Current applications, selection, and possible ...

Fish & Shellfish Immunology 64 (2017) 367e382

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Current applications, selection, and possible mechanisms of actions of synbiotics in improving the growth and health status in aquaculture: A review Truong-Giang Huynh a, b, Ya-Li Shiu a, Thanh-Phuong Nguyen b, Quoc-Phu Truong b, Jiann-Chu Chen c, Chun-Hung Liu a, * a b c

Department of Aquaculture, National Pingtung University of Science and Technology, Pingtung 912, Taiwan, ROC College of Aquaculture and Fisheries, CanTho University, CanTho, Viet Nam Department of Aquaculture, College of Life Sciences, National Taiwan Ocean University, Keelung 202, Taiwan, ROC

a r t i c l e i n f o

a b s t r a c t

Article history: Received 27 December 2016 Received in revised form 16 March 2017 Accepted 17 March 2017 Available online 20 March 2017

Synbiotics, a conjunction between prebiotics and probiotics, have been used in aquaculture for over 10 years. However, the mechanisms of how synbiotics work as growth and immunity promoters are far from being unraveled. Here, we show that a prebiotic as part of a synbiotic is hydrolyzed to mono- or disaccharides as the sole carbon source with diverse mechanisms, thereby increasing biomass and colonization that is established by specific crosstalk between probiotic bacteria and the surface of intestinal epithelial cells of the host. Synbiotics may indirectly and directly promote the growth of aquatic animals through releasing extracellular bacterial enzymes and bioactive products from synbiotic metabolic processes. These compounds may activate precursors of digestive enzymes of the host and augment the nutritional absorptive ability that contributes to the efficacy of food utilization. In fish immune systems, synbiotics cause intestinal epithelial cells to secrete cytokines which modulate immune functional cells as of dendritic cells, T cells, and B cells, and induce the ability of lipopolysaccharides to trigger tumor necrosis factor-a and Toll-like receptor 2 gene transcription leading to increased respiratory burst activity, phagocytosis, and nitric oxide production. In shellfish, synbiotics stimulate the proliferation and degranulation of hemocytes of shrimp due to the presence of bacterial cell walls. Pathogen-associated molecular patterns are subsequently recognized and bound by specific pattern-recognition proteins, triggering melanization and phagocytosis processes. © 2017 Elsevier Ltd. All rights reserved.

Keywords: Aquaculture Growth Immunity Probiotic Prebiotic Synbiotic metabolites

Contents 1. 2. 3. 4. 5.

6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368 Synbiotic concept . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368 Current applications of synbiotics in aquaculture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368 Selection of prebiotics and probiotics for synbiotic formulations in aquaculture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368 Synbiotics work as growth promoters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369 5.1. How prebiotic metabolism induces the growth and colonization of probiotic bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369 5.2. Synbiotics improve the nutrient absorptive ability of a host's intestinal tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375 5.3. Synbiotic primary and secondary metabolites as essential nutrients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375 5.4. Synbiotics provide bacterial exoenzymes and induce a host's digestive enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376 Synbiotic metabolites and immune responses of aquatic animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377 6.1. Synbiotics as immunity promoters in fish . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377 6.2. Synbiotics induced penaeid shrimp immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377

* Corresponding author. E-mail address: [email protected] (C.-H. Liu). http://dx.doi.org/10.1016/j.fsi.2017.03.035 1050-4648/© 2017 Elsevier Ltd. All rights reserved.

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7.

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6.3. Possible underlying modes of actions of synbiotics in the immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377 Concluding remarks and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378 Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378

1. Introduction Annual aquaculture production reached 73.8 million metric tons (MT) in 2014, of which inland and marine aquaculture production respectively accounted for 63.8% and 36.2% of the total and were equivalent to 47.1 and 26.7 million MT, respectively [1]. During farming operations, most recent investigations indicated that feed costs accounted for 84% of total production costs for freshwater fish [2], whereas in penaeid shrimp, they accounted for 66%e68% [3]. In order to ensure profitability, reducing feed costs through improving feed formulations, feed ingredients, and feed efficacy practices is of greatest concern. Hence, developing feed additives incorporated in feed formulations to improve the feed efficiency in aquaculture has become a major trend in the last decade. It appears that numerous researchers have been interested in incorporating prebiotics and probiotics into aquafeed to improve the food value, digestive enzymes, and growth and immune responses in aquaculture. There is no doubt that applications of probiotics and prebiotics have obtained remarkable achievements in enhancing growth and health benefits of aquaculture species. For example, previous studies reported that fish and shellfish fed diets supplemented with either prebiotics or probiotics could improve intestinal microbiota, microvilli and absorptive ability [4e9]; digestive enzyme activity [10,11]; growth performance [7e10,12]; expression levels of immune-related genes [13,14]; and disease resistance against viral and bacterial infections [12,15,16]. The advantages of prebiotics and probiotics in aquaculture have been reviewed by several researchers in recent years [17,18]. Synbiotics, a combination of probiotics and prebiotics, have been introduced and first used to enhance the immune responses of fish since 2005 [19]. Over the past 10 years, numerous studies on uses of synbiotics to improve aquatic animals' health were published. However, it is surprising that those studies still left unanswered questions regarding the underlying mechanisms of action of synbiotics in benefiting hosts. Therefore, the aims of this work were to address the current status of applications of synbiotics in aquaculture and the selection of prebiotic and probiotic for establishing relevant synbiotic formulations. In particular, this document also provides a better understanding of the mechanisms of how synbiotics work as growth and immunity promoters in aquatic animals.

probiotic is chosen based on specific effects on the host, and the prebiotic is independently chosen to selectively increase concentrations of microbiota components. The prebiotic may promote growth and activity of the probiotic, but only indirectly as part of its target range (Fig. 1) [21]. However, the situation may be more complicated that the recent studies revealed that prebiotics such as b-glucans in parts of synbiotics can act directly the immune system with disregarding the possible effect on intestinal microbiota of the aquatic animals [22,23] while others reported b-glucans provided substrates for growth, viability and colonization of probiotic bacteria [24e26]. 3. Current applications of synbiotics in aquaculture Over the past decade, most studies focused on the roles of probiotics and prebiotics in improving growth performance and immune responses of aquatic animals. To date, probiotics and prebiotics in aquaculture have mostly been reviewed separately [17,18,27,28]. Although synbiotic concepts appeared early [20], the first introduction of synbiotics were reported in rainbow trout Oncorhynchus mykiss [19] and white shrimp Litopenaeus vannamei [29]. Shortly afterward, some investigators reported the health benefits of synbiotics in various commercial fish species, such as the large yellow croaker Larimichthys crocea [30], cobia Rachycentron canadum [31], Japanese flounder Paralichthys olivaceus [32], and rainbow trout O. mykiss [33]; and in shellfish, such as the European lobster Homarus gammarus and Kuruma shrimp Penaeus japonicus [34,35]. Then, Cerezuela et al. [36] produced an overview on the uses of synbiotics in fish aquaculture. Applications of synbiotics in aquaculture have actually been blossoming since 2012. In fact, most studies investigated the effects of synbiotics on growth performance, enzymatic digestion, and immune response improvements in fish, while several studies reported on shellfish (Table 1), and then a review of the uses of a synbiotic on sturgeon culture appeared [37]. Most recently, Ringo and Song [38] reviewed applications of synbiotics and probiotics in combination with plant products and b-glucans in aquaculture. However, those reviews did not propose selection or pathways of synbiotics involved in growth and immunity enhancement when incorporated into aquafeed.

2. Synbiotic concept

4. Selection of prebiotics and probiotics for synbiotic formulations in aquaculture

Gibson and Roberfroid [20] defined a synbiotic as “a mixture of probiotics and prebiotics that beneficially affects the host by improving the survival and implantation of live microbial dietary supplements in the gastrointestinal tract, by selectively stimulating the growth and/or by activating the metabolism of one or a limited number of health-promoting bacteria, and thus improving host welfare”. Since this first definition, synbiotics have not been redefined. However, Kolida and Gibson [21] stated that both synergistic and complementary synbiotic approaches should be considered when applying synbiotics in animal science. From this, the synergistic effect of a probiotic is chosen based on effects on the host, while the prebiotic is chosen to specifically stimulate growth and activity of the probiotic. The complementary effect is when a

Since their first introduction to aquaculture, some previous studies reported that either single applications or combinations of prebiotics and probiotics had positive effects on aquatic animal health [15,32,39e42]. However, most studies clearly showed synergistic effects [43e47]. This indicates that the effects of synbiotics are now the most relevant in terms of the synergistic effects, while the primary role of prebiotics is to improve the survivability and implantation of the probiotic. To establish a relevant synbiotic, the in vitro efficacy of the specificity of the prebiotic for selective stimulation of the selected probiotic needs to be examined. The implication is that probiotic bacteria can utilize a prebiotic as a source of carbon to achieve high growth rates and cell yields during fermentation. However, this method is limited due to a lack of

