food safety tool. Some LAB strains can produce bacteriocins, which are polypeptides exhibiting antimicrobial activity against a specific class of bacteria of the same or different species. Bacteriocins, in particular, are very desirable to the food sector because they do not influence the flavor or fragrance of the end products (Moraes et al. 2010 ). The bacteriocins from lactic acid bacteria are commonly divided into three groups based on their structure and properties as discussed in Table 2 . They include the following: class I lantibiotics which are very small in size, i.e., > 5 kDa, include lactocin and nisin; class II non-lantibiotics are also small, i.e., < 10 kDa, cationic, heat stable, unmodified bacteriocins, comprising a double glycine leader being hydrophobic peptides, with plantaricin A, pediocin PA1, lactococcin G, and leucocin A as an example of class IIa and class IIb, respectively; and class III are larger in size, i.e., > 30 kDa, heat labile bacteriocins with helveticin J and enterolysin as constitutive (Nes and Holo 2000 ). Detection, purification, and characterization of several bacteriocins from lactic acid bacteria are done. However, the only bacteriocin in use is Nisin which is produced by Lactococcus lactis. It has a molecular weight of 3500 Da and consists of unusual amino acids. The utilization of cyclic peptides derived from LAB with probiotic potential has been demonstrated to be an effective way to improve one’s well-being. Cyclic peptides are immune to proteolytic enzymes as well as severe physiological stimuli with changes in pH and temperature. The LAB cyclic peptides have been known to be successful against gastrointestinal infections such as Helicobacter pylori , E. coli , and Salmonella species (Silpa and Rupachandra 2020 ). Cyclic peptides have a wide range of applications in the treatment of various diseases and disorders. Table 2 Different Classes of Bacteriocins derived from lactic acid bacteria and their characteristic features Class Subclasses Characteristic Features Cyclic peptides Reference I lantibiotic Lanthipeptides—Ia; globular and inflexible bacteriocins—IIb; sactpeptides—Iic Small (< 5 kDa) peptides consisting of lanthionine and beta-methyllanthionine. Nisin Z and Q, Nukacin ISK-1, Subtilin, Mersacidin (Ahmad et al. 2017 ; Mokoena 2017 ) II non-lantibiotic IIa—peptides like pediocin IIb two-peptides IIc leaderless Non-pediocin like single peptide—IId Small heat-stable, non-lanthionine-containing bacteriocins. Heat stable peptides active mainly against Listeria Monocytogenes. Two-peptide bacteriocins, Circular bacteriocins. Enterocin NRK-5- 3c, Enterocin A, Munditicin, Leucocin A, Lactococcin q, enterocin, nrk-5- 3az, Plantaricin Lactocyclin q, leucocyclin q (Alvarez-Sieiro et al. 2016 ; Bédard and Biron 2018 ; Borreoro et al. 2011 ; Fimland et al. 2005 ; Nissen-Meyer et al. 2010 ; Oppegard et al. 2007 ; Perez et al. 2018 ; Sawa et al. 2009 ) III Bacteriolysins-IIIa, Nonlutic-IIIb High mol. weight bacteriocins > 30 kDa which are thermolabile and unmodified peptides. Destroys target cells by disrupting plasma membrane potential. Lysostaphin, Helveticin J (Sun et al. 2018 ) iNOS  inducible NO synthase,  NF-KB  nuclear factor kappa light chain enhancer of activated B cells,  ERK  extracellular signal regulated kinase pathway,  IL  interleukin,  LPS  lipopolysaccharide Different Classes of Bacteriocins derived from lactic acid bacteria and their characteristic features IIa—peptides like pediocin IIb two-peptides IIc leaderless Non-pediocin like single peptide—IId Small heat-stable, non-lanthionine-containing bacteriocins. Heat stable peptides active mainly against Listeria Monocytogenes. Two-peptide bacteriocins, Circular bacteriocins. Enterocin NRK-5- 3c, Enterocin A, Munditicin, Leucocin A, Lactococcin q, enterocin, nrk-5- 3az, Plantaricin Lactocyclin q, leucocyclin q Bacteriolysins-IIIa, Nonlutic-IIIb High mol. weight bacteriocins > 30 kDa which are thermolabile and unmodified peptides. Destroys target cells by disrupting plasma membrane potential. Lysostaphin, Helveticin J iNOS  inducible NO synthase,  NF-KB  nuclear factor kappa light chain enhancer of activated B cells,  ERK  extracellular signal regulated kinase pathway,  IL  interleukin,  LPS  lipopolysaccharide

