Probiotics in valorization of innate immunity across various animal models

journal of functional foods 14 (2015) 549–561

Available online at www.sciencedirect.com

ScienceDirect j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / j ff

Probiotics in valorization of innate immunity across various animal models Seema Patel a, Rishikesh Shukla b, Arun Goyal c,* a Bioinformatics and Medical Informatics Research Center, San Diego State University, San Diego, CA 92182, United States b Lignocellulose Biotechnology Laboratory, Department of Microbiology, University of Delhi South Campus, New Delhi 110021, India c Department of Biotechnology, Indian Institute of Technology Guwahati, Guwahati, Assam 781 039, India

A R T I C L E

I N F O

A B S T R A C T

Article history:

Immunity is the ability of the body to counteract pathogenic invasions. Dearth of it com-

Received 26 September 2014

promises health and survival, rendering its retention and escalation to be of paramount

Received in revised form 11

importance. In this regard, probiotics, the live microorganisms that offer health benefits by

February 2015

modulating gut microbiota and reinforcing host immunity, have proven to be very crucial.

Accepted 13 February 2015

Probiotics along with their effector molecules have been demonstrated to confer immuno-

Available online

regulatory, anti-angiogenesis, anti-allergic, anti-colitis and anti-dermatitic activities, among others. Interaction between probiotics and immune cells are vital for mucosal tissue ho-

Keywords:

meostasis and innate immunity. Ample evidences have accumulated in recent times,

Probiotics

supporting these findings. The major in vitro, in vivo and clinical trial findings have been

Functional food

summarized here. How nutritional interventions with probiotics can bolster innate immu-

Immunomodulator

nity is the focal point of discussion. The immunological mechanisms of probiotic action in

Innate immunity

mucosal architecture restoration and pathogen elimination have been explained. Augmen-

Adaptive immunity

tation of probiotics by pairing with prebiotics has been briefly analyzed. The revolutionizing

Prebiotics

power of personalized probiotics in healthcare has been furnished in a nutshell. Probiotics have already been established as important components of functional foods. This review provides the immunomodulatory aspect of probiotics in appreciating their potentials, and discerning deficiencies. © 2015 Elsevier Ltd. All rights reserved.

Contents 1. 2.

Introduction ...................................................................................................................................................................................... Immunomodulatory effect of probiotics across models ........................................................................................................... 2.1. In vitro ...................................................................................................................................................................................... 2.2. Fish .......................................................................................................................................................................................... 2.3. Poultry ..................................................................................................................................................................................... 2.4. Mouse ......................................................................................................................................................................................

550 550 550 552 553 553

* Corresponding author. Department of Biotechnology, Indian Institute of Technology Guwahati, Guwahati, Assam 781 039, India. Tel.: +91 361 2582208; fax: +91 361 2582249. E-mail address: [email protected] (A. Goyal). http://dx.doi.org/10.1016/j.jff.2015.02.022 1756-4646/© 2015 Elsevier Ltd. All rights reserved.

550

3. 4. 5. 6.

1.

journal of functional foods 14 (2015) 549–561

2.5. Pig ............................................................................................................................................................................................ 2.6. Monkey ................................................................................................................................................................................... 2.7. Human .................................................................................................................................................................................... Mechanisms involved ...................................................................................................................................................................... Synergy with prebiotics .................................................................................................................................................................. Future scopes .................................................................................................................................................................................... Conclusion ........................................................................................................................................................................................ Conflict of interest ........................................................................................................................................................................... References .........................................................................................................................................................................................

Introduction

Probiotics by now is a very familiar name in the nutraceutical as well as pharmaceutical sector. This term encompasses live, generally recognized as safe (GRAS) microbes, on ingestion of which in adequate amounts, the consumer is bestowed with robust health (Chiu et al., 2013). Probiotics have been validated to improve antioxidant status, augment immune defense against viral infections and tumors and boost gastrointestinal barrier functionality (Touchefeu et al., 2014; Vieira, Teixeira, & Martins, 2013). Altered microbiota (dysbiosis) causes gastrointestinal disorders and triggers many inflammatory bowel diseases such as ulcerative colitis, necrotizing enterocolitis and Crohn’s disease (Henao-Mejia et al., 2012; Müllner, Miheller, Herszényi, & Tulassay, 2014; Vujkovic-Cvijin et al., 2013). Probiotics have been demonstrated to restore the gut homeostasis (Vieira et al., 2013). Their ameliorative significance in cancer prophylaxis and therapy has been extensively studied and reviewed (Patel & Goyal, 2013). Beneficial effects of probiotics on non-alcoholic fatty liver disease by reinforcement of intestinal integrity, reduction of colonic lipopolysaccharides (LPS) level and regulation of the immune system has been reviewed (Mohammadmoradi, Javidan, & Kordi, 2014). Probioticssupplemented alteration of gut microbial and the consequence on gut hormones, inflammatory markers and obesity control has been appraised (Baboota et al., 2013). Dominant probiotic genera are Lactobacillus, Lactococcus, Bifidobacterium, and Saccharomyces. Several species of Pediococcus, Propionibacterium, Oenococcus, Bacillus, Faecalibacterium and Enterococcus are emerging as probiotic candidates (Foligné et al., 2010; Franz, Huch, Abriouel, Holzapfel, & Gálvez, 2011; Le Maréchal et al., 2015; Lee, Kim, Choi, & Paik, 2013; Miquel et al., 2013; Park & Kim, 2014). The popularity of probiotic functional foods is rising in unprecedented manner in keeping with the consumer awareness regarding their beneficial effects. Market share analysis has revealed that a 60–70% of total functional food market is occupied by probiotic products (Tripathi & Giri, 2014). This trend is likely to continue further in the wake of alarming emergence of metabolic and degenerative diseases. Despite their wide spectrum therapeutic benefits, the impact of probiotics on consumer immune profile is yet to be precisely comprehended. Before diving into the correlation between probiotics and immunity, it is crucial to garner fair knowledge about phenotypes of the latter. Immunity can be broadly ramified into innate and adaptive (acquired). Innate immunity is the first-line of defense against colonization of pathogens.

554 554 555 555 556 556 558 558 558

It detects intracellular pathogens through pattern recognition receptors, triggers intracellular signaling, stimulates gene expression and eradicates them (Rasmussen, Reinert, & Paludan, 2009). Perturbation in innate immunity can provoke its deficiency, hyperactivity or autoimmunity, mechanisms underlying a host of diseases such as inflammation, cancer, allergy, and autoimmune diseases (Pothlichet & Quintana-Murci, 2013). Adaptive immunity expresses antigen receptors on T and B lymphocytes. In response to antigens, these lymphocytes get activated and undergo clonal expansion. Induction of adaptive immunity relies on direct antigen recognition by the antigen receptors as well as essential signals transmitted by the innate immunity (Schenten & Medzhitov, 2011). In this review, probiotics as modulators of innate immunity have been explored, but both innate and adaptive immunity being tightlycoupled the latter has also been discussed when required. A convincing literature search has been performed to shed light on the effects of probiotics on immunity of various organisms.

2. Immunomodulatory effect of probiotics across models Animal models are the ideal prototypes for evaluating the manipulation of immunity by probiotics. So, the potency of probiotics in modulating immune landscapes in various vertebrate organisms, starting from fish to humans, has been summarized here. The cross-talk between these beneficial bacteria and the host organism innate immunity has been discussed. In vitro assays are easy to perform and are effective models to furnish insights on biological mechanistic, so they have been examined as well. Researchers have shown considerable interest in the strainspecific immune modulation by probiotics. It has been observed that lactobacillus strains promote T helper 1 (Th1) cytokines, whereas bifidobacterial strains elicit anti-inflammatory cytokines (by regulating MAPK and NF-kB pathways) (Dong, Rowland, & Yaqoob, 2012). The above finding demonstrates the differential cytokine production characteristics of distinct probiotic strains. Table 1 presents information supporting the above statement.