T.-G. Huynh et al. / Fish & Shellfish Immunology 64 (2017) 367e382

Target Selective prebiotic

Target Probiotic

Specific stimulating

Aquatic animals’ benefits

369

Prebiotic Undirectly

Target

Probiotic

Complementary effect

Synergistic effect

Fig. 1. Synbiotic approaches in aquaculture.

information on interactions between selective prebiotics and indigenous microbiota [21]. In vitro selection of prebiotics for intestinal indigenous microbiota has received less attention in previous studies on aquaculture [48]. It is noted that synbiotics are perceived as a single product, in which probiotics and prebiotics must meet criteria according to definitions given by Refs. [20,49]. However, it is not clear which prebiotic carbohydrates are the most suitable substrates for the selective growth of specific strains, and this issue must be considered in developing synbiotics for aquaculture. The ability of a probiotic is to metabolize selective prebiotic oligosaccharides and provide for their selective enrichment in the intestinal tract. As a result, the formation of primary and secondary metabolites may confer health benefits to the host. One of the approaches for evaluating and optimizing combinations of probiotics and prebiotics for synbiotic formulations is based on prebiotic activity as reported by Ref. [50]. From that study, a low prebiotic activity score indicates that the prebiotic supports potential pathogenic bacterial strains. Regrettably, this issue has received less attention, although numerous commercial prebiotic and synbiotic products have intensively been used in aquaculture [5e8,11,18,28,51,52]. Compounds with prebiotic characteristics, such as mannan oligosaccharide (MOS), fructo-oligosaccharide (FOS), short chain (sc)FOS, inulin, chitosan oligosaccharide (COS), galacto-oligosaccharide (GOS), arabino-xylo-oligosaccharide (AXOS), and isomalto-oligosaccharide (IMO), have been selected for combination with probiotics to be synbiotics for aquaculture (Table 1). Theoretically, among available prebiotic and probiotic products on the market, there are therefore numerous synbiotics which can be established. However, the efficacy of growth supporting prebiotics before conjunction with probiotic bacteria should be considered, because recent studies revealed that prebiotic oligosaccharides composed of a short degree of polymerization (DP) can be preferentially metabolized faster that those with a high DP [50,53]. Therefore, in order to develop a synergistic synbiotic for use in aquafeeds, we recommend that both in vitro and in vivo examinations must be done. The purpose of in vitro test is to attain the optimal combination between prebiotic(s) and probiotic(s). From that, probiotic bacteria are screened for prebiotic utilization and growth on selective prebiotic(s) containing-medium. Then, selected prebiotic(s) must be examined for ability of supporting potential endemic pathogenic bacterial strains of aquaculture species. The aim is to exclude probability selected prebiotic(s) supports for both selected probiotic and endemic pathogenic bacteria. This implies that the efficacy of the synbiotic may be aquaculture species dependent. Finally, the productions of bacterial extracellular enzyme activities and metabolite compounds are examined. For in vivo test, probiotic(s) in synbiotic form should be evaluated for survivability and implantation in intestines of aquatic animals, subsequently alters intestinal morphology and microbiota diversity. Finally, productions of digestive enzyme, metabolite compounds, growth, immune response and disease resistance are evaluated after synbiotic administration to ensure that synbiotic

can work as growth and immunity promoters. The suggested strategy for establishing a relevant synergistic synbiotic for aquaculture is summarized in Fig. 2. 5. Synbiotics work as growth promoters 5.1. How prebiotic metabolism induces the growth and colonization of probiotic bacteria During synbiotic dietary treatment, prebiotics in the form of synbiotics are hydrolyzed to their respective sugars in the intestinal tract of the host, and are subsequently utilized as a source of carbon to increase the biomass of bacteria. According to current knowledge, the precise mechanisms of how prebiotics are metabolized by these beneficial microbes in vivo remain largely unknown, because prebiotics are utilized by intestinal bacteria under diverse mechanisms dependent on sugar linkages and the bacterial strains. It is currently assumed that Lactobacillus species have evolved to adopt such diverse transport mechanisms and catabolic pathways including intracellular and extracellular hydrolysis for specific types of oligosaccharide substrates [54]. During prebiotic metabolism, diverse transporters involved in prebiotic metabolism are known, such as the adenosine triphosphate (ATP)-dependent binding cassette (ABC), phosphoenolpyruvate-dependent, phosphotransferase system (PTS), and major facilitator superfamily (MFS). For instance, in Lactobacillus acidophilus, FOSs are transported by an ABC transporter and hydrolyzed by intracellular bfructofuranosidases (b-FFases). In Lac. plantarum, FOS is internalized via a sucrose PTS transporter, and hydrolysis is catalyzed by a cytoplasmic b-FFase. Lac. ruminus can translocate and hydrolyze FOS and inulin via the MFS transporter. In contrast, Lac. paracasei and Lac. casei have different strategies for metabolizing FOS using a cell-wall-anchored b-FFase (FosE). The presence of a cell wallanchoring motif establishing the cell surface localization of FosE indicates that FOS is hydrolyzed extracellularly in an exo-type fashion, followed by the subsequent uptake of the hydrolytic fructose via the fructose PTS transporter [54,55]. Goh and Klaenhammer [54] also revealed that bacteria with an extracellular FOS degradation mechanism are able to potentially provide crossfeeding of hydrolytic products generated by the cell surface bFFase. In many cases, prebiotics cannot be metabolized by probiotic bacteria due to the restricted capacity of transporter systems. For GOS, in Lac. acidophilus, GOS is transported via the galactoside-pentose-hexuronide (GPH)-type lactose permease (LacS) and hydrolyzed by two cytoplasmic b-galactosidases (LacA and LacLM) into glucose and galactose. Afterward, glucose is metabolized via the glycolytic pathway, whereas galactose is metabolized via the Leloir pathway [56]. Probiotic bacteria containing the lac operon are able to metabolize lactose and GOS and potentially other galactosides. Therefore, without LacS or LacA, probiotic bacteria cannot ferment GOS, lactose, or lactitol as carbon sources. For instance, Lac. gasseri, a probiotic species cannot

Aquaculture species

370

Table 1 Status of applications of synbiotics in aquaculture species. Synbiotic Probiotic

Prebiotic

Duration of Impactsyy administration

Uses of synbiotics in freshwater aquaculture fish Rainbow trout Oncorhynchus FOS mykiss (average of 126 g) (13.2 ± 0.25 g) MOS

Lactobacillus rhamnosus Enterococcus faecalis

(100 ± 10 g) (36.27 ± 0.42 g)

Lac. rhamnosus 60 days E. faecalis (inactivated) 84 days

MOS MOS

30 days 84 days

-

FOS

E. faecium (Biomin IMBO®)

60 days

(4.48 ± 0.2 g)

FOS

E. faecium (Biomin IMBO®)

60 days

(15.04 ± 0.52 g)

GOS

Pediococcus acidilactici 56 days

-

P. acidilactici

-

(15.04 ± 0.52 g)

GOS

56 days

-

Koi Cyprinus carpio (24.9 ± 0.52 g) COS

Bacillus coagulans

56 days

Conmon carp C. carpio (4.3 ± 0.1 g) FOS

E. faecium IMB52 (Biomin IMBO®) E. faecium IMB52 (Biomin IMBO®)

60 days

E. faecium IMB52 (Biomin IMBO®) E. faecium IMB52 (Biomin IMBO®) E. faecium IMB52 (Biomin IMBO®) E. faecium IMB52 (Biomin IMBO®) Lac. brevis, Lac. pentosus, Lac. plantarum Weissella cibaria

60 days

B. licheniformis

56 days

(10 ± 1 g)

FOS

Gibel carp Carassius auratus gibelio (15.5 ± 0.2 g) Grass carp Ctenopharyngodon idella (15.41 ± 0.51 g) Zebrafish Danio rerio (0.21 ± 0.09 g) (0.21 ± 0.09 g)

FOS

(~0.2 g)

FOS FOS FOS Ecklonia cava

Hybrid surubins Pseudoplatystoma Inulin sp. (73.6 ± 19.5 g)

Triangular bream Magalobrema terminalis (30.5 ± 0.5 g)