This review provides an overview of the current knowledge on anti-inflammatory and wound-healing properties of lactic acid bacteria and its derived peptides which is very essential in combating modern day diseases. Certain LAB strains and their cyclic peptides downregulated the expression of proinflammatory cytokines and upregulated the production of anti-inflammatory cytokines respectively thereby aiding in the wound-healing process. The rise in pathogenic organisms and mortality rate remains a major concern around the world, necessitating the development of a new approach for the prevention and treatment of infectious diseases. Lactic acid Bacteria has attracted a lot of attention due to their unique properties and ability to produce bacteriocins. They have the ability to reduce the perpetual demand for natural products and functional food which appears to be an emerging field of research. Bacteriocins have diverse applications in various fields which have led them to gain a lot of importance in the scientific world and are also considered to provide therapeutic properties to cure inflammation-related diseases like ulcerative colitis. Previous studies have explored the potential of LAB strains in food industries without harmful effects. Cyclic peptides derived from lactic acid bacteria produce inhibitory effects against food-borne pathogens and elevate the levels of serum anti-inflammatory cytokines. Novel cyclic peptides can decrease drug dependence and also provide aid in disease resistance. The role of cyclic peptides in areas other than the food industry has to be explored further. Nano-drug delivery systems of LAB-derived cyclic peptides can have the potential to deliver drugs to a specific site of action effectively. Peptide-incorporated nanomaterials can open opportunities against the treatment of disorders like cancer. The advantages of LAB and its derived peptides being evaluated with the help of in vivo and in vitro assays provide substantial support for their great application in a variety of medical therapies.

Lactic acid bacteria represent a cohort of microorganisms that are available in food sources, fermented foods, intestinal walls of humans and animals and have been consumed by humans without any side effects. Several selected strains, with well-defined characteristics, are included as probiotics in order to highlight the special advantages to consumers. Probiotic LAB has shown to aid in the prevention and treatment of diseases such as intestinal inflammation (LeBlanc et al. 2008 ). Inflammation is a consequent reaction of immune system to fight infections and heal wounds (Le Blanc et al. 2020 ). Numerous studies have shown that LAB strains and their associated peptides can modulate the host’s immune response by influencing the production of cytokines involved in the process of regulating and activating immune cells. They can exert immunomodulatory activities by stimulating the production of interleukin (IL)10 and/or lowering the levels of proinflammatory cytokines (Choi et al. 2019 ; La Manna et al. 2018 ; Dos Santos et al. 2016 ; Shadnoush et al. 2013 ). Studies have shown that the modulation of the host’s immune response is the main mechanism by which LAB implies benefits against inflammatory bowel diseases (IBD). Inflammatory bowel disease (IBD) is a group of disorders consisting of ulcerative colitis (UC) and Crohn’s disease (CD) (Tiwari  2022 ). LAB has proven to have known effects in treating paucities, UC, and CD (Florou-Paneri et al. 2013 ). The bacteriocins produced by LAB can repair the cell damage by modulating the expressions of anti-inflammatory cytokines (Hernández-González et al. 2021 ). Cyclic peptides exhibit better biological activity as compared to the other compounds due to their conformational rigidity. The rigidity of cyclic peptides decreases the entropy of Gibbs free energy, thereby allowing the enhanced binding toward target molecules. The cyclic structure renders them resistant to hydrolytic actions of enzymes such as exopeptidases and endopeptidases. Their structural rigidity, receptor selectivity, and biochemical stability also make them more membrane permeable as compared to the other counterparts. Novel cyclic peptides derived from LAB have sought attention due to their antibacterial activity making them applicable to use in the food