2.1.

In vitro

In last few years, many in vitro studies have validated the immune-stimulatory properties of probiotics. Ghadimi et al.

551

journal of functional foods 14 (2015) 549–561

Table 1 – Probiotic strains with their immunological functions in vitro and various animal models. Probiotic strains

In vitro/animal model

Immunological function

Reference

Lactobacillus rhamnosus GG Lactobacillus rhamnosus CRL1505 Lactobacillus rhamnosus CICC 6141 Lactobacillus gasseri PA16/8 Lactobacillus crispatus Lactobacillus plantarum06CC2 Lactobacillus plantarum VSG3 Lactobacillus plantarum DK119 Lactobacillus plantarum 299v Lactobacillus plantarum WCFS1 Lactobacillus plantarum NC8-pSIP409 Lactobacillus plantarum NC8-pSIP409 Lactobacillus acidophilus NCFM Lactobacillus acidophilus IMV B-7279 Lactobacillus acidophilus LA-5 Lactobacillus delbrueckii subsp. bulgaricus IMVB-7281 Lactobacillus casei IMV B-7280 Lactobacillus casei CRL 431 Lactobacillus salivarius UCC118 Lactobacillus delbrueckii ssp. Bulgaricus OLL1073R-1 Lactobacillus paracasei

In vitro Fish Poultry Mouse Pig Macaque Human

Ghadimi et al., 2008 Rizzo et al., 2013 Takeda et al., 2013 Giri et al., 2013 Talpur et al., 2014 Ahmed et al., 2014 Wang et al., 2012 Mokrozub et al., 2012 Chiba et al., 2013 Kato-Mori et al., 2010 Park et al., 2013 Smelt et al., 2013 Kano et al., 2013 Kim, Kim et al., 2013 Kim, Park et al., 2013 Aragón et al., 2014 Shi et al., 2014 Vlasova et al., 2013 Chattha et al., 2013 Klatt et al., 2013 Rask et al., 2013 Ericson et al., 2013 Bertelsen et al., 2014 Qin et al., 2013

Lactococcus lactis BFE920 Lactococcus lactis spp. lactis Lactococcus lactis MG1363 Lactococcus lactis JCM5805

Fish Mouse

Bifidobacterium bifidum MP20/5 Bifidobacterium longum (SP07/3) Bifidobacterium animalis subsp. lactis Bifidobacterium lactis Bi-07 Bifidobacterium lactis Bb12 Bifidobacterium animalis VKL Bifidobacterium animalis VKB Bifidobacterium infantis35624

In vitro Mice Pig Human

Bacillus coagulans Bacillus subtilis B10 Bacillus pumilus Bacillus licheniformis Bacillus circulans

In vitro Fish Poultry

Pediococcus acidilactici MA18/5M

Fish

Propionibacterium freudenreichii

Mouse

Enterococcus faecium

Poultry

Faecalibacterium prausnitzii A2-165 S. boulardii S. cerevisiae

Mouse Poultry Rats Human

Inhibit Th2-cytokines (IL-4 and IL-5) from allergens and enhanced the stimulation of IFN-γ Protect from Candida albicans infection through modulation of TLR2/4, IL-8 and human β-defensin 2 and 3 Elevate the level of IL-12 and IFN-γ Improve phagocytosis Resist Aeromonas hydrophila Increase serum IgM concentration and inhibit the proliferation of E. coli Increase fecal bifidobacteria and lactobacilli Boost the activity of phagocytic cells and increased interferon production Attenuate Th2 reactions associated with RSV challenge Eliminate listeria from spleen and liver Elevate CD4+ and CD8+ T-cell counts Inhibit the development of dermatitis and the elevation of inflammation marker, serum amyloid A Delay tumor development by modulation of immune response Stimulate AttHRV vaccine Boost NKT cell population Lower the risk of atopic eczema and rhinoconjunctivitis in infants Enhance fecundity and improve offspring immunity during early developmental stages Protect from Streptococcus iniae by increasing IL-12 and IFN-γ level Improve innate immune response Decrease the expression of GATA-3 and T-bet in the gut lamina propria Increase the ability to produce IFNs Inhibit IL-4 and IL-5 from pathogens and enhance the stimulation of IFN-γ Stabilize cytokine pattern produced by GALT Increase fecal bifidobacteria and lactobacilli Boost the activity of phagocytic cells Elevate CD4+ and CD8+ T cells, IFN-γ and IL-12 Stimulate AttHRV vaccine and reduce viral shedding Reduce NF-α and IL-6 secretion by peripheral blood mononuclear cells Minimize risk of atopic eczema and rhinoconjunctivitis in infants Show bactericidal activity Up-regulate gene expression levels of MHC-II, CD40, CD80 and CD86, improvement of TLR expressions Improve hematocrit values and leukocytic counts Protect from V. vulnificus infection Enhance innate immunity Increase serum IgM concentration and inhibit the proliferation of E. coli Elevate leucocyte, neutrophils and monocytes levels Lower bacterial load in mucosa Stimulate the function of innate immune system, eliminate listeria and improve CD4+ and CD8+ T-cell counts Increase serum IgM concentration and inhibit the proliferation of E. coli Protect against TNBS-induced colitis Ameliorate the immunosuppressive effect of Trypanosoma infections Reduce severity of diarrhea and Clostridium difficile infection Improve mucosal immunity Increase serum IgM concentration and inhibit the proliferation of E. coli

Kim, Beck et al., 2013 Geraylou et al., 2013 Smelt et al., 2013 Sugimura et al., 2013

Ghadimi et al., 2008 Hidalgo-Cantabrana, Nikolic et al., 2014 Wang et al., 2012 Mokrozub et al., 2012 Shao et al 2013 Chattha et al., 2013 Groeger et al., 2013 Bertelsen et al., 2014

Pan et al., 2013 Rajput et al., 2013 Aly et al., 2008 Pan et al., 2013 Zhang et al., 2013 Ahmed et al., 2014

Standen et al., 2013 Abid et al., 2013 Kato-Mori et al., 2010 Ahmed et al., 2014 Miquel et al., 2013 Eze et al., 2012 Kelesidis, 2012 Rajput et al., 2013 Ahmed et al., 2014