FOS

60 days

-

60 days

-

90 days

-

90 days 21 days

15 days

Intestinal microbiotaþ TBC and LAB [ Immune responseþ ACH50, RB, PA, Ig [; LSZ d Growth performanceþ 33.7% WG [, SGR [ (2.8% day1 vs. 2.4% day1); FCR Y Haematology and immune responseþ Hct, PA, mucus weight [ Disease resistanceþ SR [ by 52.1% after 14 days of challenge with Vibrio anguillarum at dose of 105 CFU fish1. Intestinal microbiotaþ LAB [ Growth performanceþ 44.2% WG [ at EM0.5 treatment, SGR [ (1.5% vs. 1.2%); FCR Y Haematology and immune responseþ Hct [, PA [, mucus weight [ for both EM0.25 and EM0.5 treatments Disease resistanceþ SR [ by 70% roughly after 14 days of challenge with Aeromonas salmonicida at 2 dose of 2.4  10 CFU fish1. Growth performance and survivalþ 146.3% WG [, SGR [; FCE [ þ SR [ (100% vs. 83.3%) Haematologyþ TP, ALB and GLU [; GLO and TG d Growth performance and survivalþ SGR; SR [; FCR Y Haematology and immune responseþ WBC, RBC, lymphocyte, LSZ [; monocyte and neutrophil cells Y Disease resistanceþ SR [ by 55.5% after 15 days of challenge with fungus Saprolegnia parasitica at 3  105 spores L1. Growth performance and survivalþ %WG and DWG [ by 10.7% and 0.19 g day1, respectively; SR d; FCR Y Haematologyþ Erythrocyte count, Hct, MCH, MCHC and MCV d Intestinal microbiotaþ TBC and LAB [. Immune responseþ ACH50, RB, LSZ [, skin mucus protein levels [; bactericidal activity of skin mucus [ Disease resistanceþ RPS [ after 18 days of challenge with Streptococcus iniae at dose of 2  106 CFU fish1. Growth performance and survivalþ 49.8% of WG [, SGR [; SR d; FCR Y Haematology and immune responseþ WBC, leucocyte count, RB, SOD, LSZ and PA [ Disease resistanceþ SR [ by 30.6% after 14 days of challenge with A. veronii at 2.4  108 CFU fish1. Growth performanceþ %WG [ by 10.1% and SGR [; FCR Y Haematologyþ WBC, RBC, Hct, Hb, ALB and GLO [; TP and TG d; GLU and CHO Y. Growth performanceþ SGR [ (1.39% vs. 0.82% day1) Digestive enzyme activityþ Trypsin and chymotrypsin activities [; a-amylase, lipase and alkaline phosphatase d Growth performanceþ %WG [ by 19% (2% trt.), SGR [; FCR Y Immune responseþ Ig and LSZ [. Growth performance and survivalþ WG, DWG and SGRd; FCR d þ SR [ by 12.2%. Fecundity [ (3.75 fold), hatching rate [ by 35.5%, hatching time Y. 1

1

- Growth performance and survivalþ WG [ 90% (average of 0.38 g day vs. 0.20 g day ), SGR [; SR [ by 18%; FCR Y (3.73 vs. 5.27) - Growth performanceþ BW [ after 3 weeks - Inflammation responseþ Expression of NOS and COX2 [ - Disease resistanceþ SR [ after 7 days of challenge with E. tarda at dose of 3  104 CFU fish1. - Intestinal microbiotaþ TBC d; TVC and total Pseudomonas spp. Y; LAB [ - Haematologyþ Erythrocytes [; Thrombocytes, leucocytes, lymphocytes, monocytes, eosinophils, basophils, Hct d; Neutrophils Y. þ Total Ig [; GLU, TP and LSZ d - Optimal combination: 0.3% FOS þ 1  107 CFU B. licheniformis g1 diet - Immune responseþ Leucocyte count, ACP, ACH50, PO, LSZ, GLO, IgM [ þ SOD, CAT and GPx in liver and plasma [, MDA Y

[19] [39]

[138] [59]

[33]

[151]

[152]

[153]

[43]

[52] [154]

[155] [51] [156] [157] [133]

[76]

[130]

T.-G. Huynh et al. / Fish & Shellfish Immunology 64 (2017) 367e382

(4.59 ± 0.2 g)

References

(30.5 ± 0.5 g)

FOS

56 days

Beluga Huso huso (26.45 ± 0.19 g) FOS

E. faecium (Biomin IMBO®)

56 days

Siberian sturgeon Acipenser baerii (48.4 ± 1.4 g)

AXOS

Lactococcus lactis spp. lactis or B. circulans

28 days

Nile tilapia Oreochromis niloticus (4.07 ± 0.30 g) (15e20 g)

MOS

B. subtilis

42 days

Extract of sweet potato Bacillus sp. Ipomoea batatas var. sukuh

14 days

Caspian roach Rutilus rutilus (4.14 ± 0.25 g)

FOS

E. faecium (Biomin IMBO®)

60 days

Tambaquis Colossoma macropomum (2.4 ± 0.2 g) Pearl gourami Trichogaster leeri (0,45 ± 0,05 mg)

MOS

B. subtilis

56 days

MOS

B. subtilis

28 days

Angelfish Pterophyllum scalare (3.2 ± 0.13 g)

FOS

P. acidilactici

49 days

Striped catfish Pangasianodon hypophthalmus (6.54 ± 0.17 g)

MOS

Bacillus sp.

30 days

B. subtilis

98 days

B. subtilis

70 days

Uses of synbiotics in marine aquaculture fish Spinefoot rabbitfish Siganus Allicin rivulatus (average of 10.3 g) Large yellow croaker Larimichthys FOS crocea (7.82 g ± 0.68) Cobia Rachycentron canadum (10.1 ± 0.5 g)

COS

B. subtilis

56 days

Japanese flounder Paralichths olivaceus (average of 21 g)

MOS, FOS

B. clausii

56 days

Olive flounder Paralichthys olivaceus (300e350 g)

E. cava powder

Lac. plantarum

112 days

1

1

- Growth performanceþ SGR [ (2.09% day vs. 1.41% day ); FCR Y (1.77 vs. 2.28) - Disease resistanceþ SR [ by 66.7% (85.2% vs. 18.5%) after 14 days of challenge with Streptococcus agalactiae at dose of 104 CFU fish1. - Growth performance and survivalþ WG [ by 63.2 g (168.8 g vs. 105.6 g), SGR [ by 0.63% day1; SR [ by 21.1% (95.6% vs. 74.5%); FCR Y (2.79 vs. 4.41) - Intestinal microbiotaþ TBC d, LAB [ (2% synbiotic) - Immune responseþ LSZ, ACH50, total Ig [ (2% synbiotic) - Stress toleranceþ SR [ after 40 h exposure to high salinity (138 ppt). - Growth performanceþ Biomass [ by 0.68 kg m3; SR d; FCR Y (1.42 vs. 1.88) - Economic efficiencyþ Operating profit [ (7.14 vs. 5.83 US$ m3) - Growth performanceþ SGR [ (14.1% vs. 12.3%); SR [ (66.6% vs. 46%) - Intestinal morphologyþ Microvillus height [; intestinal lumen area d - Stress resistanceþ SR [ after challenge with different exposure times to air. - Growth performanceþ WG, SGR [ (2.36% vs. 1.69%); SR d - Intestinal microbiotaþ LAB [; TVC Y - Immune responseþ LSZ, protease and Ig of skin mucus [ - Stress toleranceþ SR [ after 18 h exposure to low temperature (17  C) and high salinity (120 ppt). - Growth performance and survivalþ SGR [ (2.51% day1 vs. 1.79% day1); SR d; FCR Y (1.34 vs. 2.11) - Intestinal microbiotaþ TBC and Bacillus spp. [ - Haematologyþ Hct, Hb, erythrocyte count [, leukocyte count d after 30 days - Immune responseþ PA and RB d after 30 day, and [ after 34e41 days of feeding - Disease resistanceþ SR [ after 9 days of challenge with A. hydrophila at dose of 1  106 CFU fish1. - Growth performance and survivalþ WG [ by 9 g (44.8 vs. 53.8 g); SGR [ by 0.2% (1.7 vs. 1.9% day1); SR /; FCR Y (2.6 vs. 3.6) - Growth performanceþ SGR [; FCR Y - Immune responseþ LSZ and SOD [; RB and ACH50 d - Disease resistanceþ SR [ after 10 days of challenge with V. harveyi at dose of 2.1  108 CFU fish1. - Optimal combination: 6 g COS þ 2  1010B. subtilis kg1 feed - Growth performanceþ SGR [ (2.57% day1 vs. 1.99% day1) - Immune responseþ PA, RB, LSZ and ACH50 [ - Disease resistanceþ SR [ after 7 days of challenge with V. harveyi at dose of 1.2  107 CFU fish1. - Optimal combination: 0.5% MOS þ 107 CFU Bacillus g1 feed; 0.5% FOS þ 107 CFU Bacillus g1 feed; and 0.25% MOS þ 0.25% FOS þ 107 CFU Bacillus g1 feed - Growth performanceþ %WG [ by 12.8%; FCR Y; FI d - Haematologyþ TG, LDL-C and LSZ [; CHO, HDL-C and PA d - Digestive enzyme activityþ Protease and amylase activities [. - Growth performanceþ %WG d; SR [ - Immune responseþ RB, LSZ, MPO [; - Haematologyþ TP, TG, AST, ALT, GLU, PHOS, CHO and Hct d

[47]

[46]

[158]

[61] [159]

[79]

[160] [92]

[78]

[80]

[161]

T.-G. Huynh et al. / Fish & Shellfish Immunology 64 (2017) 367e382

B. licheniformis

- Disease resistanceþ SR [ after 7 days of challenge with A. hydrophila at dose of 5  107 kg1 body weight of fish. - Optimal combination: 0.3% FOS þ 1  107 cfu g1 Bacillus - Growth performance and survivalþ %WG [ by 50%, SGR [; SR [; FCR Y - Intestinal morphology and digestive enzymeþ Protease, lipase and Naþ, Kþ-ATPase [, amylase activity d þ Microvilli length in the mid-intestine [. - Growth performance and survivalþ Optimal dose: 2 g kg1 of feed þ %WG and SGR d; SR d; FCR d - Haematology and immune responseþ RBC, Hct, monocyte, lymphocyte, neutrophil, GLU, TP and LSZ d; WBC, ACH50 and Ig [ - Intestinal microbiotaþ TBC and LAB d. - Optimal combination: 2% AXOS and 1  109 CFU of Lac. lactis spp. lactis g1 - Growth performance and survivalþ WG [ by 55.8% (56.8 vs. 37.0 g), SGR [; SR d; FCR Y - Immune responseþ PA, RB and ACH50 [; Ig d - Intestinal microbiotaþ Richness and Shannon index Y, bacterial diversity Y. - Biomass, relative gain in biomass (RGB) [; FCR Y.