and therapeutic industries. They have been extensively studied for other applications because of their heat stability, pH tolerance, and property to resist enzymatic actions. While most cyclic peptides derived from LAB are known to have antimicrobial properties against pathogenic microorganisms, certain peptides also have anti-inflammatory and wound healing properties. The cyclic peptides from Lactobacillus reuteri inhibit enteropathogens like yeast, fungi, protozoa, and viruses and promote the growth of beneficial Gram-positive bacteria (Liu et al. 2020 ). They also play a major role in intestinal dysbiosis and immunopathogenesis of IBD. Cyclic peptides from Lacticaseibacillus casei , Lactiplantibacillus plantarum , Lacticaseibacillus rhamnosus , and Lactobacillus acidophilus competed with intestinal pathogens and lowered cholesterol level and improved IBD (Abdi et al. 2021 ). Recent studies reported that the topical application of formulations of cyclic LAB cyclic peptides can improve skin health and combat alteration of skin homeostasis. L. rhamnosus LR improves skin barrier function and is effective in improving the healing of infected chronic ischemic wound lesions (Venosi et al. 2019 ). Cyclic peptides from L. reuteri ATCC-55730 have been reported to have an anti-inflammatory effect on infected keratinocytes by reducing the transcription level of interleukin-8 (IL-8) and human-beta-defensin-2 (hBD) (Widyarman et al. 2018 ); L. plantarum K8 inhibits the tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) expression (Jeon et al. 2016 ). This review focuses on discussing the anti-inflammatory properties exhibited by LAB strains and the cyclic peptides derived from LAB. A summary about the nano-drug delivery systems of the peptides has also been included.

Inflammation is a sequence of innate defense mechanisms that are generated by the vascular tissue against infectious and noninfectious stimuli such as damaged cells, irritants, or pathogens. The inflammatory processes are generally controlled and self-limiting while some progress as chronic inflammatory diseases (Cañedo-Dorantes and Cañedo-Ayala 2019 ; Mathews et al. 2015 ). Local and systemic inflammatory responses seek to eliminate the triggering stimuli while promoting tissue repair and healing processes, whereas, in the case of an infection, it tends to generate an immunological memory so that the host can respond more quickly and more effectively to a future encounter (Fullerton and Gilroy 2016 ). An inflammatory response involves four components: inflammatory inducers, detecting sensors, downstream mediators, and affected target tissues (Freire and Van Dyke 2013 ). Following a wounding event, the main cells engaged in an inflammatory response are neutrophils, macrophages, mast cells, and lymphocytes. These cells are crucial in generating and stopping inflammation at the wound site, as well as facilitating subsequent stages of the healing process (Koh and DiPietro 2011 ). Cytokines are important mediators that help to coordinate the inflammation and repair processes in injured muscles. Proinflammatory cytokines not only initiate inflammation but also initiate repair, emphasizing the close relationship between inflammatory and repair/regeneration mechanisms (Oishi and Manabe 2018 ). Anti-inflammatory cytokines are molecules that are generally involved in the process that regulates the production of proinflammatory cytokine responses. Anti-inflammatory macrophages also release growth factors to promote re-epithelization, fibroplasia, and angiogenesis (Wilkinson and Hardman  2020 ). The collective behaviors of macrophages promote scavenging of bacteria and proinflammatory cytokines (Nosbaum et al. 2015 ). Cytokines that promote inflammation include IL1β, IL2, IL6, IL8, IL12, IL17, tumor necrosis factor (TNF)α, interferon (IFN) γ, and colony stimulating factor (CSF) 1, whereas anti-inflammatory cytokines include interleukin 4, interleukin 10, interleukin 13, and tumor growth factor TGF β (Ermakova 2018 ). The type and severity of the inflammatory responses are determined by the nature of the inflammatory stimulus (bacterial, viral, or parasitic) as well as its persistence (Medzhitov 2010 ). Toll-like receptors (TLRs) expressed by tissue resident macrophages recognize bacterial pathogens. Inflammatory