552

journal of functional foods 14 (2015) 549–561

(2008) assessed the effect of different probiotics on the proinflammatory Th1 (IFN-γ, TNF-α, IL-6) and anti-inflammatory Th2 (IL-4, IL-5, IL-13) responses of peripheral blood mononuclear cells (PBMC) derived from patients allergic to enterotoxin A and dust mite. The probiotic strains (Lactobacillus rhamnosus GG, Lactobacillus gasseri PA16/8, Bifidobacterium bifidum MP20/5 and Bifidobacterium longum SP07/3) and their genomic DNA inhibited Th2-cytokines (IL-4 and IL-5) and enhanced the stimulation of IFN-γ in the patients. Also, Bifidobacterium adolescents B-2458 and Bifidobacterium longum subsp. infantis GB1496 isolated from human breast milk augmented Th1 and attenuated Th2 cytokine production from human PBMC cells (Chiu, Tsai, Lin, Chotirosvakin, & Lin, 2014). Bacillus coagulans possesses bactericidal activity against the pathogens Staphylococcus aureus, Streptococcus agalactiae, Escherichia coli, Klebsiella oxytoca, Pseudomonas aeruginosa and Vibrio vulnificus (Pan, Wang, & Chen, 2013). These pathogens weaken host immunity by exerting cytotoxicity and by releasing pro-inflammatory mediators. It was observed that Lactobacillus crispatus ATCC 33820 promotes human epithelial carcinoma HeLa cell defense against Candida albicans infection through the involvement of tolllike receptor TLR2/4, IL-8 and human β-defensin 2 and 3 (Rizzo, Losacco, & Carratelli, 2013). TLRs are innate immunity receptors capable of conserved pathogen motif recognition. It was demonstrated that Saccharomyces boulardii and Bacillus subtilis B10 modulate immunological functions of chicken bone marrow dendrite cells (chi-BMDCs) by targeting TLRs (TLR1, TLR2, TLR4, TLR15), up-regulating gene expression of MHC-II, CD40, CD80 and CD86 and altering the level of other associated factors (NFκB, IL-1β, IL-17, IL-4, IL-10, IL-8, INF-γ and transforming growth factor β (TGF-β) (Rajput et al., 2013). The proliferation and cytokine production by gut-associated lymphoid tissue (GALT) and PBMC of rats in the presence of the three isogenic Bifidobacterium animalis subsp. lactis strains as well as their purified polymers was investigated (Hidalgo-Cantabrana, Nikolic et al., 2014). The cytokine pattern was stable in the presence of strains and their polymers. Also, they activated blood monocytes as well as T lymphocytes towards a mild inflammatory Th1 response. Lactobacillus plantarum 06CC2 strain prepared from Mongolian dairy products was effective in elevating the level of IL-12p40 in co-culture with mouse macrophage-like J774.1 cell line and the levels of IL-12 and IFN-γ in co-culture with mouse spleen cells (Takeda et al., 2013). IL-12p40 is a component of IL-12 and IL-23, serving as a chemo-attractant and involved in pathogenic immune responses (Chen et al., 2013). Propionibacterium freudenreichii ssp. shermanii JS elicited IL-8 from human colon adenocarcinoma HT-29 cell line (HidalgoCantabrana, Kekkonen et al., 2014). The chemokine IL-8 acts as chemotactic factor and plays a role in the inflammatory cascade of innate immunity.

2.2.

Fish

Probiotics are well-documented to enhance the immune status and improve disease resistance of fish. The bolstered immunity promotes digestibility, stress tolerance and fecundity. Consequently, the usage of probiotics as feed additives in aquaculture is a common practice (Martínez Cruz, Ibáñez, Monroy Hermosillo, & Ramírez Saad, 2012). The potential benefit of Bacillus pumilus and a commercial product (‘Organic Green’™) in

the culture of tilapia was evaluated (Aly, Mohamed, & John, 2008). Post-administration significant changes in hematocrit values, total leukocyte counts (TLC) and differential leukocyte counts (DLC) were observed in the treated groups. The body weight and survival rates of the treated fish were significantly higher. Lactococcus lactis BFE920-fed olive flounder group was protected from Streptococcus iniae challenge with a 66% survival rate (Kim, Beck et al., 2013). The pathogenic resistance was attributed to flounder’s innate immunity activated by the probiotic strain. The administration led to increased lysosomal activity with subsequent phagocytosis and production of IL-12 and IFNγ. Results indicated that this strain of Lactococcus lactis could be developed as a functional feed additive for olive flounders. Grouper and zebrafish were fed with Bacillus coagulans mixed with 50 g of eel powder for 30 days. The treatment significantly reduced mortality at 24, 48, 72, and 96 h after infection with Vibrio vulnificus. It came forth that the probiotic supplementation enhances the expression of immune-related genes and protects the treated-fish against the pathogenic invasion (Pan, Wang, & Chen, 2013). Up-regulation of genes encoding the myeloid differentiation factor (MyD88), IL-1β, TNF-2, IL-1β in groupers, and TLR-4, TNF-α, TRAM 1, NF-κB in zebrafish were unravelled to be the mechanism. The probiotic effect of Pediococcus acidilactici on Nile tilapia was evaluated, with emphasis on gut health, growth rate, feed utilization and hematological parameters (Standen et al., 2013). Six weeks supplementation led to higher density of intraepithelial leukocytes in the intestine as well as higher level of goblet cells (known to secrete the protective mucin glycoproteins). Further, an increased level of circulating neutrophils and monocytes were observed. The effect of a diet comprising of Pediococcus acidilactici MA18/5M and short-chain fructooligosaccharide (FOS) on Atlantic salmon gut health was determined (Abid et al., 2013). Significant attenuation in the total bacterial levels in the anterior mucosa, posterior mucosa and posterior digesta of the symbiotic-fed fish was observed in the synbiotic diet when administered for 63 days. Compared to the control-fed fish, the mucosal fold length and the infiltration of epithelial leukocytes were significantly higher in the anterior and posterior intestine of the synbiotic group. Real-time PCR demonstrated that all of the investigated immune genes were significantly upregulated in the anterior and posterior intestine of the symbioticfed salmon, compared to the control group (Abid et al., 2013). The serum lysozyme level (a manifestation of macrophage activity) was significantly higher in the symbiotic-fed fish. It was inferred that the synbiotic modulation of the gut microbiota has a protective action on the intestinal mucosal cells, which stimulates the innate immune response. The effects of dietary doses of L. plantarum VSG3 on the growth performance, immunity, and disease resistance of rohu juveniles against Aeromonas hydrophila infection was evaluated (Giri, Sukumaran, & Oviya, 2013). After 60 days of feeding, significant improvement in specific growth rate and feed utilization efficiency of the fish was recorded. The intervention increased the serum lysozyme, phagocytosis, respiratory burst activity and superoxide dismutase (SOD) activity. It was shown that the combination of 1 × 107 cfu g/l B. licheniformis and 0.3% FOS enhances innate immunity and antioxidant status of triangular bream (Zhang et al., 2013). The effect of administration of putative endogenous probiotics L. lactis ST G45 with 2% arabinoxylan-oligosaccharides (AXOS) in juvenile

journal of functional foods 14 (2015) 549–561

Siberian sturgeons was investigated (Geraylou et al., 2013). After four weeks, growth performance and feed conversion ratio significantly improved in the symbiotic blend-fed fish. Innate immune responses of fish were increased, manifested in higher ACP activities. AXOS improved the proliferation of L. lactis strain. The efficacy of Lactobacillus rhamnosus CICC 6141 in augmenting the offspring immunity of zebrafish was reported (Qin et al., 2013). The effects of commercially-available probiotics and prebiotics on growth, blood and immunity profile of snakehead murrel fingerlings against the pathogen Aeromonas hydrophila was evaluated (Talpur, Munir, Mary, & Hashim, 2014). On nurturing the fish with six different diets comprising Lactobacillus acidophilus, yeast, β-glucan, galacto-oligosaccharide (GOS) and mannan-oligosaccharide (MOS) for 12 weeks followed by intraperitoneal introduction of A. hydrophila, improved growth was observed. The fish showed substantial increase in weight, protein efficiency ratio, feed conversion ratio and reduced mortality rate. The hematological and immunological parameters and resistance towards pathogens were significantly improved.

2.3.

Poultry

As consumer and governmental demand to reject antibiotics for poultry production picks momentum, the use of probiotics as substitute finds favor. The advantages of probiotics on poultry range from improved metabolism, immuno-stimulation, antiinflammatory status to elimination of pathogens. Also, the healthful carcass enhances nutrient absorption and lowers the risk to consumers (Edens, 2003). The effect of S. boulardii and B. subtilis B10 on ultra-structure modulation and mucosal immunity development in broiler chickens was evaluated through a randomized study (Rajput et al., 2013). The response elicited by probiotics administered for 72 days was compared with that of antibiotic virginiamycin (used to inhibit Clostridium perfringenes, the etiologic agent of necrotic enteritis). A significant improvement in the body weight, mass of bursa of Fabricius and thymus, intestinal villi dimensions, and number of goblet cells was observed in probiotic-supplemented groups. Modification in the intestinal composition and increased mRNA expression levels of occludin, claudin2, claudin3 (key proteins of tight junctions) and increased IgA-positive cells in the jejunum were observed. The effect of probiotics-fermented Japanese lemon by-products for their immune-stimulatory potential in poultry was assessed (Ahmed et al., 2014). The fermentation product of S. cerevisiae, E. faecium, L. acidophilus, and B. subtilis, when administered at 5 g/kg dose, significantly increased body weight and average daily feed intake of broiler during the experimental period. Serum IgM concentration was significantly elevated and at a dose of 20 g/kg, it significantly inhibited the proliferation of E. coli without affecting the lactobacillus or bacillus spp. population.