[30]

[31]

[32]

[131]

(continued on next page) 371

Aquaculture species

372

Table 1 (continued ) Synbiotic Probiotic

Atlantic salmon Salmo salar (250 ± 13 g)

scFOS

Prebiotic

Duration of Impactsyy administration

63 days

Gilthead seabream Sparus aurata L. Inulin (average of 80 g)

Yeast Debaryomyces hansenii

28 days

(average of 50 g)

Inulin

B. subtilis

28 days

(average of 50 g)

Inulin

B. subtilis

28 days

(14.0 ± 1.5 g)

b-1,3/1,6-glucan

Shewanella putrefaciens

28 days

Ovate pompano Trachinotus ovatus FOS (10.32 ± 0.46 g)

B. subtilis

56 days

Leopard grouper Mycteroperca rosacea (35 ± 5.0 g)

Inulin

Lac. sakei

56 days

Humpback grouper Cromileptes altivelis (4.75 ± 0.02 g)

Extract of sweet potato I. batatas

Sphingomonas paucimobilis Pseudomonas flourescens

40 days

Uses of synbiotics in Penaeid shrimp White shrimp Litopenaeus IMO vannamei (average of 1.75 g)

Bacillus OJ

28 days

(1.4 ± 0.31 g)

Inulin

Bacillus sp.

60 days

(6,0 ± 1,3 g)

Inulin

Lac. plantarum

42 days

(1e2 g)

Extract of banana Musa (ABB group)

B. subtilis

90 days

-

(0.33 ± 0.02 g)

Sweet potato extract

SKT-b®Vibrio alginolyticus

30 days

-

Optimal combination: 0.2% IMO þ 1  108 CFU Bacillus g1 feed Intestinal microbiotaþ TBC and VBC Y Immune responseþ ACP, AKP, PA, PO and RB [ Disease resistanceþ SR [ after challenge with WSSV. Optimal combination: 0.4 g inulin þ 1  105 CFU g1 feed Growth performance and survival d Disease resistanceþ SR [ after challenge with WSSV (100% vs. 89%) þ Prevalence of WSSV in shrimp Y by 22.2%. Intestinal microbiotaþ LAB [; TVC Y Immune responseþ THC, PO, serum antimicrobial activity d Disease resistanceþ SR d after 48 h challenge with V. alginolyticus at dose of 2.5  106 CFU shrimp1 Growth performanceþ Optimal combination for growth: B. subtilis þ 10% extract of Musa. þ FW d Immune responseþ THC, PO [ Disease resistanceþ SR [ after 15 days of challenge with V. harveyi at dose of 107 CFU/mL by immersion. Optimal combination: 1% probiotic þ 2% prebiotic Growth performanceþ SGR [; FCR Y

[44]

[145]

[134]

[91,146]

[22]

[45]

[40]

[162]

[29]

[135]

[77]

[136]

[137]

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P. acidilactici

- Disease resistanceþ SR [ after 14 days of challenge with Edwardsiella tarda, Streptococcus iniae, or V. harveyi at dose of 3  104 CFU fish1. - Growth performance and survivalþ FW, SGR; SR d; FCR d - Intestinal morphology and microbiotaþ Villi length in anterior intestine [ þ TBC in the anterior and posterior intestinal tract Y - Immune response and immune related gene expressionþ LSZ activity [ þ Expression of TLR3, MX-1, IL-1b, IL-8 and TNF-a genes [. - Intestinal microbial diversityþ Shannon index [ at 2 weeks, then Y at 4 weeks - Immune response and immune related geneþ PA, RB, ACH50 and total IgM d, peroxidase activity [ after 4 weeks. þ Expressions of: MHCIIa (skin, liver, head kidney) [; C3 [ (intestine); IgM, C3, IL-1b, CSF-1R, NCCR1, Hep and TCR-b [ (head kidney) after 4 weeks of feeding. - Immune response and immune related geneþ Complement activity, IgM [ þ Expressions of MHCIIa and CSF1R (2 weeks) [; IgM, TCR-b, MHCIa, MHCIIa and CSF-1R (4 weeks) Y - Disease resistanceþ SR [ after 15 days of challenge with Photobacterium damselae subsp. piscicida at dose of 109 CFU g1 fish. - Intestinal morphology and microbiotaþ Villus area, intestinal wall area, intestinal lumen area d þ Villus height, intestine diameter [ þ Microvillus height [ þ Richness and Shannon index Y, bacterial diversity Y - Intestinal gene expressionþ Expression of proinflammatory genes as IL-1, IL-8 and CASP-1 [; IL-6 Y þ Digestive and transport genes: Amylase, tripsin, ALP, Tf and PepT-1 [. - Growth performanceþ %WG, SGR d - Immune response and gene expressionþ Serum antiprotease activity and PA [; IgM and leucocyte peroxidase activity d; serum peroxidase activity Y þ Expression of immune related genes as INF-g, IL-1b[, IgM Y. - Optimal combination: 0.2% FOS þ 5.62  107 CFU Bacillus g1 feed - Growth performance and survivalþ SGR [, FE [; SR d - Immune response and disease resistanceþ RB, PA, ACH50 and LSZ activity [ þ SR [ after 10 days of challenge with V. vulnificus at dose of 1.9  106 CFU fish1. - Growth performanceþ WG [ - Haematology and immune responseþ Hb, TP, LSZ, IgM [; mieloperoxidase activity d þ Expression of IgM gene [ - Growth performance and survivalþ WG [ (56 g vs. 36.8 g), SGR [ (2.32% vs. 1.79%); SR d; FCR Y (0.99 vs. 1.27) - Haematologyþ Hb, Hct, PA [ - Digestive enzyme activityþ Protease, lipase d; amylase [.

References

(0.16 g ± 0.039 g)

b-glucan

(0.15 ± 0.03 g)

b-glucan

Kuruma Penaeus japonicus (5.20 ± 0.15 g)

IMO

90 days

B. licheniformis and B. subtilis

56 days

Uses of synbiotics in European lobster Homarus gammarus (larvae) MOS

Bacillus spp.

18 days

H. gammarus (larvae)

Bacillus spp.

12 days

MOS

90 days

- Growth performance and survivalþ WG [ by 80.7% (22.3 ± 0.72 vs. 12.15 ± 1.24 mg), SGR [; SR [ by [34] 7% from metamorphosis to post-larval stage IV); abnormality rate Y by 70%; FCR Y - Intestinal morphology and microbiotaþ Density and length of microvilli [ þ Species richness and Shannon index Y, bacterial diversity Y; VBC Y, LAB [ - Growth performance and survivalþ WG and carapace length d; SR d; stress tolerance [ (cumulative [60] sensitivity index Y) - Intestinal microbiota and diversityþ Species richness and Shannon index [, bacterial diversity [; TBC and VBC d; LAB [.