cytokines, chemokines, and proinflammatory lipid mediators like prostaglandins are released due to the binding of Toll-like receptors (Aderem and Ulevitch 2000 ). There are 2 phases of inflammation that are acute and chronic phases, though there is overlap between these processes. The acute inflammatory response is the initial response which is complicated but well-coordinated cascade of events involving cellular, molecular, and physiological modifications. It initiates from the production of soluble mediators which are vasoactive amines, complement, cytokines, chemokines, free radicals, and eicosanoids (prostaglandins) by resident cells, i.e., lymphocytes, tissue macrophages, dendritic cells, fibroblasts, endothelial cells, and mast cells in wounded or infected tissue (Fullerton and Gilroy 2016 ). These mediators elevate vascular permeability, allowing plasma containing antibodies and so many more soluble components, such as complement, which are essential for the humoral immune response (bacterial opsonization), and the dilution of harmful factors. Resident cell produces chemokines which establish gradients on the microvascular endothelium’s intraluminal surface, trapping and attracting neutrophils with the help of chemokine receptors. Activated neutrophils enter inflamed tissue via the endothelium and engage in intense antibacterial killing activities like degranulation and formation of reactive oxygen species via the oxidative burst. Monocytes follow neutrophils and link the adaptive and innate immune responses, deciding whether or not the damage can be healed with or without the support and help of the adaptive immune system (Headland and Norling 2015 ). This acute cellular phase is enough to repair any injury depending upon the severity of the damage. Chronic inflammation can occur because of the prolonged exposure to inflammatory stimulus or an inappropriate response to self-molecules. During this phase, active immune cell populations can lead to the transition in to a mononuclear phenotype, causing tissue injury and fibrosis (Germolec et al. 2018 ). Inflammation that fails to heal for several months or years is referred to as chronic inflammation. In chronic inflammation, plasma cells, lymphocytes, and macrophages predominate over neutrophils, which predominate in acute inflammation (Pahwa et al. 2018 ). When inflammatory responses become chronic, cell mutation and proliferation can occur, often creating an environment favorable to cancer development (Singh et al. 2019 ). Chronic inflammation has been linked to a wide range of diseases and disorders such as cancer, cardiovascular disease, diabetes, autoimmune diseases, arthritis, asthma, pulmonary diseases, atherosclerosis, Alzheimer’s disease, and aging-related conditions. Chronic inflammation has been linked to invasion, promotion, proliferation, cellular transformation, survival, angiogenesis, and metastasis, among other steps in tumorigenesis (Germolec et al. 2018 ; Pahwa et al. 2018 ; Singh et al. 2019 ).

Cyclic peptides from LAB are reported to be primarily active against closely related organisms (Zacharof and Lovitt  2012 ). Their application in controlling human pathogens is promising with a suitable mode of delivery. The emerging applications of LAB peptides in adjuvant therapy, vaccine development, and bioprotective agents are relevant in prevention of infection and amelioration (Mokoena  2017 ). They are typically composed of two or more amino acids linked together by peptide bonds and depict a broad spectrum of biological activities like antibacterial, antifungal, anti-inflammation, and so on (Zhang et al. 2019 ). Peptides that can mimic the activity of mediators involved in inflammation-related diseases are gaining popularity these days. Following the injury, the vessels constrict rapidly to reduce bleeding from the wound. Platelet plug is formed which releases growth factors that are important in the phases of healing. DAMPs, hydrogen peroxide, LPS, and interferons activate macrophages at the site of injury. In the early stages of wound healing, macrophages are proinflammatory, expressing TNF-α and IL-6 and IL-1β. Proinflammatory macrophages recognize and engulf pathogens into phagosomes, rapidly killing them. Proinflammatory macrophages also recruit MMPs which aid