The LAB can produce a wide range of inhibitory compounds to reduce pathogens invasion (Table 3). These include AMPs such as bacteriocins, organic acids, ethanol, diacetyl, carbon dioxide, and hydrogen peroxide (Liao and Nyachoti, 2017).

Bacteriocins are ribosomally synthesized AMPs produced by both Gram-negative and Gram-positive bacteria (Drider and Rebuffat, 2011). Bacteriocins produced by LAB referred here as LAB-bacteriocins are most often devoid of cytotoxic traits (Belguesmia et al., 2010), and endowed with antagonistic functions as well as additional beneficial attributes (Drider et al., 2016; Chikindas et al., 2018). LAB-bacteriocins are emerging as a novel wave of antibiotics with potent in vitro and in vivo activities (Stern et al., 2008; Rihakova et al., 2010; Al Atya et al., 2016; Jiang et al., 2016; Caly et al., 2017; Seddik et al., 2017). In contrast to traditional antibiotics, LAB-bacteriocins target specific species and do not affect other population within the same ecosystem. LAB-bacteriocins are known to exert either bacteriostatic or bactericidal activity toward sensitive organisms. Their modes of action have been widely but not thoroughly investigated. Recent insights on modes of action are reviewed elsewhere (Cavera et al., 2015; Drider et al., 2016; Woraprayote et al., 2016; Ben Lagha et al., 2017; Perez et al., 2018). Combinations of LAB-bacteriocins and antibiotics are emerging as novel therapeutic options for food-producing animals (Naghmouchi et al., 2010, 2011, 2013; Al Atya et al., 2016). Different reports have established the main advantages and synergistic actions of LAB-bacteriocins with other biomolecules. These are the case of enterocin AS-48 and ethambutol against Mycobacterium tuberculosis (Aguilar-Pérez et al., 2018), nisin and citric acid against Staphylococcus aureus and Listeria monocytogenes (Zhao et al., 2017), nisin and beta-lactams against Salmonella enterica serovar Typhimurium (Rishi et al., 2014; Singh et al., 2014), and Garvicin KA-farnesol against a set of Gram-positive and Gram-negative bacteria (Chi and Holo, 2018). Orally administration of these substances is a challenge because of their enzymatic degradation. This case was reported in vivo for lacticin 3147 and nisin (Gardiner et al., 2007; Gough et al., 2018).

Organic acids, including short chain fatty acids, lactic and formic acids, were shown to inhibit potentially pathogenic bacteria of importance for livestock animals. LAB are producing lactic acid as the main product of sugar metabolism (Russo et al., 2017). However, LAB metabolically known as hetero-fermentative species can concomitantly produce other end-products such as acetic acid (Oude Elferink et al., 2001; Schnürer and Magnusson, 2005). Organic acids are known to act by reducing the intracellular pH and inhibiting the active transport of excess internal protons which requires cellular adenosine triphosphate (ATP) consumption leading to cellular energy depletion (Ricke, 2003). The main targets of organic acids are the bacterial cell wall, cytoplasmic membrane, and specific metabolic functions (e.g., replication and protein synthesis) of pathogenic microorganisms leading to their disturbance and death (Surendran Nair et al., 2017; Zhitnitsky et al., 2017). Lactic acid produced by LAB induces an unfavorable local microenvironment for pathogenic bacteria (Dittoe et al., 2018). Wang C. et al. (2015) showed that concentrations of 0.5% (v/v) lactic acid could completely inhibit growth of pathogens such as Salmonella spp., E. coli or L. monocytogenes. Nevertheless, these acids do not affect animal epithelial cells because of the mucus layer that creates a gradient of pH (Allen and Flemström, 2005). Feeding with organic acids such as propionic has some limits because their dissociation before they reach the small intestine (Hume et al., 1993).

Ethanol produced by hetero-fermentative LAB is generated from the glycolysis pathway (Elshaghabee et al., 2016). Ethanol affects the membrane fluidity and integrity resulting in bacterial cell death due to plasma membrane leakage (Ingram, 1989). Oh and Marshall (1993) reported that ethanol concentration at 5% inhibited L. monocytogenes replication.