2.4.

Mouse

Most significant findings on immunomodulation by probiotics have been obtained from mice models. Fermented milkfortified with 2 probiotic strains, B. lactis Bi-07 and L. acidophilus NCFM, and a prebiotic, isomaltooligosaccharide (IMO) when administered to mice, exerted biological effects (Wang et al., 2012). The fecal enterobacilli were found significantly decreased,

553

whereas fecal bifidobacteria and lactobacilli were increased. The synbiotic milk showed promise to be implicated in intestinal health and humoral as well as cell-mediated immunity of consumers. The immunomodulatory properties of L. delbrueckii subsp. bulgaricus IMVB-7281, L. casei IMV B-7280, L. acidophilus IMV B-7279, B. animalis VKL and B. animalis VKB strains on the mice models of staphylococcus infection were determined (Mokrozub et al., 2012). The treatment restored the phagocytic activity and increased the endogenous interferon production. It was reported that S. cerevisiae supplementation is capable of bolstering immune defense against Trypanosoma brucei brucei in rats, by abating parasitemia (Eze et al., 2012). The treatment of 3 week old BALB/c mice with L. rhamnosus CRL1505 significantly reduced lung viral loads and ameliorated tissue lesions after the exposure to respiratory syncytial virus (RSV) (Chiba et al., 2013). The protective effect was traced down to the capacity of the strain to differentially modulate respiratory antiviral immune response. The antiinflammatory cytokines IFN-γ and IL-10 secreted in response to the probiotics was assumed to modulate the pulmonary innate immune profile, with the resultant attenuation of the damaging Th2 reactions associated with RSV challenge. Fermentation metabolites of L. gasseri and P. freudenreichii stimulated the function of innate immune system, promoting the elimination of L. monocytogenes from spleen and liver of mice (Kato-Mori et al., 2010). Elevation in CD4+ and CD8+ T-cell counts was elucidated to be the underlying mechanism. Thymosin alpha-1 (Tα1) is a peptide fragment capable of immunity reconstitution (Tuthill, Rios, & McBeath, 2010). In order to improve its administration convenience, a human Tα1 gene-transformed B. longum (BL-Tα1) was constructed and its effect on mice immunity was investigated (Shao et al., 2013). The results showed that the CD4+ and CD8+ T-cells in thymus and spleen of BL-Tα1 group were significantly elevated. Also, the IFN-γ and IL-12 concentration in serum of BL-Tα1 group was improved. The potential of L. plantarum DK119 isolated from the fermented Korean cabbage in inhibiting influenza virus in mice was evaluated (Park et al., 2013). The strain conferred 100% protection against subsequent lethal infection with influenza A virus, reducing the lung viral burden. The treatedmice had high levels of IL-12 and IFN-γ in bronchoalveolar lavage fluids, and a low degree of inflammation upon infection with the virus. Alteration of dendritic and macrophage cell innate immunity and cytokine production pattern appeared to be the possible mechanisms by which the probiotic strains tackled the virus infection. The invigorating effect of L. plantarum WCFS1, L. salivarius UCC118, and L. lactis MG1363, on the intestinal regulatory phenotype in healthy mice was investigated (Smelt et al., 2013). L. salivarius UCC118 tilted the balance towards regulatory phenotype in the small intestine lamina propria and activated both CD4+ and CD8+ T-cells in the large intestinal lamina propria. Contrary to it, L. plantarum WCFS1 skewed the balance towards regulatory phenotype in the large intestinal lamina propria and decreased the Th1/Th2 ratio in small intestinal lamina propria. However, to a moderate degree, L. lactis MG1363 also displayed immunomodulatory effects and decreased the expression of the trans-acting T-cell-specific transcription factor (GATA-3) and T-box transcription factor (Tbet) (proteins known to regulate the CD4+ T-cell Th1/Th2 cell fate decision) in the lamina propria. It was demonstrated that

554

journal of functional foods 14 (2015) 549–561

feeding C75BL/6 mice infant with kefir reduces Giardia intestinalis infection and promotes the activation of humoral and cellular immunity impaired by parasitic infection (Franco et al., 2013). Increment in the expression of IFN-γ was observed in the lamina propria of mice receiving kefir for 14 days. Oral administration of L. plantarum 06CC2 strain prepared from Mongolian dairy products augmented the gene expression of IFN-γ and IL12p40 and proliferated the population of CD4+, CD25+, and CD49b+ T-cells in the spleens of mice. Also, it significantly elevated the gene expression of IL-12 receptor β2 as well as IL12p40 and IFN-γ in Peyer’s patches. Thus, oral administration of this strain is deemed effective in inducing Th1 cytokine production activating the Th1 immune response associated with intestine (Takeda et al., 2013). The ingestion of heat-killed L. delbrueckii ssp. bulgaricus OLL1073R-1 strains was shown to inhibit both the development of dermatitis and the elevation of an acute inflammation marker, serum amyloid A in NC/ Nga mice (Kano, Kita, Makino, Ikegami, & Itoh, 2013). The crucial role of IL-6 in the development of dermatitis by sensitizing the keratinocytes and suppressive effect of this strain was discovered. The inhibitory effects of L. sakei probio 65 isolated from kimchi on induced-atopic dermatitis in NC/Nga mice was investigated (Kim, Beck et al., 2013). Oral administration of viable or heat-attenuated strain healed the skin lesions and reduced scratching frequency. Serum levels of IgE and cutaneous T-cellattracting chemokine (CTACK) were significantly decreased. The high serum CTACK levels is a hallmark of inflammatory skin ailments such as atopic dermatitis and psoriasis vulgaris (Kakinuma et al., 2003). Even the heat-killed strains were capable of decreasing IL-4 and IL-6 serum concentrations, the cytokines involved in dermatitis progression. It was investigated whether L. rhamnosus can confer immune-benefits to asthmatic mice (Kim, Beck et al., 2013). Allergic asthma is associated with the adoptive transfer of dendritic cells and regulatory T cells (Tregs). However, evidences of innate immunity components (bronchial epithelial cells, alveolar macrophages and TLRs) in asthma pathogenesis are surfacing (Suarez, Parker, & Finn, 2008). On oral or intravenous treatment with the strain, bronchial hyperresponsiveness, total cell counts in the bronchoalveolar lavage fluid, production of IgE, and pulmonary eosinophilic inflammation were suppressed. It came forth that Tregs suppresses the Th2 response in the respiratory organs mediated by dendritic cells. Administration of Faecalibacterium prausnitzii A2165 and its culture supernatant to mice protected them against 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced colitis (Miquel et al., 2013). The beneficial effect was explained as the balanced immunity in the intestine. Lactobacillus rahmanosus CRL1505 supplementation to malnourished mice could restore bone marrow from Streptococcus pneumonia infection, manifested in increased myeloid progenitors and mobilization of granulocytes (Herrera, Salva, Villena, Barbieri, & Alvarez, 2013). Toomer et al. (2014) observed that mice fed with probiotics diet (Primalac 454 Feed Grade Microbials) increased the splenic naturally-occurring and induced Tregs, enhanced TGFβ gene expression and reduced the expression of allergic mediator IL13. The effect of L. casei CRL 431-fermented milk on a murine breast cancer model was evaluated (Aragón, Carino, Perdigón, & de Moreno de LeBlanc, 2014). The fermented product moderated angiogenesis and delayed the onset of tumor by circumventing the immune response. Mice immunized with