in migration of new keratinocytes. During the later stages of inflammation, there is a transition of proinflammatory macrophages to anti-inflammatory macrophages which contribute to new vessel formation and re-epithelialization (Rodrigues et al. 2019 ). The cyclic peptide entering the site of injury helps in the downregulation of various proinflammatory cytokines. They also promote macrophage recruiting to the margin of wound area. Various peptides can also elevate the expression of transforming growth factor (TGF). Cyclic peptides can also promote wound contraction, expression of alpha-smooth muscle actin (α-SMA), and differentiation of fibroblast to myofibroblasts (Tang et al. 2014 ). Figure  1 depicts the mechanism by which cyclic peptides act upon its exposure toward the site of inflammation. Although some of them are found in nature, the majority of them are encoded in the structure of related proteins and can be released through various processes (La Manna et al. 2018 ). Lactic acid bacteria can be found in many sources. Cyclic peptides derived from LAB act as an immune modulating agent and showcase anti-inflammatory properties in affected tissues by promoting a reduction in the proinflammatory cytokines and a rise in the anti-inflammatory cytokines (Hernández-González et al. 2021 ). Fig. 1 Schematic representation of anti-inflammatory activity of cyclic peptides at the site of inflammation. Abbreviations used: TNFα, tumor necrosis factor α; DAMP , damage-associated molecular pattern; IL 1, 6, 12 , interleukin 1, 6, 12; COX 2 , cyclooxygenase 2; LOX 2 , lipoxygenase 2; iNOS , inducible nitric oxide synthase Schematic representation of anti-inflammatory activity of cyclic peptides at the site of inflammation. Abbreviations used: TNFα, tumor necrosis factor α; DAMP , damage-associated molecular pattern; IL 1, 6, 12 , interleukin 1, 6, 12; COX 2 , cyclooxygenase 2; LOX 2 , lipoxygenase 2; iNOS , inducible nitric oxide synthase Nisin is a lantibiotic produced by Gram-positive bacteria Lactococcus and Streptococcus species (Shin et al. 2016 ). It is an antibacterial peptide that consists of 34 amino acid residues and has a wide range of applications (Kitagawa et al. 2019 ). The class I lantibiotic consists of five methyl lanthionine rings that require various post-translational modifications that are then introduced in the precursor peptide (Reiners et al. 2020 ). Different variants of Nisin have been identified. Some of the natural variants are Nisin A, Z, Q, and U (Piper et al. 2011 ). There are many research studies on the anti-inflammatory and wound-healing activities of Nisin. Recent findings suggested that Nisin along with kanamycin helped in reducing the cytokines involved in inflammation and accelerated the production of anti-inflammatory cytokines in rats, which can be used in the treatment of Staphylococcus -induced endometriosis (Jia et al. 2019 ). Nisin along with different licorice polyphenols has been shown to inhibit NF κβ activation induced by E. faecalis implying that these combinations have anti-inflammatory properties (Grenier et al. 2020 ). Nisin Z modulated innate immune responses by inducing chemokine synthesis and suppressing LPS induced proinflammatory cytokines (Kindrachuk et al. 2013 ). In addition, Nisin can also be used in wound dressings. Nisin A has been proven to have immunomodulatory effects and also enhances the wound-healing process in human keratinocytes, human umbilical vein in vitro and porcine model ex vivo as it enhances skin cell mobility, impedes the effect of lipopolysaccharide, proinflammatory cytokines, and inhibits bacterial growth (Mouritzen et al. 2019 ). Studies also showed that Nisin preconditioned with mesenchymal stem cells on PLLA (poly-(l-lactide)-acid) scaffold helped in reducing the expression of inflammatory genes, making it useful in wound healing (Karimi et al. 2021 ). Nisin is also reported to be effective in the treatment of various infections when administered via subcutaneous, intraperitoneal, intranasal and intravenous studies (Campion et al. 2013 ; Jabes et al. 2011 ; De Kwaadsteniet et al. 2009 ; Kruszewska et al. 2004 ). The half-life of nisin is reported to be 7–10 min due to the rapid adsorption on to surface of the microbiota within the intestine (Dobson et al. 2011 ). Enhanced nisin