Diacetyl is produced from citrate uptake and metabolism in LAB. Notably Lb. plantarum, Lb. helveticus, Lb. bulgaricus, Ent. faecalis, and mainly Leuc. mesenteroides and Lc. lactis biovar diacetylactis are the most commonly known LAB species producing diacetyl (García-Quintáns et al., 2008; Singh, 2018). Diacetyl interferes with arginine utilization by reacting with the arginine-binding protein of Gram-negative bacteria (Lindgren and Dobrogosz, 1990), while carbon dioxide liberated in the near environment by LAB creates an anaerobic environment where aerobic bacteria cannot grow (Singh, 2018).

Some species of LAB are able to produce hydrogen peroxide (H₂O₂) and can inhibit pathogenic bacteria devoid of catalase (Mitchell et al., 2015), through superoxide anion chain reaction enhancing toxic oxidation. H₂O₂ bactericidal action depends on the concentrations and environmental factors such as pH and temperature (Surendran Nair et al., 2017). Lc. lactis and Ent. faecium species were reported to produce H₂O₂ with strong antimicrobial effects (Yang et al., 2012).

Reuterin, is a secondary metabolite associated with glycerol metabolism by Lb. reuteri. This potent inhibitory compound has a broad spectrum of activity exerted in a pH-independent manner. Reuterin is known to inhibit DNA replication and is resistant to proteolytic and lipolytic enzymes (Singh, 2018). In terms of spectrum of activity, reuterin was shown to be active against E. coli, Staphylococcus aureus, and Candida spp. (Helal et al., 2016).

Competitive exclusion (CE) can occur after addition of any culture containing at least one non-pathogenic bacteria to the gastrointestinal tract of animals. This will decrease the number of pathogenic bacteria, through direct or indirect competition for nutrients and adhesion for sites in the gut (Callaway et al., 2008). These LAB-probiotics are able to form biofilms and communicate through Quorum Sensing (QS) upon producing and releasing of autoinducers (Tannock et al., 2005). Pathogens are not able to adhere to the intestinal mucosa, which blocks the development of their population by the constant flow of digesta (Callaway et al., 2008; Yirga, 2015; Liao and Nyachoti, 2017). Some studies aimed at highlighting this mechanism are briefly described below. Carter et al. (2017) reported the protective effect exerted by the combination of 5 × 10⁷ CFU/mL of Lb. salivarius 59 and Ent. faecium PXN33 by reducing Salmonella Enteritidis S1400 colonization in chicks. Penha Filho et al. (2015) reported the effect of 1 × 10⁵ CFU of a Lb.-based probiotic suspension on reducing Salmonella colonization when this strain was provided to chicks from 1 to 7 days of age. Arruda et al. (2016) showed that a commercial probiotic of Lactobacillus spp. decreased prevalence of Clostridium difficile infections in pigs when administrated at a concentration of 7.5 × 10⁹ CFU. Sha et al. (2016a) showed through feeding trial assays that 1 × 10⁹ CFU/mL of Lb. pentosus HC-2 strongly inhibited the growth of Vibrio parahaemolyticus in the intestine of shrimp.

Lactic acid bacteria have been widely described for their capabilities to enhance the animal immune system, by positively affecting the innate and adaptive immune response (Tellez et al., 2012; Tsai et al., 2012; Ashraf and Shah, 2014) by helping protect from pathogen disorders (Ashraf and Shah, 2014). The innate immune system induces immediate defense against infection, but also activates a long-lasting adaptive immunity. Components of the innate system recognize the molecular patterns associated with pathogens through pattern recognition receptors (PRRs). The recognition of these patterns by PRR leads to the induction of inflammatory responses and innate host defenses. In addition, the detection of microbes by PRR expressed in antigen-presenting cells, particularly dendritic cells (DC), leads to the activation of adaptive immune responses, by means of T and B cells (Iwasaki and Medzhitov, 2015). Various immune cells types, including granulocytes, macrophages, DCs, and T and B lymphocytes, are involved with inflammatory responses which are mediated by several cytokines like TNFα, IL-1β, IL-6, IL-8, and IL-15 interleukins. The anti-inflammatory/suppressive responses are mediated for their part by IL-10, IL-12, and TGFβ (Hardy et al., 2013). LAB have different immunomodulatory properties associated with their capabilities to induce cytokine production, impact immunomodulation by innate or adaptive immune responses (Kiczorowska et al., 2017a). Those immunomodulation abilities are considered as a crucial criterion for probiotic assessment, through various mechanisms (Wells, 2011; Hardy et al., 2013).