a recombinant L. plantarum NC8-pSIP409-hemagglutinin strain elaborated IgA, IgG antibodies and induced CD8+ T-cell immune responses (Shi et al., 2014). Also, it offered protection against mouse-adapted H9N2 influenza A virus. The results implied that such recombinant probiotic strain with both innate and adaptive immunity-eliciting potency could be developed as an oral vaccine candidate against avian influenza. The oral administration of Lactobacillus helveticus HY7801 impeded collagen-induced arthritis progression in mice model by manipulating the underlying immunological mechanism. The probiotic strain reduced the antigen specific IgG levels and resultant inflammatory cascade. Moderation of the collageninduced pro-inflammatory process and elevation of IL-10 expression mainly in CD4+ T cells was delineated as the underlying mechanism. The study implied that myeloid CD11c+ dendritic cells might be mediating the probiotics-mediated immune modulation (Kim et al., 2015). Role of the CD11c+ cells in amelioration of autoimmune diseases by increased IL-10 production has been already validated (Min et al., 2006).

2.5.

Pig

The effects of colonizing virulent human rotavirus (HRV)infected gnotobiotic (asceptic born, germ-free) pigs with L. rhamnosus GG and B. lactis Bb12 were assessed (Vlasova et al., 2013). Euthanizing the animals followed by immunological analysis revealed the immune-maturation potential of the probiotic combination. The elevated frequency of CD4+, SWC3a, CD11R1 and MHCII-expressing antigen-presenting cells in the intestinal tissues and blood reflected the immunostimulation ability of the probiotics on the attenuated HRV vaccine. It was inferred that the probiotics regulate immune homeostasis and moderate HRV diarrhea by differential TLR expression of plasmacytoid and conventional dendritic cells. Further, the T-cell and cytokine responses to attenuated as well as virulent HRV in gnotobiotic pigs colonized with the above probiotic strains was investigated (Chattha, Vlasova, Kandasamy, Rajashekara, & Saif, 2013). The administration induced Th1 stimulation by attenuated HRV vaccine that mitigated the severity of diarrhea and reduced virus shedding in infected pigs.

2.6.

Monkey

Several proofs of probiotics improving gut immunity of monkeys have accumulated. Simian immunodeficiency virus (SIV)/human immune deficiency virus (HIV) infection disrupts the integrity of gastrointestinal tract (blunts villi, crypts develop hyperplasia, enterocytes undergo apoptosis, defensin peptides decline, CD4+ T-cells deplete, etc.), encourages microbial invasion and sets off immune reactions (Brenchley & Douek, 2008). To enhance gut physiology and reduce morbidity rate, SIV-infected pigtail macaques were treated with anti-retroviral drugs, probiotics, and prebiotics. The synbiotic (VSL#3, Culturelle and prebiotic inulin) treatment amplified gut antigen-presenting cells, restored CD4+ T-cells, and mitigated the fibrosis of lymphoid follicles in the colon. The findings build hope that probiotic supplementation might be harnessed to boost immunity against HIV (Klatt et al., 2013).

journal of functional foods 14 (2015) 549–561

2.7.

Human

Human immune-potentiation by probiotics has gained so much credence in recent times that a separate branch of study ‘pharmacobiotics’ has emerged (Hill, 2010). A placebo-controlled trial was conducted to find the immunomodulatory effects of daily intake of six different strains of lactobacilli for 2 or 5 weeks (Rask, Adlerberth, Berggren, Ahrén, & Wold, 2013). The results showed that the strain L. plantarum 299v steps up the expression of the activation marker CD25 on CD8+ T-cells and the memory cell marker CD45RO on CD4+ T-cells. The consumption of L. paracasei induces proliferation of natural killer T (NKT) cell population. The phagocytic activity of granulocytes was escalated following the ingestion of L. plantarum 299v, L. plantarum HEAL, L.µparacasei or L. fermentum. The impact of B. infantis 35624 intake for 6–8 weeks, on inflammatory biomarker and plasma cytokine levels in patients with ulcerative colitis, chronic fatigue syndrome and psoriasis was assessed through randomized, double-blind, placebo-controlled interventions (Groeger et al., 2013). B. infantis 35624 feeding resulted in declined plasma C-reactive protein levels in all three inflammatory disorders compared to placebo. Plasma TNF-α level receded in chronic fatigue syndrome and psoriasis, while IL-6 level dwindled in ulcerative colitis and chronic fatigue syndrome. Also, in B. infantis 35624-treated healthy subjects, lipopolysaccharide (LPS)stimulated TNF-α and IL-6 secretion from PBMC significantly subsided. Whether the ingestion of probiotic L. reuteri could influence salivary IgA and specific anti-mutans streptococci IgA antibody levels was investigated (Ericson, Hamberg, Bratthall, Sinkiewicz-Enggren, & Ljunggren, 2013). The level of total IgA percentage increased significantly between pre-treatment and follow-up period, while the level of specific antibodies against streptococci decreased significantly between pre- and posttreatment intervals. It confirmed the transforming influence of probiotics on adaptive immune response of the host. Whether the consumption of probiotic milk products protects from atopic eczema and rhinoconjunctivitis in early childhood was assessed in a large population-based pregnancy cohort (Bertelsen et al., 2014). The link between the probiotic consumption and infantile immune status was analyzed through a questionnaire. Probiotic milk ingestion in pregnancy was associated with a slightly reduced relative risk of atopic eczema at 6 months and rhinoconjunctivitis between 18 and 36 months. A randomized, placebo-controlled trial was conducted to assess the effects of probiotic supplementation on atopic sensitization and asthma/wheeze prevention in children (Elazab et al., 2013). When administered prenatally, probiotics were effective in lessening total IgE level and the risk of atopic susceptibility. It was reported that L. lactis JCM5805 consumption can activate plasmacytoid dendritic cells and augment interferon secretion, proving to be a robust barricade against viral pathogens (Sugimura et al., 2013). The effect of probiotics on innate immune responses of infants to bacterial metabolites and the expression of associated TLRs was analyzed (Forsberg, Abrahamsson, Björkstén, & Jenmalm, 2014). It came forth that the probiotics lowered lipoteichoic acid-induced CCL4, CXCL8, IL-1β and IL-6 responses at 12 months and CCL4 and IL-1β secretion at 24 months. NKT cells being a type of cytotoxic lymphocytes play pivotal role in innate immunity. A randomized, double-blind study demonstrated that two probiotic strains,

555

L. grasseri SBT2055 and B. longum SBT2928, when used as starter in yoghurt, enhanced the NKT cell activities of consumers (Nishihira et al., 2014). The findings discussed above confirm the role of probiotics in reinforcing immune status and could be further explored to tackle the diseases developed owing to frail immunity.

3.