could be relevant if the conventional antibiotic therapy fails or safety issues predominate. Hagiwara et al. ( 2010 ) have established the safety of nisin in 90-day oral toxicity study involving rats where the rats were fed a diet containing nisin. No adverse effects were observed even at a dosage of 0.13mg/kg body weight/day. Reports also indicate the absence of hemolytic activity even at concentrations of 500 mg/L. S. aureus –infected mice treated with Nisin showed a rapid decrease in the bioluminescence due to the rapid cell lysis (Van Staden et al. 2016 ). Reports suggest that nisin inhibits cell wall biosynthesis by binding to cell wall precursor thereby disrupting synthesis of peptidoglycan. Binding of nisin leads to pore formation resulting in the leakage of cellular components (Van Staden 2012 ). A significant reduction of Clostridium difficille after nisin treatment was reported in a human colon model (Le Lay et al. 2015 ). Plantaricin is a bacteriocin produced by Lactobacillus plantarum that is known to possess anti-microbial activity. The major types of plantaricin are A, C, W, and S that first began as a precursor which consists of a double glycine moiety, later synthesized by L. plantarum via the PlnE and PlnF genes. The PlnG and PlnH proteins then export and process these peptides (Kareem and Razavi 2020 ). Various other strains of plantaricin have also been identified and are known to have great importance in different areas. There are many research studies on the anti-inflammatory and wound healing activities of Plantaricin. Plantaricin NC8 αβ showed to suppress the proinflammatory mediators of S. aureus and also increased the keratinocyte’s inflammatory responses when infected with S. aureus infection (Musa et al. 2021 ). L. plantarum strains have shown potential in the treatment of irritable bowel syndrome using probiotics to decrease abdominal discomfort and gas (Li et al. 2020 ). They also dampen inflammatory reactions in the host’s gut by modulating the immune response, improving the barrier function of the epithelium (Hirao et al. 2014 ) and reducing the translocation of native microbes (Pavan et al. 2010 ). L. plantarum ability to synthesize PlnEFI contributes anti-inflammatory potential. The TNBS persuaded wild type strain NCIMB8826 R will not be restricted to colitis. The pathogenesis of Crohn’s disease in people is comparable to that of severe colitis in acute TNBS model (Scheiffele and Fuss 2002 ). Evidence suggests that a single colony isolation of NCIMB8826 ( L. plantarum WCFS1 ) notably reduced TNBS-induced inflammation (Yin et al. 2018 ) yet no confirmation is established for disease attenuation, non-significant reduction in inflammatory responses . L. plantarum NCIMB8826 R and LM0419 were detected in equal amounts in the stool and in the appendix contents of mice according to 16 s rRNA sequencing, q PCR. This indicates that in both healthy and diseased GI tracts, PlnEFI is not a primary determinant of L. plantarum (Ilott et al. 2015 ). Native strains of lactobacilli are able to withstand inflammatory diseases in the gastrointestinal tract, including dextran sulfate sodium–induced colitis (Tachon et al. 2014 ) and Salmonella infection. L. plantarum WCFS1 showed promising effects in gut microbiota whereas both L. plantarum NCIMB8826 R and LM0419 showed minor effects on the bacterial composition of the fecal and appendix (Yin et al. 2018 ). An abundance of certain intestinal bacterial groups has been detected for other class IIb bacteriocin producing, lactic acid bacteria including other L. plantarum strains, L. salivarus , Lactobacillus sake , Pediococcus acidilactici , Enterococcus faecium , and Lactococcus garveiae (Feller et al. 2007 ). Many studies have repeatedly found a substantial link between Crohn’s disease and mycobacterium, which can be blocked by specific bacteriocins like L. plantarum WCFS1 (Singh et al. 2018 ). The biosynthesis of plantaricin is a distinctive feature that is pertinent to host microbe interaction in the digestive tract. Synthesis of PlnEFI produced by plantaricin is proven to be highly beneficial in maintaining a healthy GI tract (Ilott et al. 2015 ). The mechanism of action of plantaricins on conditions like IBD is not well explored. The in vivo studies report that L. plantarum can induce