Feed digestibility reflects the amount of absorbed feed and the nutrient’s availability used for the animal growth and reproduction (ILCA, 1990). It is possible to measure the apparent or real digestibility by comparing nutrients contained in the feces from nutrients contained in the dietary intake, or adding external markers (such as titanium dioxide, chromium oxide and rare-earth elements) into feed (ILCA, 1990; Safwat et al., 2015). The improvement of this nutrient digestibility is measured by an indirect method: feed conversion ratio, a correlation between weight of feed administered over the lifetime of an animal and weight gained, which is a valuable indicator of feeding systems efficiency (Wenk et al., 1980; Fry et al., 2018). LAB-probiotics improved nutrient digestibility because of their highly fermentative activities. Indeed, they can enhance the whole digestive process, the metabolic utilization of nutrients, and improve the feed efficiency by producing digestive enzymes (e.g., amylases, chitinases, lipases, phytases, proteases) or by just generating volatile fatty acids and B-vitamins: riboflavin, biotin, B12 vitamin (Russo et al., 2014; Liao and Nyachoti, 2017; Sharifuzzaman and Austin, 2017). In addition, LAB-probiotics can indirectly modify the gut microsystem (FAO, 2016) by helping in the assimilation of nutrients through activation of the host immune cells and increasing the number of antibodies leading to animal welfare improvement (Forte et al., 2016).

Protective effects of LAB-probiotics can result in inhibition of toxin expression in pathogens (Liao and Nyachoti, 2017). It was also reported that LAB can constitute natural barriers against mycotoxins considered as potentially harmful compounds for animals (Tsai et al., 2012; Peng et al., 2018). Several investigators reported that Lb. plantarum, Lb. acidophilus, Lb. paracasei, and Ent. faecium could mitigate the effect of aflatoxins for improving human and animal health (Gratz et al., 2007; Ahlberg et al., 2015; Abbès et al., 2016; Damayanti et al., 2017; Li et al., 2017).

Lactic acid bacteria act as a biological barrier in the intestinal tract, decreasing availability of ingested mycotoxins and neutralizing their adverse effects. Detoxifying capabilities of LAB are associated with their capacities to bind and sequester mycotoxins, boosting their excretion by digestive system in the feces (Zoghi et al., 2014; Damayanti et al., 2017; Li et al., 2017). Mycotoxins can bind to viable and non-viable bacterial surface by adhesion to their cell wall components (Damayanti et al., 2017; Li et al., 2017), and aflatoxin B1 (AFB1), for example, was bound to LAB by non-covalent interactions (Haskard et al., 2001). Tests aimed at controlling mycotoxins have been carried out with Lb. casei DSM20011, Lb. casei Shirota (Liew et al., 2018), Lb. rhamnosus strains LGG and LC 705 (El-Nezami et al., 1998, 2002; Nybom et al., 2007), Lb. acidophilus 24 (Pizzolitto et al., 2012), and Lb. plantarum Lb. brevis, Lb. sanfranciscensis, from LOCK collection (Piotrowska, 2014). Piotrowska (2014) suggested that the binding to mycotoxins, particularly to ochratoxin was ascribed to hydrophobic properties of the cell wall, and also by electron donor-acceptor and Lewis acid-base interactions. LAB have additional anti-mycotoxin mechanisms based on a study performed on mice wherein the diet was supplemented with Lb. plantarum C88 (1 × 10¹⁰ CFU/mL). This supplementation weakened oxidative stress induced by aflatoxin AFB1. Likewise, this strain decreased lipid peroxidation in serum and the liver due to hepatic damage caused by AFB1 toxicity (Li et al., 2017). LAB produce exopolysaccharides, which are important compounds capable of inhibiting bacterial toxins as reported by Ruas-Madiedo et al. (2010) for the interactions between Lb. rhamnosus GG against Bacillus cereus. Further mechanisms including pH decrease and blockage of QS have been reported during co-existence of C. perfringens type A and LAB particularly Lb. acidophilus CGMCC 11878 and Lb. fermentum CGMCC12029 (Guo et al., 2017).