Prebiotic abbreviations: AXOS: arabino-xylo-oligosaccharide; COS: chitosan oiligosaccharide; FOS: fructo-oligosaccharide; GOS: galacto-oligosaccharide; IMO: isomalto-oligosaccharide; MOS: mannan oligosaccharide; scFOS: short chain fructo-oligosaccharide. Abbreviation parameters investigated: ACH: alternative complement pathway; ACP: acid phosphatase activitity; AKP: alkaline phosphatase activity; ALB: albumin; ALP: alkaline phosphatase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; BW: body weight; C3: complement component C3; CASP-1: caspase 1; CAT: catalase; CHO: cholesterol; COX-2: cyclooxygenase 2; CSF-1R: colony-stimulating factor receptor-1; DWG: daily weight gain; EF1a: elongation factor 1a; FE: feed efficiency; FCR: feed conversion rate; FI: feed intake; FW: final weight; GLO: globulin; GLU: glucose; GPx: glutathione peroxidase; Hb: hemoglobin; Hct: hematocrit; HDL-C: high-density lipoprotein cholesterol; Hep: hepcidin; Ig: immunoglobulin; IL: interleukin; INFg: interferon g; IMNV: infectious myonecrosis virus; LAB: lactic acid bacteria; LDL-C: low-density lipoprotein cholesterol; LGBP: lipopolysaccharide and b-1,3-glucan-binding protein; LSZ: lysozyme; MDA: malondialdehyde; MCHC: mean corpuscular haemoglobin concentration; MCV: mean corpuscular volume; MCH: mean corpuscular haemoglobin; MHC: major histocompatibility complex class; MX-1: myxovirus-resistant protein-1; MPO: myeloperoxidase; NCCRP-1: nonspecific cytotoxic cell receptor protein-1; NOS: nitric oxide synthase; OSM: osmolarity; PA: phagocytic activity; PepT-1: peptide transporter 1; PE: peroxinectin; PHOS: phosphorus; PO: phenoloxidase activity; proPO: prophenoloxidase; RB: respiratory brurst; RBC: red blood cells; RPS: relative percentage of survival; SGR: specific growth rate; SOD: superoxide dismutase; SP: serine protease; SR: survival rate; TBC: total viable bacterial counts; TCR-b: T-cell receptor b; Tf: transferring; TG: triglycerides; THC: total haemocyte counts; TLR3: toll-like receptor 3; TNFa: tumour necrosis factor a; TP: total protein; VBC: total vibrio counts; vs.: versus; WBC: white blood cells; WG: weight gain; WSSV: white spot syndrome virus. Symbol yy indicates mechanisms of actions are unknown (except the study of Guzman-Villanueva et al. [22]). Symbols represent a significant increase (↑), decrease (↓), or no change (d) in the parameter of the synbiotic relative to the control.

T.-G. Huynh et al. / Fish & Shellfish Immunology 64 (2017) 367e382

B. subtilis and P. acidilactici B. subtilis and P. acidilactici

- Immune response and disease resistanceþ THC, PO and RB [ þ SR [ after 7 days of challenge with co-infection IMNV and V. harveyi at dose of 103 CFU shrimp1. - Immune response and gene expressionþ THC and LSZ d; SOD and PO [ [26] þ Expression of genes as LGBP [ (b-glucan þ Pediococcus); ProPO and SP [ (b-glucan þ Bacillus); PE d [23] - Growth performance and survivalþ WG [ (b-glucan þ Pediococcus); SR and FE d - Intestinal microbiotaþ TBC, fungi, Bifidobacterium spp. d; LAB [ (b-glucan þ Bacillus); TVC Y (bglucan þ Bacillus) - Haemolymph chemistryþ GLU, TG, BUN, CHO, TP, and OSM d [35] - Survival of shrimp d (85.6e91.1%) - Intestinal microfloraþ TBC [; VBC Y - Immune responseþ THC, PO, RB, NOS, LSZ, and SOD [ - Disease resistanceþ SR [ after 10 days of challenge with V. alginolyticus at dose of 1  106 shrimp1.

373

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Fig. 2. Suggested strategy for establishing a relevant synergistic synbiotic for aquaculture. Abbreviations: DGGE: denaturing gradient gel electrophoresis; DWG: daily weight gain; FCE: feed conversion efficiency; GC: gas chromatography; HPLC: high performance liquid chromatography; MS: mass spectroscopy; NGS: next generation sequencing; NMR: nuclear magnetic resonance; ODmax: maximum optical density; PCR: polymerase chain reaction; SGR: specific growth rate; Tmax: the time needed to reach the ODmax; TBC: total bacterial counts; TEM: transmission electron microscopy; TVC: total vibrio counts; WG: weight gain. Symbol y indicates the observation of pH value is needed for lactic acid bacteria fermentation. Symbols represent an increase (↑), decrease (↓).

ferment GOS, and instead possesses lactose PTS transporters and phospho-b-galactosidase for lactose metabolism. In Lac. ruminus, GOS is transported and hydrolyzed by LacY and b-galactosidases (LacZ) [54]. Some previous studies stated that there are several mechanisms for xylo-oligosaccharide (XOS) and arabino-XOS (AXOS) metabolism. In Bifidobacterium lactis BB-12, XOS is transported via the ABC system and hydrolyzed by endo-1,4-b-xylanases and b-xylosidases to D-xylose. In B. lactis B1-04, XOS and AXOS are imported via an ABC transporter substrate-binding protein (BIAXBP) and a glycoside hydrolase (GH)43 b-xylosidase; two GH43 arabinofuranosidases, two esterases, and enzymes are required to convert metabolic intermediates for entry into the bifid-shunt pathway [57]. Therefore, the presence of arabinofuranosidases and carbohydrate esterases indicates the capability of a probiotic to remove arabinosyl and acetyl or feruloyl side chains from intracellular AXOS substrates [54]. Of interest, a bacterial strain that lacks xyloglycan-utilization loci (XyGUL) is totally unable to grow on xyloglucans as the sole carbon source [58]. For MOS, the mechanisms of MOS utilization by Bacillus probiotic bacteria are unknown, although some previous studies reported that MOS alters the gut microbiota and works as growth and immunity promoters in aquaculture [59e61]. Most recently, however, the mechanisms of MOS utilization and degradation by probiotic bacteria Bacteroides thetaiotaomicron were unraveled by Ref. [62]. From this, limited cleavage of a-mannan on the surface generates large oligosaccharides that are subsequently depolymerized to mannose by the action of periplasmic enzymes. To utilize MOS as a sole carbon source, probiotic bacteria must contain polysaccharide utilization loci (PULs) namely MAN-PUL1, MANPUL2, and MAN-PUL3. Probiotic bacteria lacking MAN-PUL2 or MAN-PUL1/2/3 are unable to grow on MOS. The MOS utilization ability of probiotic bacteria is dependent on types of mannan from diverse yeasts, such as Saccharomyces cerevisiae, Schizosaccharomyces pombe, and the pathogenic yeast Candida albicans [62]. For example, MAN-PUL1 contains an a-galactosidase, which targets agalactosyl linkages absent from Sac. cerevisiae mannan, explaining why inactivation of MAN-PUL1 affects the growth of probiotic

bacteria on medium containing MOS from Sac. cerevisiae as a carbon source. Paradoxically, unlike other prebiotics above, with MOS from yeast, the majority of glycan degradation occurs in the periplasm and not on the surface [62,63]. For depolymerization, mannose from MOS interacts with surface glycan-binding proteins (SGBPs) on the surface of bacteria through GH18 endo-b-N-acetylglucosaminidase, while binding of the starch utilization system SusD homologue to the reducing end N-acetylglucosamine (GlcNAc) directs the N-glycan, and these are transported across the outer membrane by SusC-like proteins [64]. Oligosaccharides are degraded into their component mono- or disaccharides by periplasmic enzymes such as a-1,2-, a-1,3-, and a-1,6-mannosidases. The liberated saccharides serve as signals for transcriptional regulators that activate PUL gene expressions. The end products of depolymerized sugars are imported across the cytoplasmic membrane as nutrients for bacterial growth [62,64]. To increase bacterial colonization after synbiotic treatment, probiotic bacteria must confer protection against pathogens by competitive exclusion for adhesion sites with synergistic action of prebiotic by different mechanisms. For instance, the presence of isolated exopolysaccharide (EPS, 2-substituted (1e3)-b-D-glucan) from probiotic Pediococcus parvulus potentiates in vitro adhesion of the probiotic Lac. plantarum to human intestinal epithelial cells Caco-2. This indicates that b-D-glucans promote the initial steps of adhesion to host intestinal cells [25]. However, several recent studies revealed that probiotic bacteia were able to inhibit biofilmforming exopolysaccharide as well as altered cell surface hydrophobicity of vibriosis. For example, quorum-quenching activity of the N-acylated homoserine (AHL)-lactone from Bacillus licheniformis or Pseudomonas spp. inhibited biofilm formation of Vibrio parahaemolyticus strains, resulting reductions in colonization of Vibrio in the intestine and mortality of Indian white shrimp Fenneropenaeus indicus and zebrafish Danio rerio [65,66]. From another point of view, Likotrafiti et al. [67] debated that mucosal adhesion of probiotic bacteria may be strain-specific and dependent upon substrate availability. This was demonstrated by their in vitro investigation, in which Lac. fermentum grown on scFOS exhibited higher percentage of adhesion to human colon adenocarcinoma