secretion of IL-10 in splenocytes and mesentric lymphocytes, and blocks proinflammatory cytokine expression (IL-1β, IL-6, TNF-α, COX-2 etc.). Another report suggests that L. plantarum decreased expression of IL-1a and IL-8 while increasing the expression of IFN-c and IL-10 (Le and Yang  2018 ). With respect to dosages, the most optimal dose for plantaricins like plantaricin E and plantaricin F was reported to be 250 mg/kg/BMW and 500 mg/kg/BMW respectively. The plantaricins were found to maintain leukocyte level and reduce mononuclear infiltration within the intestinal track (Hanny et al. 2019 ). Plantaricin A was also reported to induce keratinocyte and fibroblast migration and differentiation and collagen formation eventually leading to rapid wound healing. It also shortened the inflammatory phase of wound healing (Heydari et al. 2011 ), and complete re-epithelization of the wound was observed within 12 days in male Wistar rats (Moysidis et al. 2022 ). Enterococci are a Gram-positive, facultative anaerobic-based LAB that produces a bacteriocin named Enterocin (Szabóová et al. 2011 ). Different types of Enterocin have been identified; some include Enterocin A, B, Q, P, and RJ (Fimland et al. 2005 ). Recent studies showed that the TNF α levels were reduced by enterocin OE 342 from LPS-stimulated PBMC cells by increasing the percentage of IFN γ to 72.2% post-treatment (Franz et al. 2007 ). LAB modify the expression of different cytokines by increasing phagocytosis thus preventing inflammatory responses in the intestine. Also in the mouse experimental model, they restore the synthesis of IgA and replace Th1/Th2 balance (Al-Fakharany et al. 2018 ). Apart from being immunomodulators, this strain of LAB has close relationships with human infections. Enterocin has been shown to inhibit bacteria from wounds and while also assisting in physiological wound healing (Fang et al. 2000 ). Lactobacillus salivarius UC118 is known for its probiotic properties and constitution of intestinal microbiota (Riboulet-Bisson et al. 2012 ). It is a type II bacteriocin that normally occurs in human oral cavities, vagina, and intestine. Majority of L. salivarius isolates belonged to the bacteriocin producers of subclasses IIa, IIb, and IId (O’Shea et al. 2011 ). A probiotic mixture containing LAB has been shown to improve intestinal epithelial integrity and protection, in case of inflammatory luminal elements which are food and bacteria derived. Few strains also have immunomodulatory action. During recent research, CECT5713 a strain of L. salivarius , obtained from breast milk, was shown to promote host immunity by generating IL 10 and specific immunoglobulins, and also shows a rise in monocyte count and natural killer cells (Sierra et al. 2010 ). Additional evidence suggests Lactobacillus salivarius B1 enhances Interleukin 6 gene expression and population of immunocompetent cells in the intestines of pigs (Zhang et al. 2011 ). Probiotic microorganisms such as L. acidophilus , L. rhamnosus , and Lactobacillus salivarius DPC6005 can incite changes in host microbiota activity or composition since few microbial colonies are related to intestinal disorders such as inflammatory bowel disease (IBD) and hemorrhoids (Ley 2010 ). L. salivarius UCC118 exhibits probiotic properties and provides protection against infections from Salmonella typhimurium UK1 and LO28 and Listeria monocytogenes EGDe due to the production of the bacteriocin Abp118 (Corr et al. 2007 ). Several strains of Lactobacilli have been identified which can modify host immunity (Walsh et al. 2008 ). Research conducted on L. salivarius UCC118 concluded that the strain had no effect on cytokine levels of IL 8 and IL 10 in pigs, but there is a possibility in the development of various cytokines like interleukin 6 and 12 by modulation of UCC118 as seen by other L. salivarius strain (Peran et al. 2005 ; Riboulet-Bisson et al. 2012 ). L. salivarius and its derived peptide, salivaricin LHM, are of therapeutic use by stimulating the immune system through overproduction of proinflammatory cytokines like interleukin 10 and interleukin 4. Lactobacillus salivarius and Salivaricin LHM exhibit antimicrobial activity as well as immunomodulatory properties by increasing the production of proinflammatory cytokines (Mahdi et al. 2019 ).