Different investigators have reported the potential effect of LAB to decrease the risk of infections and intestinal disorders associated with pathogens such as Salmonella spp., E. coli, Campylobacter, or Clostridium spp. LAB-probiotics were used preventively and therapeutically to treat infections by these pathogens (Tellez et al., 2012; Layton et al., 2013; O’Bryan et al., 2014; Gómez et al., 2016; Park et al., 2016).

Lactobacilli produce lactic acid and proteolytic enzymes, which enhance nutrient digestion in the GIT and feed supplementation with Lactobacillus strains can induce weight gain in livestock animals (Angelakis, 2017), in a strain strain-specific dependent manner (Drissi et al., 2017). For instance, Lb. delbrueckii, Lb. acidophilus, Lb. casei, Lb. agilis, Lb. salivarius, Lb. fermentum, and Lb. ingluviei were described as weight enhancers (Drissi et al., 2017). The last two species were associated with a substantial weight gain effect in ducks and chicks (Million et al., 2012; Drissi et al., 2017). LAB-probiotics improved the feed conversion efficiency by modifying the intestinal microbiota, limiting the growth of pathogens, promoting non-pathogenic bacteria, and enhancing nutrients use and digestion (Yang Y. et al., 2015). Some LAB-probiotics provided similar benefits as antibiotics in terms of weight gain, feed intake, and feed efficiency, as in the case of Lb. plantarum P-8 (2 × 10⁶ CFU/mL) (Wang L. et al., 2015).

Baldwin et al. (2018) showed that a LAB-probiotics consortium containing Lb. ingluviei, Lb. agilis, and Lb. reuteri strains improved weight gain when they were inoculated early at the hatchery, modifying intestinal microbiota and decreasing the pathogenic taxa numbers in chicks (Baldwin et al., 2018). On the other hand, a feed supplementation with 1 × 10⁶ CFU/g feed Lb. johnsonii BS15 in broilers enhanced digestive abilities, promoting growth performance, and lowering body fat content (Wang H. et al., 2017).

Another study carried out on pigs fed with Lb. plantarum ATCC 4336, Lb. fermentum DSM 20016, and Ent. faecium ATCC 19434 at concentrations of 10¹¹ CFU/kg resulted in a weight gain due to the ability of these strains, mainly Lb. ones, to produce enzymes enhancing feed digestion, besides lactic acid production (Veizaj-Delia et al., 2010). Lan et al. (2016) showed that a strain of Lb. acidophilus increased digestibility in weaning piglets of 14 days-old and improved their growth performance.

However, supplementation of feed with LAB-probiotics did not induce any effect on the animal weight in all cases. Wang et al. (2012) showed that Lactobacillus or Pediococcus fermented maize feed can modify the microbiota but did not affect pig’s production performances. This variability is related to a heterogeneity between trials. Nonetheless, for pigs, environmental factors such as pen, litter… the sow and piglet are closely related according to Zimmermann et al. (2016).