Mechanisms involved

Precise knowledge of molecular mechanisms behind the immunomodulatory attributes of probiotics is a requisite for their optimal usage. However, in vivo systems are intricate and unravelling the mechanisms are challenging, hence many of them are unresolved. Nevertheless, progressively more facts are emerging, answering the missing links. There could be myriad immunoregulatory mechanisms behind therapeutic relevance of probiotics. Some cardinal pathway interventions have been discussed below. Probiotics along with their effector molecules (peptidoglycan, lipoteichoic acid, glycoproteins, polysaccharides) control mucus production, reduce bacterial adhesion, increase tight junctions and induce defensins or IgA, thereby influencing the gut barrier (García-Lafuente, Antolín, Guarner, Crespo, & Malagelada, 2001). Mucosal immunity is further upheld by modulation of gut microbiota, enhancement of mineral adsorption, intervention in lipid metabolism and inhibition of pathogens (Steed & Macfarlane, 2009). Intestinal epithelial cells constitute the interface between the gut lumen and the innate and adaptive immune system. Both components of the immune system work in coordination to protect the host from external and internal injuries (Donkor, Shah, Apostolopoulos, & Vasiljevic, 2010). It was demonstrated that various bacterial species employ Jun N-terminal kinase (JNK) as the key activation pathway (Weiss et al., 2011). Jun dimerization protein 2 (JDP2), a transcription factor inhibiting the JNK, has shown to be induced by B. bifidum Z9. The preventive effect of L. rhamnosus 35 on allergic asthma BALB/c mice model was evaluated (Kim, Beck et al., 2013). On oral as well as intravenous treatment of the ovalbumin-sensitized mice with the probiotic strain, suppression of asthmatic response was observed. In addition, lowered bronchial hyper-responsiveness, total cell counts in the bronchioalveolar lavage fluid, production of ovalbuminspecific IgE and pulmonary eosinophilic inflammation were witnessed. These actions of L. rhamnosus 35 were correlated to Tregs that suppresses the Th2 response in respiratory organs of the asthma models. It was reported that the supplementation with L. casei C1 and L. plantarum C4 strains can inhibit Yersinia enterocolitica, by lowering pH as a result of glucose fermentation (Bujalance et al., 2014). Literature agreed with this finding as the presence of organic acids is known to reduce the virulence of the pathogen. Proteomic methods were employed and the crucial role of P. freudenreichii surface proteins in adhesion and immune-stimulation was identified (Le Maréchal et al., 2015). This insight might pave the way for further exploration of their role in eliciting immunity. Fig. 1 depicts the important immunological interventions by probiotics.

556

journal of functional foods 14 (2015) 549–561

Fig. 1 – Effects of probiotic and prebiotic ingestion on innate and adaptive immune responses. (1) Stimulation of innate immune cells: As a consequence of viral infection, NK cells displaying enhanced cytotoxic activity and macrophage showing increased phagocytosis resulting in non-specific antiviral effect. (2) Stimulation of adaptive immune response: Probiotic intake may cause activation of pro- (Th1 cells) or anti- (Th2 and Tregs) inflammatory responses by release of pro(IFN-γ, IL-2 and TNF-α) or anti- (IL-10) inflammatory cytokines, respectively (Gourbeyre, Denery, & Bodinier, 2011).

4.

Synergy with prebiotics

Assorted studies have delineated that the blending of probiotics with prebiotics (mostly non-digestible oligosaccharides) imparts robustness to innate immunity (Zhang et al., 2013). It was suggested that synbiotic supplementation may have positive effects on the immune makeup of breast milk and the reduction of diarrhea incidences in infants (Nikniaz, Ostadrahimi, Mahdavi, Hejazi, & Salekdeh, 2013). The IgA and the TGF-β2 levels of breast milk increased in the supplemented group. The role of prebiotics (organic selenium and Lithothamnium muelleri) and probiotics (S. boulardii UFMG 905 and Bifidobacterium sp.) in stimulating gut immunity have been reviewed (Vieira et al., 2013). The synergistic effects of probiotics and prebiotics have been established through compelling number of studies and it is beyond the scope of this review to mention them all. Some functional combinations referred in this paper are B. lactis Bi-07 and L. acidophilus NCFM with IMO (Wang et al., 2012), B. licheniformis with FOS (Zhang et al., 2013), P. acidilactici MA18/5M with FOS (Abid et al., 2013), L. lactis spp. lactis with AXOS (Geraylou et al., 2013) and L. acidophilus with GOS and MOS (Talpur et al., 2014).

An empirical study reported that only specific combinations of prebiotics and probiotics are capable of promoting the latter’s survival and proliferation. The prebiotics lactulose and lactobionic acid at 1% level were effective in protecting Lactobacillus acidophilus NCFM and Lactobacillus reuteri NCIMB 11951 against 2 mM cholic and taurocholic acid but not against glycocholic, glycochenodeoxycholic and chenodeoxycholic acid (Adebola, Corcoran, & Morgan, 2014). Above studies furnished crucial insights on synbiotic approach for immunomodulation.

5.

Future scopes

Studies reflect that probiotic strains differ in their immunomodulatory responses, which necessitates their characterization before administration, as unspecified applications will be futile. An interesting review depicting the salience of screening effector molecules from probiotics and assessing their impact on host immunity has been published (Lee, Tomita, Kleerebezem, & Bron, 2013). It was highlighted that the

journal of functional foods 14 (2015) 549–561

recognition and functional elucidation of the effector components could expand pharmacological applications of probiotics. The potency of supplemented Lactobacillus helveticus HY7801 to arthritic-mice, in eliciting CD11c+ dendritic cells, capable of down-regulation of pro-inflammatory cytokines and upregulation of anti-inflammatory cytokines emphasized the importance of criterion-based probiotic strain selection (Kim et al., 2015). The screening of novel probiotic strains from various sources such as fermented dairy products, fruits, vegetables, cereals has been recommended (Ashraf, Vasiljevic, Day, Smith, & Donkor, 2014). Sensitivity to the harsh gastric juice is a major hurdle in the viability and optimal efficacy of probiotics. In this context, encapsulation has proved effective by improving survival. Microencapsulation in alginate, chitosan, gelatin, carrageenan, whey protein, resistant starch have been certified to protect the probiotics from stressors like oxygen, low pH, bile salts, heat and cold shocks (Tripathi & Giri, 2014; Ying et al., 2013). The viability of probiotic strains Lactobacillus acidophilus PTCC1643 and Lactobacillus rhamnosus PTCC1637, trapped in alginate microspheres was significantly higher than their uncoated counterparts, when exposed to simulated gastrointestinal juice milieu (Mokarram, Mortazavi, Najafi, & Shahidi, 2009). A type of bread was prepared with sodium alginate and whey protein-encapsulated and air-dried L. rhamnosus GG (Soukoulis et al., 2014). The coating significantly improved the viability of the strain throughout the desiccation and room temperature storage. The immunomodulatory effect of probiotics has been shown mainly in gastrointestinal immune disorders and scanty information is available on the inflammation of the central nervous system. It was reported that IRT5 probiotics (a mixture of 5 probiotics) could suppress diverse

557

inflammatory ailments, including encephalomyelitis, a T-cell mediated inflammatory autoimmune disease of the central nervous system (Kwon et al., 2013). The blend inhibited the proinflammatory Th1/Th17 differentiation while inducing Tregs (IL10). The encouraging finding raises hope that probiotics could be implicated to modulate multiple sclerosis (inflammatory autoimmune disease) as well. Also, the emerging roles of innate immunity in mediating pathogenesis of multiple sclerosis could be intervened with probiotics. As preliminary success has been achieved, the effect of probiotics on allergic conditions like rhinitis, atopic dermatitis and food allergy can be explored further. It was reported that grass pollen-triggered persistent allergic rhinitis might be mitigated using L. paracasei subsp. paracasei LP-33 (Costa et al., 2014). Mending the imbalance between Th1 and Th2 was elucidated to be the mechanism of probiotic action. Attempts should be made to investigate the feasibility of probiotics usage in tackling unconventional diseases via modulation of immune landscape. Clinical trial results tend to be conflicting owing to probiotics as well as host factors, which summons for consistency. In this pursuit, personalized probiotics administration is being contemplated as the emergent paradigm for immunity correction (Peterson, Sharma, Elmén, & Peterson, 2014). Personalized probiotics supplementation is touted to alleviate immune-dependent maladies as asthma, allergies, obesity, cancers, to a name a few (Barzegari, Eslami, Ghabeli, & Omidi, 2014). Probiotics as functional food are prevailing in the nutraceutical sector. For their immune modification trait, they are being exploited in gastroenterology, weight management, microbial pathogenesis, pediatric and geriatric nutrition, aquaculture and veterinary practices. The physiological benefits of probiotics on gut health and

Fig. 2 – The modulations of innate immunity in gut mucosa by probiotics.