T.-G. Huynh et al. / Fish & Shellfish Immunology 64 (2017) 367e382

epithelial cells HT29 than those of Lac. rhamnosus GG (control), whereas Bifidobacterium longum showed the lowest percentage of adhesion when grown on IMO. Remarkably, bacterial adhesion to the intestinal surface is often mediated by specific attachment of bacteria surface proteins to complementary oligosaccharide on the tissue surface. However, bacteria can also adhere non-specifically and adhesive ability depends on the contact between the matrix and mucin layer. These imply that prebiotics can decrease the adhesion of bacteria due to lower matrix surface tention or higher kinematic viscosity of mucus. This fact has been demonstrated in gut model SHIME (simulator of the human intestinal microbial ecosystem) when AXOS increased kinematic viscosity, resulting in more difficult bacterial movement toward the mucin layer and less chances to adhere [68]. On the other hand, prebiotics not only modulate the adhesive of selective probiotic bacteria but also can act as antiadhesion agents to opportunistic pathogens. In fact, a previous study found that long-chain arabinoxylans (LC-AXOS) lowered the initial mucin-adhesion of adherent invasive Escherichia coli (AIEC) under SHIME experimental condition [69]. This finding is also in accordance with a recent study which concluded that introducing oligosaccharides into pure or mixed cultures has affected adhesion of gut bacteria [70]. In human, cross-talk between probiotic bacteria and colonocytes is established through surface layer proteins of the probiotic and extracellular matrix components known as collagens, laminin, fibronectin, and lipoteichoic acids on the surface of intestinal epithelial cells of the host. For instance, the surface layer protein CbsA of Lac. crispatus is involved in adherence to these matrix components [71]. To date, some surface layer proteins from probiotics have been identified, for example, SlpA, SlpB, and SlpX from Lac. acidophilus [72]; Cbp from Lac. plantarum [73]; and SlpH from Lac. helveticus [74]. In B. longum subsp. infantis, colonization is recognized by interaction between bacterial Family 1 of solute binding proteins (F1SBPs) and mammalian glycans of host. Some of these proteins were found to be adherent to intestinal epithelial cells in vitro [75]. In aquaculture, very little research has highlighted prebiotic metabolism in probiotic microbes or insights into the cross-talk between probiotic strains and intestinal epithelial cells of the host after synbiotic treatment, although several studies reported that synbiotics induced intestinal bacterial abundances and better colonization potential of probiotic strains [19,23,29,35,44,76e80]. Therefore, it is thought that further understanding of the mechanisms how prebiotics improve growth, viability and colonization of probiotic microorganisms in aquatic animals is needed to provide better strategies in developing the relevant synbiotics for aquaculture. 5.2. Synbiotics improve the nutrient absorptive ability of a host's intestinal tract Transmission electron microscopic (TEM) micrographs demonstrated that synbiotics improved the intestinal absorptive surface area in European lobsters H. gammarus [34] and triangular bream (Magalobrema terminalis) [47]. The underlying mechanism of this benefit can be explained along the intestinal tract, where alimentary and endogenous proteins are hydrolyzed into peptides and amino acids by host- and bacterium-derived proteases and peptidases [10,81,82]. During microbial metabolism processes, free amino acids are produced [83]. Then, amino acids are further utilized by both intestinal bacteria and the host. However, substantial amounts of free amino acids seem to escape assimilation and participate in the synthesis of short-chain fatty acids (SCFAs) [84]. Among SCFAs, butyrate acts as a signal transduction molecule responsible for developing and augmenting the barrier function of the human colonic epithelium [84,85]. This SCFA is bound by G-

375

protein-coupled receptors (GPCRs) which are expressed by gut epithelial and enteroendocrine cells [86]. In addition, lactate is a metabolite of glucose and also an energy source for many tissues. zGPR81-1 and -2 were identified as lactate receptors in fish [87]. SCFAs stimulate the physiological pattern of proliferation and permeability of colonic epithelial cells that improve the gut's nutrient absorptive ability [88,89]. Moreover, SCFAs exert potent effects on maintaining normal cell numbers in the intestine and suppressing cancerous intestinal epithelial cells of the host [88,90]. Impacts of SCFAs on human gut as noted above may provide the hypothesis for aquatic animals that are fed synbiotics can improve nutrient utilization and growth performance by increasing the absorptive surface area of intestinal microvilli as per evidence provided by Refs. [34,44,47,91,92]. However, the interactions between SCFAs produced from synbiotic metabolism and aquatic animals' colonic epithelial cells should be elucidated in further research. In addition, the correlations between SCFAs production after feeding synbiotic and intestine diameter, villus height, density and lenght of microvilliare also considered. 5.3. Synbiotic primary and secondary metabolites as essential nutrients Synbiotic metabolism produces a vast array of compounds that can be further utilized by both gut bacteria and the host. Previous studies on synbiotic administration reported that essential amino acids, including histidine, isoleucine, leucine, lysine, phenylalanine, valine, and tryptophan, and nonessential amino acids, such as alanine, glutamate, and tyrosine, are released during synbiotic fermentation [93,94]. In human, SCFAs and branched-chain fatty acids (BCFAs) were also identified, in which acetate, propionate, and butyrate accounted for 90%e95% [85]. In the experimental condition of a semi-continuous colon fermentation model, Makivuokko et al. [95] detected the polyamines, cadaverine, putrescine, methylamine, and tyramine, after fermenting a synbiotic comprised of lactitol and Lac. acidophilus. Moreover, some synbiotic metabolites like vitamins and derivatives, such as choline, ascorbate (vitamin C), folate (vitamin B9), and cyanocobalamin (vitamin B12), have also been explored [94,96,97] (Table 2). These identified metabolic compounds might be considered essential nutrients for assimilation and play important roles in biological functions for growth of aquatic animals. Obviously, in human, numerous studies have been intensively documented the biofunctions of these compounds. For examples, amino acids are building blocks for proteins [98]; SCFAs are considered major energy sources for the colonic epithelium as well as precursors of gluconeogenesis in the liver [85]. In addition, polyamine putrescine is a precursor of spermine that is associated with nucleic acids and stabilizes helical structures [99]. Tyramine is a precursor of octopamine under activation of the tyramine b-hydroxylase (tbh) enzyme [100,101]. Octopamine can act as a neurotransmitter, and its catabolism can be achieved in different ways including uptake in the terminal part of neurons, degradation by aminoxidase enzymes, or conversion to noradrenaline. Octopamine is known as a lypolytic factor, and its also increases induction of hypothermia and locomotor activity related to orientation and feeding activity [102], changes in tension, and contraction strength of exoskeletal muscles of invertebrates [100]. Known as a synbiotic metabolite, choline is a structural component of the major phospholipid, phosphatidylcholine, and as a precursor of the neurotransmitter, acetylcholine, that acts in the heart and at a variety of postsynaptic targets in the central and peripheral nervous systems [103]. The signs of choline deficiency include growth retardation, poor survival and feed efficiency, and increased liver lipid concentration and stress tolerance in aquatic animals [104,105]. Interestingly, folate is necessary for normal cell division

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Table 2 Identified compounds from synbiotic metabolism studies. Synbiotic

Short chain fatty acids (SCFA)

Prebiotic

Lactobacillus acidophilus NCFM Lac. acidophilus NCFM Lac. plantarum WCFS1 Bacillus subtilis

Cellobiose; isomaltulose; 24 h raffinose Lactitol 48 h Glucose; scFOS

Vitamins

Inoculum origin

References

Acetate, propionate, and butyrate

Modified MRS

[163]

Acetate, propionate, butyrate, and lactate

Colon model*

[95]

Lactate and acetate

Chemically defined [126] medium Chemically defined [48] medium Modified MRS [48]

time

5e8 h

b-glucan; inulin; 18e24 h oligofructose; XOS, AXOS b-glucan; inulin; 18e24 h oligofructose; XOS; AXOS

Acetate, propionate, butyrate, and branched acids Acetate, propionate, butyrate, and branched acids

Carnobacterium piscicola Lac. delbrueckii Lac. plantarum Lac. fermentum B5 FOS; GlOS; GOS

18 h

Lac. sakei S161

FOS; GlOS; GOS

18 h

FOS

48 h

FOS

60 days

Lac. acidophilus

FOS

30 days

Lac. acidophilus NCFM Lac. casei-01

Lactitol

48 h

Bacterial suspension Lactate and acetate Bacterial suspension 2-methyl butyrate, 2-methyl-5-ethyl-pyrazine, and 2Fecal butanone slurries þ prebiotic Phenylalanine, tryptophan, histidine, tyrosine, Cheese containing isoleucine, leucine, valine, lysine, and alanine synbiotic Isoleucine, valine, phenylalanine, lysine, glycine, alanine, Fecal sample glucine, valine, leucine, and tyrosine Cadaverine, putrescine, methylamine, and tyramine Colon model*

FOS

60 days

Choline

FOS; GOS FOS; GOS

24 h 24 h

Folate Folate

Cheese containing [94] synbiotic MRS [97] MRS [97]

FOS

36 h

Cyanocobalamin

Modified MRS

[166]

FOS; inulin

24 h

Ascorbate

MRS and faecal sample

[96]

Branched-chain Lac. helveticus fatty acids (BCFA) Bar13 Amino acids Lac. casei-01

Polyamins

Fermented Metabolic compounds

Probiotic

Lac. plantarum Lac. delbrueckii ssp. bulgaricus Lac. fermentum CFR 2195 Bifidobacterium spp.