Concerning ruminants, calves fed with a mixture of 1 × 10⁹ CFU of Lb. casei DSPV 318T, Lb. salivarius DSPV 315T, and Ped. acidilactici DSPV 006T exhibited higher daily weight gain, total feed intake, and starter diet intake (Frizzo et al., 2010). Furthermore, calves fed with 6.8 × 10⁸ CFU of Lb. acidophilus and Lb. plantarum fortified milk (Gupta et al., 2015) or 1 × 10¹⁰ CFU of Lb. plantarum DSPV 354T (Soto et al., 2014) consumed more milk, in addition to body weight gain and growth performance. A similar effect has been reported for post weaning lambs. When they were fed with Pediococci (1 × 10⁶ CFU/g) an increased intake of dry matter feed and better growth performances were shown (Saleem et al., 2017).

In the aquaculture sector, Zheng et al. (2017) showed a size improvement in white shrimps (Litopenaeus vannamei) when their diet was supplemented with 1 × 10⁹ CFU/mL of Lb. plantarum. Furthermore, Lb. delbrueckii also enhanced the production performance of Cyprinus carpio Huanghe var., when added at a concentration of 10^6–7 CFU/g in feed (Zhang et al., 2017). In abalones (Haliotis discus hannai Ino) feed intake and growth increases were observed when Lb. pentosus was supplied at concentration of 10^3–5 CFU/g (Gao et al., 2018).

There are several examples of Lactobacillus spp. as probiotic improving meat quality in chickens, including tenderness, appearance, texture, and juiciness among other parameters (Park et al., 2016). It is known that addition of LAB to broiler’s feed reduced the cholesterol content of meat (Popova, 2017). Administration of Lb. salivarius SMXD51, at a concentration of 10⁷ CFU/mL, can partially prevent the impact of Campylobacter in chickens due to ability of this strain to produce an anti-Campylobacter bacteriocin with strong activity against four tested Campylobacter jejuni strains (Messaoudi et al., 2012; Saint-Cyr et al., 2017). In addition, the probiotics can improve the production and quality of eggs. Thus, the supplementation of Ped. acidilactici MA 18/5M (10⁸ CFU/kg feed) to the chicken feed revealed an effect on the eggs’ quality by increasing their weight, eggshell thickness and decreasing cholesterol on the egg yolk (Mikulski et al., 2012).

In pigs, Ped. acidilactici was shown to improve meat quality (Dowarah et al., 2018). Kiczorowska et al. (2017b) compared four groups of cows and demonstrated that cows under an intensive production system receiving a probiotic treatment [Lb. casei, Lb. plantarum (5 × 10⁶ CFU/mL)], and S. cerevisiae (5 × 10³ CFU/mL) produced higher milk quality with higher protein content and fat that contained a higher amount of unsaturated fatty acids conversely to cows in intensive production system. It was shown that supplementation of feed with 4 × 10⁹ CFU Lb. acidophilus NP51 and Propionibacterium freudenreichii NP24 increased milk production and improved apparent digestibility of dietary nutrient (Boyd et al., 2011).

Probiotics are associated with fish reproduction by enhancing their fecundity rate (Banerjee and Ray, 2017; Carnevali et al., 2017). The direct effects are reportedly due to increasing expression of genes encoding several hormones and enhancing gonadal growth, fecundity, and embryo survival (Gioacchini et al., 2010, 2012). Probiotics also enhance follicules maturation and development, and embryo quality. For example, several strains of Lb. rhamnosus can improve the fecundity in zebrafish (Danio rerio) model (Hai, 2015; Banerjee and Ray, 2017).

The quality of water on the fish farms is clearly an important factor to avoid the spread of diseases. The parameters to measure this quality are based on the pH of the water and the amounts of CO₂, ammonia, nitrate, and phosphorus found in it. Lb. plantarum and Lb. casei reportedly maintained or improved water quality during fish production (Banerjee and Ray, 2017).

A major concern is related to water pollution with heavy metals provoking fish diseases. This can be avoided by the use of some LAB-probiotics such as Lb. plantarum CCFM639, which restored the integrity of damaged tight junction proteins and maintained intestinal permeability leading to decrease of aluminum-induced gut injuries (Yu et al., 2016). Yu et al. (2017) also reported reduction of aluminum accumulation in tilapia tissues and lower death rate upon incorporation of 10⁸ CFU/g Lb. plantarum to the feed.