558

journal of functional foods 14 (2015) 549–561

associated immune components has been illustrated in Fig. 2 (Pagnini et al., 2010).

6.

Conclusion

Probiotics have established themselves as a ubiquitous segment of current functional food domain. They are capable of augmenting the production of a gamut of pro- and antiinflammatory mediators, thus invigorating host innate immunity. Probiotics research represents a fast evolving field which has expanded from the traditional digestive comfort to diverse health benefits. Optimizing supplementation period, competent strain selection, and deciphering the influence of host factors might enhance biological efficiency. Probiotics are capable of increasing production. Immune-stimulatory properties of strains vary widely, so the bioprospecting for potent strains is required. Some less conventional bacteria, from allochthonous or extremophilic origin might be screened. Proper understanding of the development of immunity, intestinal barrier function, gut microbiota, homeostasis and systemic immunity is paramount for appreciating the beneficial effects of probiotics. It can be a potential substitute for antibiotic as a live therapeutic agent to improve animal health. As probiotics are making foray into innovative fields and approaching a paradigm shift in healthcare, it seems requisite to keep abreast of their latest advances. This review is expected to provide comprehensive insight on probiotics with regard to various facets of innate immunity.

Conflict of interest The authors declare there is no conflict of interest in submission of this paper to this journal.

REFERENCES

Abid, A., Davies, S. J., Waines, P., Emery, M., Castex, M., Gioacchini, G., Carnevali, O., Bickerdike, R., Romero, J., & Merrifield, D. L. (2013). Dietary synbiotic application modulates Atlantic salmon (Salmo salar) intestinal microbial communities and intestinal immunity. Fish & Shellfish Immunology, 35(6), 1948–1956. Adebola, O. O., Corcoran, O., & Morgan, W. A. (2014). Synbiotics: The impact of potential prebiotics inulin, lactulose and lactobionic acid on the survival and growth of lactobacilli probiotics. Journal of Functional Foods, 10, 75–84. Ahmed, S. T., Mun, H.-S., Islam, M. M., Kim, S.-S., Hwang, J.-A., Kim, Y.-J., & Yang, C.-J. (2014). Effects of citrus junos byproducts fermented with multistrain probiotics on growth performance, immunity, caecal microbiology and meat oxidative stability in broilers. British Poultry Science, 55(4), 540–547. Aly, S. M., Mohamed, M. F., & John, G. (2008). Effect of probiotics on the survival, growth and challenge infection in Tilapia nilotica (Oreochromis niloticus). Aquaculture Research, 39(6), 647–656. Aragón, F., Carino, S., Perdigón, G., & de Moreno de LeBlanc, A. (2014). The administration of milk fermented by the probiotic Lactobacillus casei CRL 431 exerts an immunomodulatory

effect against a breast tumour in a mouse model. Immunobiology, 219(6), 457–464. Ashraf, R., Vasiljevic, T., Day, S. L., Smith, S. C., & Donkor, O. N. (2014). Lactic acid bacteria and probiotic organisms induce different cytokine profile and regulatory T cells mechanisms. Journal of Functional Foods, 6, 395–409. Baboota, R. K., Bishnoi, M., Ambalam, P., Kondepudi, K. K., Sarma, S. M., Boparai, R. K., & Podili, K. (2013). Functional food ingredients for the management of obesity and associated co-morbidities – A review. Journal of Functional Foods, 5(3), 997–1012. Barzegari, A., Eslami, S., Ghabeli, E., & Omidi, Y. (2014). Imposition of encapsulated non-indigenous probiotics into intestine may disturb human core microbiome. Frontiers in Microbiology, 5, 393. Bertelsen, R. J., Brantsæter, A. L., Magnus, M. C., Haugen, M., Myhre, R., Jacobsson, B., Longnecker, M. P., Meltzer, H. M., & London, S. J. (2014). Probiotic milk consumption in pregnancy and infancy and subsequent childhood allergic diseases. The Journal of Allergy and Clinical Immunology, 133(1), 165–171, e1–8. Brenchley, J. M., & Douek, D. C. (2008). HIV infection and the gastrointestinal immune system. Mucosal Immunology, 1(1), 23–30. Bujalance, C., Jiménez-Valera, M., Moreno, E., Ruiz-López, M.-D., Lasserrot, A., & Ruiz-Bravo, A. (2014). Lack of correlation between in vitro antibiosis and in vivo protection against enteropathogenic bacteria by probiotic lactobacilli. Research in Microbiology, 165(1), 14–20. Chattha, K. S., Vlasova, A. N., Kandasamy, S., Rajashekara, G., & Saif, L. J. (2013). Divergent immunomodulating effects of probiotics on T cell responses to oral attenuated human rotavirus vaccine and virulent human rotavirus infection in a neonatal gnotobiotic piglet disease model. Journal of Immunology (Baltimore, Md.: 1950), 191(5), 2446–2456. Chen, L., Lei, L., Zhou, Z., He, J., Xu, S., Lu, C., Chen, J., Yang, Z., Wu, G., Yeh, I. T., Zhong, G., & Wu, Y. (2013) Contribution of interleukin-12 p35 (IL-12p35) and IL-12p40 to protective immunity and pathology in mice infected with Chlamydia muridarum. Infection and Immunity, 81(8), 2962–2971. Chiba, E., Tomosada, Y., Vizoso-Pinto, M. G., Salva, S., Takahashi, T., Tsukida, K., Kitazawa, H., Alvarez, S., & Villena, J. (2013) Immunobiotic Lactobacillus rhamnosus improves resistance of infant mice against respiratory syncytial virus infection. International Immunopharmacology, 17(2), 373–382. Chiu, Y.-H., Lin, S.-L., Ou, C.-C., Lu, Y.-C., Huang, H.-Y., & Lin, M.-Y. (2013). Anti-inflammatory effect of lactobacilli bacteria on HepG2 cells is through cross-regulation of TLR4 and NOD2 signalling. Journal of Functional Foods, 5(2), 820–828. Chiu, Y.-H., Tsai, J.-J., Lin, S.-L., Chotirosvakin, C., & Lin, M.-Y. (2014). Characterisation of bifidobacteria with immunomodulatory properties isolated from human breast milk. Journal of Functional Foods, 7, 700–708. Costa, D. J., Marteau, P., Amouyal, M., Poulsen, L. K., Hamelmann, E., Cazaubiel, M., Housez, B., Leuillet, S., Stavnsbjerg, M., Molimard, P., Courau, S., & Bousquet, J. (2014) Efficacy and safety of the probiotic Lactobacillus paracasei LP-33 in allergic rhinitis: A double-blind, randomized, placebo-controlled trial (GA2LEN Study). European Journal of Clinical Nutrition, 68(5), 602–607. Dong, H., Rowland, I., & Yaqoob, P. (2012). Comparative effects of six probiotic strains on immune function in vitro. The British Journal of Nutrition, 108(3), 459–470. Donkor, O. N., Shah, N. P., Apostolopoulos, V., & Vasiljevic, T. (2010). Development of allergic responses related to microorganisms exposure in early life. International Dairy Journal, 20(6), 373–385. Edens, F. (2003). An alternative for antibiotic use in poultry: Probiotics. Revista Brasileira de Ciência Avícola, 5(2), 75–97.