Lactate and acetate

[164] [164] [165] [94] [93] [95]

Notes: AXOS: arabino-xylo-oligosaccharide; Cellobiose: disaccharide composed of glucose-glucose; *Colon model: semi-continuous colon fermentation model; FOS: fructooligosaccharide; GlOS: gluco-oligosaccharides; GOS: galacto-oligosaccharide; Isomaltulose: disaccharide composed of glucose-fructose; Maltotriose: trisaccharide composed of glucose-glucose-glucose; Melibiose: disaccharide composed of galactose-glucose; MO: maltooligosaccharide; Modifed MRS: medium containing no carbon source, and supplemented with prebiotics; Raffinose: trisaccharide composed of galactose, glucose, and fructose; scFOS: short chain fructo-oligosaccharide; XOS: xylo-oligosaccharide; Xylobiose: disaccharide composed of xylose.

and multiplication [106]. Ascorbic acid is involved in the synthesis of hydroxyproline, a major component of protein collagen, and essential in connective tissues and bone matrix formation [107,108]. Ascorbic acid regulates cell division and growth and is involved in signal transduction. In fact, aquatic animals are unable to synthesize ascorbic acid from D-glucose due to the lack of Lgulonolactone oxidase [109]. Thus, an exogenous source of ascorbic acid is required in the diet, and ascorbic acid from synbiotic metabolism should be considered in aquaculture. Last but not least, cyanocobalamin is required for normal red blood cell formation and also regulates the production of new bone cells and DNA methylation that have been demonstrated in mouse [110]. It is also a cofactor for the enzyme methylmalonyl CoA mutase in fatty acid metabolism. These are important processes in normal cell differentiation, and cyanocobalamin is therefore essential for optimal growth and health [111]. Prominent signs of cyanocobalamin deficiency in animals are a poor appetite, impaired hematopoiesis, and poor growth [112]. To date, it is no doubt that some compounds discussed above, such as amino acids, choline, folate, ascorbic acid, and cyanocobalamin, have been widely used to improve the growth of aquaculture species using commercial products [105,106,109,111e113]. However, in formulating a commercial diet for a cultivated aquaculture species, nutritional values have been optimized, in which the amino acids or vitamins supplemented may exceed the marginal production of those by synbiotics. In other words, the release of amino acids or vitamins during synbiotic

dietary is unlikely to benefits significantly to the host. Hence, we assume the fact that synbiotic metabolites such as SCFAs and polyamines, known as bioactive compounds, could be of most concerns when establishing the synbiotics. At present, some commercial SCFAs as butyrate, propionate, acetate and succinate have been also reported as growth promoters in aquacultured species [114,115] and reviewed by Ref. [116]. However, how these compounds released from synbiotic metabolism processes participate in improving aquatic animals' growth still remains poorly understood. Therefore, further studies are imperatively needed to unravel whether dietary polyamins as putrescine, tyramine, or their derives as spermin and octopamine could involve in cell multiplication and locomotor activity that related to growth and feeding efficiency in aquatic animals. Identified metabolic compounds from synbiotic studies are summarized in Table 2.

5.4. Synbiotics provide bacterial exoenzymes and induce a host's digestive enzymes Synbiotics directly or indirectly affect digestive enzymatic activities in the intestines of aquatic animals. Synbiotic metabolisms directly activate enzyme biosynthesis in the pancreas or hepatopancreas and induce secretion of digestive enzymes into the intestines of fish and shellfish, respectively. Some previous studies proved that feeding diets incorporating a single prebiotic or probiotic could directly activate digestive enzyme activities in the

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hepatopancreas of penaeid shrimp [10,117]. Moreover, Ye et al. [32] found that a synbiotic affected enzyme biosynthesis in the pancreas or in changing the secretion pancreatic enzymes into fish intestines. This pathway is complex, and the underlying mechanism has not been fully elucidated yet. In human, it is known that regulation of pancreatic digestive enzyme secretion is controlled by intestinal hormones like cholecystokinin (CCK) produced by intestinal endocrine cells. This hormone plays important roles in appetite, satiation, and the release of pancreatic enzymes [118]. In crustaceans, proteolytic enzymes are supposedly secreted and activated in the mid-gut gland in response to stimuli produced by the ingestion of food [119]. Interestingly, feeding commercial SCFAs induced digestive enzymes such as trypsin and chymotrysin activity via lowering the pH and triggering a calcium-binding motif during enzyme activation [115,120,121]. As to indirect effects, probiotic bacteria were reported to be able to release extracellular enzymes involved in the digestion of proteins [10,122], carbohydrates [123,124], and fats [125]. In the presence of FOS and scFOS as sources of carbon, enzymes such as b-galactosidase and b-fructofuranosidase released from Lactobacillus spp. were demonstrated during synbiotic metabolism [126]. Proteases are known as enzymes that hydrolyze peptide linkages of proteins to simpler proteins, peptides, and amino acids. In probiotic bacteria, “zymogens”, known as inactive precursors of proteolytic enzymes, are converted to their active forms and are secreted into the environment by the cleavage of one or more peptide bonds via a signal-peptidedependent pathway [127,128]. Regulation of bacterial protease activity depends on transcription and translation protease gene expressions. However, changes in environmental factors like the pH, ionic strength, or temperature can also result in zymogen conversion by an autocatalytic mechanism [129]. Feeding activity is closely related to appetite, which in turn determines the amount of food intake. A synbiotic in the digestive tract can serve as a provider of exogenous enzymes and assist the process of simplifying feed macromolecules into micromolecules that can be used as sources of energy or as precursors for the synthesis of cellular components. 6. Synbiotic metabolites and immune responses of aquatic animals 6.1. Synbiotics as immunity promoters in fish Administration of synbiotics to improve immune responses and disease resistance in fish has been intensively investigated. Synbiotics have the ability to activate nonspecific and specific immune responses of fish. For the nonspecific immune response, fish fed diets incorporating synbiotics had significantly higher total leukocytes, monocytes, neutrophils, and lymphocytes [43,46,130]. The main sources of lysozymes are monocytes, macrophages, and neutrophils. Therefore, previous studies also demonstrated increased serum lysozyme activities in koi fish Cyprinus carpio [43], large yellow croaker L. crocea [30], Japanese flounder P. olivaceus [32,131], Atlantic salmon Salmo salar [44] after synbiotic dietary administration, and in striped catfish Pangasianodon hypophthalmus after probiotic treatment [132]. Protective responses of fish species can be achieved by upregulating phagocyte activity. Upregulation of phagocytic activity in fish is caused by increases in neutrophil cells and macrophages [46], resulting increases of respiratory bursts (RBs) [30,43,131] and antioxidative enzyme superoxidase dismutase (SOD) activity [43,130]. Moreover, Abid et al. [44] found that epithelial leucocytes were significantly increased in the intestines of fish, and all immune-related genes, such as interleukin (IL)-1b, tumor necrosis factor (TNF)-a, IL-8, toll-like receptor (TLR)3, and myxovirus-resistant protein (MX)-1, were upregulated in Atlantic salmon S. salar after being fed diets

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containing a synbiotic comprised of the probiotic, P. acidilactici, and the prebiotic, scFOS. Synbiotics were also reported to induce serum alternative complement pathway (ACP) activity and phenoloxidase (PO) activity in large yellow croaker and triangular bream M. terminalis [30,130]. In zebrafish D. rerio, the feeding of Ecklonia cava powder and Lac. plantarum improved the survival after Edwardsiella tarda infection by regulating the expression of inflammatory molecules as nitric oxide synthase (NOS) and cyclooxygenase 2 (COX2) [133]. As to specific immune responses, fish are capable of generating specific immunoglobulin M (IgM) antibodies after being fed synbiotics [40,130,134]. 6.2. Synbiotics induced penaeid shrimp immunity So far, few papers have reported applications of synbiotics in cultured penaeid shrimp. According to previous studies, it was found that synbiotics have the ability to trigger encapsulation and phagocytosis processes in shrimp. Li et al. [29] demonstrated that a synbiotic (Bacillus sp. and IMO) induced RBs, phagocytic activity, and PO activity of shrimp, resulting in significantly lower mortality with white spot syndrome virus (WSSV) infection. Similarly, Partida-Arangure et al. [135] reported that a synbiotic (Bacillus sp. and inulin) improved total hemocyte counts and lysozyme activity, and thereby reduced the prevalence of WSSV in white shrimp L. vannamei. In addition, a positive synergistic effect was demonstrated by increased proliferation of hemocytes, RBs, PO, lysozyme, SOD activity, and NOS activity [29,35,136,137]. Significantly lower cumulative mortality after challenge with V. alginolyticus was observed in Kuruma shrimp Penaeus japonicus after being fed diets incorporating synbiotics (Bac. licheniformis/Bac. subtilis and IMO) [35]. 6.3. Possible underlying modes of actions of synbiotics in the immune system As mentioned above, synbiotics obviously enhance the immunity of aquaculture species after administration. However, researchers in the synbiotic field are still left with the open question regarding the modes of actions of positive protection of synbiotics in aquatic animals against invaders. Most observations have been of immune parameters, while evidence of pathways of the actions is still sparse. Herein, we propose a possible mode of action potentials through which synbiotics can modulate nonspecific cellular and humoral defense mechanisms, among which the mucosal immune response is considered the first line of defense against invading pathogens. In fact, mucous membranes are in direct contact with the outside environment, and the intestinal epithelium is known as a natural barrier of the digestive tract providing defense against extrinsic invasions. During synbiotic dietary administration, the main characteristic of prebiotics is the selective stimulation of probiotic bacterial growth. Large numbers of probiotic bacteria indeed colonize on mucus membranes and prevent pathogens from adhering by competition for substrates and places of adhesion. However, the in vitro demonstrations of this phenomenon are less attention in aquaculture although most observations have been of reductions of bacterial diversity or decrease of prevalence of Vibriosis in intestines of shrimp and fish after synbiotic administrations [23,29,34,35,60,76e78,91,138]. At present, the several studies on competitive adhesion between probiotic and pathogenic bacteria have been described in human. For example, Yadav et al. [73] revealed that collagen binding protein (Cbp) from Lac. plantarum is enable to adhere into human collagen type-1 and is the major influencing factor in inhibition of enteric E. coli pathogen adhesion. In addition, oligosaccharide-binding proteins from probiotics exhibit adherence to glycans commonly found on epithelial

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cells. For instance, inulin was reported to increase the expression of F1SBPs and prevent the binding of several pathogens to intestinal surfaces [75]. On the other hand, MOS from the yeast Sac. cerevisiae is able to competitively bind mannose-specific lectin, namely FimH, of gram-negative bacteria expressing type 1 fimbriae of pathogenic bacteria, thereby reducing their adherence to mannose-containing glycoprotein receptors on intestinal epithelial cells of the host [139,140]. According to above demonstrations, it is recommended that instead of observing bacteria diversity or presence of both beneficial and pathogenic bacteria, these mechanisms should be unraveled aquatic animal models. From another aspect, most researchers believe that cell wall components of probiotic bacteria, such as b-glucan and lipopolysaccharides, contribute to the immunostimulatory effects through the presence of foreign molecules with pathogen-associated molecular patterns (PAMPs) that are recognized and bound by patternrecognition proteins (PRPs) [141]. Recently, mannose-binding lectin (MBL) that mediates cellular recognition was also reported [142]. The complementary effect of synbiotics comprised of the probiotic Enterococcus faecalis and MOS was that probiotic bacteria induced intestinal epithelial cells to secrete cytokines and modulate the functions of dendritic cells (DCs). T cells and B cells in the gut are associated with lymphoid tissues; while MOS stimulates mannose receptors and MBL by liver secretion triggering a complete cascade stimulating the immune system of rainbow trout O. mykiss [39]. Of interest, synbiotic metabolites may affect the immune system of aquatic animals. In fact, amino acids are key factors regulating activation of T lymphocytes, B lymphocytes, natural killer cells, and macrophages, as well as lymphocyte proliferation, and the production of antibodies, cytokines, and other cytotoxic substances [143,144]. In addition, several recent reports in aquaculture species assumed that expressions of immune related-genes as major histocompatibility complex class IIa (MHCIIa), complement component 3 (C3), IgM, colony-stimulating factor receptor-1 (CSF-1R), nonspecific cytotoxic cell receptor protein-1 (NCCR-1), hepcidin (Hep), T-cell receptor b (TCR-b), TLR3, IL-1, IL-1b, IL-8 and TNF-a and INF-g were up-regulated after synbiotic dietary [22,44,134,145,146]. However, which synbiotic metabolite involves in this regulation is still unknown in aquaculture. Meanwhile, in human, Lee and Hase [90] reported that butyrate and niacin (vitamin group B) suppress the proliferation of cancerous epithelial cells, and simultaneously induce transforming growth factor (TGF)b secretion by epithelial cells. Butyrate and niacin are bound by receptor GPR109a expressed on epithelial cells to trigger production of the cytoprotective cytokine, IL-18, and stimulate DCs and macrophages to produce the cytokine, IL-10, thereby enhancing immunity. This mechanism coincides with those reported in succinate [147]. Furthermore, the synbiotic metabolite, putrescine, has a major impact on neuronal integrity and cerebral homeostasis during immune insults. In mouse, the decrease in putrescine levels largely prevents the ability of LPS to trigger tumor necrosis factor (TNF)-a and TLR2 gene transcription that cause activation of macrophages, leading to increased respiratory activity, phagocytosis, and nitric oxide production [148,149]. Interestingly, the regulatory role of polyamines in cellular innate immune response of fish has been observed in vitro. In this investigation, head-kidney leucocytes of gilthead seabream S. aurata were incubated with putrescine (0.005 and 0.0025%) showed an increase in respiratory burst, phagocytic ability and immune-related gene expression (including C3, MHCIa, cluster of differentiation 8 (CD8), IgM and Hep) [150]. Therefore, we expected that future studies in this direction using aquatic animal models will provide the key understanding the biochemical dialogues between synbiotic metabolites and aquatic animals' immune system.

7. Concluding remarks and perspectives Since they were first realized and used in aquaculture in 2005, synbiotics have been used to promote growth and immune systems of aquatic animals. Synbiotics change intestinal bacterial communities and enhance colonization. Their metabolism promotes health benefits through enhancing immune responses, thereby lowering the cumulative mortality after a challenge with various pathogens. Although many studies have been carried out on applications of synbiotics in aquaculture, the modes of actions of synbiotics in improving growth and immune responses are still unclear. The mechanisms of actions of synbiotics have been widely documented in humans and other mammals. We imperatively need to evaluate how in vitro selected prebiotics support the growth of probiotics for aquaculture use. In addition, the structures of prebiotics, and the dose and colonization ability of probiotic bacteria must be primarily considered. Molecular studies are also required to assess the mechanisms by which bioactive compounds from synbiotics exert their activities in vivo in aquaculture. We expect that further understanding of the pathways of synbiotic metabolic compounds in enhancing the growth and health of aquatic animals will be an important step forward. Practically, it is assumed that using the purified commercial prebiotics for developing the synbiotics may increase the feed costs in intensive aquaculture. Therefore, we recommend that extracts from plants, e.g. copra meal, sweet potato, seaweed etc, with prebiotic characteristics should be continuously screened for farming practices in the further works. To our best knowledge, this is the first paper to review and propose advanced mechanisms of synbiotics and their perspectives for improving the growth performance and immunity of aquatic animals. Acknowledgement Heartfelt gratitude is expressed to the Ministry of Education of Taiwan for providing a scholarship to the first author. References [1] FAO, Aquaculture Department, in Brief the State of World Fisheries and Aquaculture 2016, Food and Agriculture Organization of the United Nations, Rome, 2016, p. 8. [2] T.P. Nguyen, On-farm feed management practices for striped catfish (Pangasianodon hypophthalmus) in Mekong River Delta, Viet Nam, Fisheries and Aquaculture Technical Paper No. 583, in: M.R. Hasan, M.B. New (Eds.), Onfarm Feeding and Feed Management in Aquaculture, Food and Agriculture Organization (FAO), Rome, 2013, pp. 241e267. [3] L.T. Hung, O.M. Quy, On farm feeding and feed management in whiteleg shrimp (Litopenaeus vannamei) farming in Vietnam, Fisheries and Aquaculture Technical Paper No. 583, in: M.R. Hasan, M.B. New (Eds.), On-farm Feeding and Feed Management in Aquaculture, Food and Agriculture Organization (FAO), Rome, 2013, pp. 337e357. [4] C. Suzer, D. Coban, H.O. Kamaci, S. Saka, K. Firat, O. Otgucuoglu, H. Kucuksari, Lactobacillus spp. bacteria as probiotics in gilthead sea bream (Sparus aurata, L.) larvae: effects on growth performance and digestive enzyme activities, Aquaculture 280 (2008) 140e145. [5] S. Torrecillas, A. Makola, T. Benítez-Santana, M.J. Caballeroa, D. Monteroa, J. Sweetmanb, M. Izquierdo, Reduced gut bacterial translocation in European sea bass (Dicentrarchus labrax) fed mannan oligosaccharides (MOS), Fish Shellfish Immunol. 30 (2011) 674e681. [6] J. Zhang, Y. Liu, L. Tian, H. Yang, G. Liang, D. Xu, Effects of dietary mannan oligosaccharide on growth performance, gut morphology and stress tolerance of juvenile Pacific white shrimp, Litopenaeus vannamei, Fish Shellfish Immunol. 33 (2012) 1027e1032. [7] S.H. Hoseinifar, M. Khalili, H.K. Rostami, M.A. Esteban, Dietary galactooligosaccharide affects intestinal microbiota, stress resistance, and performance of Caspian roach (Rutilus rutilus) fry, Fish Shellfish Immunol. 35 (2013) 1416e1420. [8] H.D. Huu, C.M. Jones, Effects of dietary mannan oligosaccharide supplementation on juvenile spiny lobster Panulirus homarus (Palinuridae), Aquaculture 432 (2014) 258e264. [9] S.H. Hoseinifar, Z. Roosta, A. Hajimoradloo, F. Vakili, The effects of Lactobacillus acidophilus as feed supplement on skin mucosal immune parameters,

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