journal of functional foods 14 (2015) 549–561

Elazab, N., Mendy, A., Gasana, J., Vieira, E. R., Quizon, A., & Forno, E. (2013). Probiotic administration in early life, atopy, and asthma: A meta-analysis of clinical trials. Pediatrics, 132(3), e666–e676. Ericson, D., Hamberg, K., Bratthall, G., Sinkiewicz-Enggren, G., & Ljunggren, L. (2013). Salivary IgA response to probiotic bacteria and mutans streptococci after the use of chewing gum containing Lactobacillus reuteri. Pathogens and Disease, 68(3), 82–87. Eze, J. I., Orajaka, L. J. E., Okonkwo, N. C., Ezeh, I. O., Ezema, C., & Anosa, G. N. (2012). Effect of probiotic (Saccharomyces cerevisiae) supplementation on immune response in Trypanosoma brucei brucei infected rats. Experimental Parasitology, 132(4), 434–439. Foligné, B., Dewulf, J., Breton, J., Claisse, O., Lonvaud-Funel, A., & Pot, B. (2010). Probiotic properties of non-conventional lactic acid bacteria: Immunomodulation by Oenococcus oeni. International Journal of Food Microbiology, 140(2–3), 136–145. Forsberg, A., Abrahamsson, T. R., Björkstén, B., & Jenmalm, M. C. (2014). Pre- and postnatal administration of Lactobacillus reuteri decreases TLR2 responses in infants. Clinical and Translational Allergy, 4(1), 21. Franco, M. C., Golowczyc, M. A., De Antoni, G. L., Pérez, P. F., Humen, M., & Serradell Mde, L. (2013). Administration of kefirfermented milk protects mice against Giardia intestinalis infection. Journal of Medical Microbiology, 62(Pt. 12), 1815–1822. Franz, C. M. A. P., Huch, M., Abriouel, H., Holzapfel, W., & Gálvez, A. (2011). Enterococci as probiotics and their implications in food safety. International Journal of Food Microbiology, 151(2), 125–140. García-Lafuente, A., Antolín, M., Guarner, F., Crespo, E., & Malagelada, J. R. (2001). Modulation of colonic barrier function by the composition of the commensal flora in the rat. Gut, 48(4), 503–507. Geraylou, Z., Souffreau, C., Rurangwa, E., De Meester, L., Courtin, C. M., Delcour, J. A., Buyse, J., & Ollevier, F. (2013). Effects of dietary arabinoxylan-oligosaccharides (AXOS) and endogenous probiotics on the growth performance, nonspecific immunity and gut microbiota of juvenile Siberian sturgeon (Acipenser baerii). Fish & Shellfish Immunology, 35(3), 766–775. Ghadimi, D., Fölster-Holst, R., de Vrese, M., Winkler, P., Heller, K. J., & Schrezenmeir, J. (2008). Effects of probiotic bacteria and their genomic DNA on TH1/TH2-cytokine production by peripheral blood mononuclear cells (PBMCs) of healthy and allergic subjects. Immunobiology, 213(8), 677–692. Giri, S. S., Sukumaran, V., & Oviya, M. (2013). Potential probiotic Lactobacillus plantarum VSG3 improves the growth, immunity, and disease resistance of tropical freshwater fish, Labeo rohita. Fish & Shellfish Immunology, 34(2), 660–666. Gourbeyre, P., Denery, S., & Bodinier, M. (2011). Probiotics, prebiotics, and synbiotics: Impact on the gut immune system and allergic reactions. Journal of Leukocyte Biology, 89(5), 685–695. Groeger, D., O’Mahony, L., Murphy, E. F., Bourke, J. F., Dinan, T. G., Kiely, B., Shanahan, F., & Quigley, E. M. M. (2013). Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut. Gut Microbes, 4(4), 325–339. Henao-Mejia, J.,Elinav, E., Jin, C., Hao, L., Mehal, W. Z., Strowig, T., Thaiss, C. A., Kau, A. L., Eisenbarth, S. C., Jurczak, M. J., Camporez, J. P., Shulman, G. I., Gordon, J. I., Hoffman, H. M., & Flavell, R. A. (2012). Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature, 482(7384), 179–185. Herrera, M., Salva, S., Villena, J., Barbieri, N., & Alvarez, S. (2013). Lactobacillus rhamnosus CRL1505 enhances systemic and respiratory innate immune response in immunocompromised malnourished mice. Journal of Functional Foods, 5(4), 1693–1704.

559

Hidalgo-Cantabrana, C., Kekkonen, R., de los Reyes-Gavilán, C. G., Salminen, S., Korpela, R., Gueimonde, M., & Ruas-Madiedo, P. (2014). Effect of bacteria used in food industry on the proliferation and cytokine production of epithelial intestinal cellular lines. Journal of Functional Foods, 6, 348–355. Hidalgo-Cantabrana, C., Nikolic, M., López, P., Suárez, A., Miljkovic, M., Kojic, M., Margolles, A., Golic, N., & RuasMadiedo, P. (2014). Exopolysaccharide-producing Bifidobacterium animalis subsp. lactis strains and their polymers elicit different responses on immune cells from blood and gut associated lymphoid tissue. Anaerobe, 26, 24–30. Hill, C. (2010). Probiotics and pharmabiotics: Alternative medicine or an evidence-based alternative? Bioengineered Bugs, 1(2), 79–84. Kakinuma, T., Saeki, H., Tsunemi, Y., Fujita, H., Asano, N., Mitsui, H., Tada, Y., Wakugawa, M., Watanabe, T., Torii, H., Komine, M., Asahina, A., Nakamura, K., & Tamaki, K. (2003). Increased serum cutaneous T cell-attracting chemokine (CCL27) levels in patients with atopic dermatitis and psoriasis vulgaris. The Journal of Allergy and Clinical Immunology, 111(3), 592–597. Kano, H., Kita, J., Makino, S., Ikegami, S., & Itoh, H. (2013). Oral administration of Lactobacillus delbrueckii subspecies bulgaricus OLL1073R-1 suppresses inflammation by decreasing interleukin-6 responses in a murine model of atopic dermatitis. Journal of Dairy Science, 96(6), 3525–3534. Kato-Mori, Y., Orihashi, T., Kanai, Y., Sato, M., Sera, K., & Hagiwara, K. (2010). Fermentation metabolites from Lactobacillus gasseri and Propionibacterium freudenreichii exert bacteriocidal effects in mice. Journal of Medicinal Food, 13(6), 1460–1467. Kelesidis, T. (2012). Efficacy and safety of the probiotic Saccharomyces boulardii for the prevention and therapy of gastrointestinal disorders. Therapeutic Advances in Gastroenterology, 5(2), 111–125. Kim, D., Beck, B. R., Heo, S.-B., Kim, J., Kim, H. D., Lee, S.-M., Kim, Y., Oh, S. Y., Lee, K., Do, H., Lee, K., Holzapfel, W. H., & Song, S. K. (2013). Lactococcus lactis BFE920 activates the innate immune system of olive flounder (Paralichthys olivaceus), resulting in protection against Streptococcus iniae infection and enhancing feed efficiency and weight gain in large-scale field studies. Fish & Shellfish Immunology, 35(5), 1585–1590. Kim, H.-J., Kim, Y.-J., Lee, S.-H., Kang, M.-J., Yu, H.-S., Jung, Y.-H., Lee, E., Seo, J. H., Kwon, J. W., Kim, B. J., Yu, J., Park, H. M., & Hong, S.-J. (2013). Effects of Lactobacillus rhamnosus on asthma with an adoptive transfer of dendritic cells in mice. Journal of Applied Microbiology, 115(3), 872–879. Kim, J.-E., Chae, C. S., Kim, G.-C., Hwang, W., Hwang, J., Hwang, S.-M., Kim, Y., Ahn, Y.-T., Park, S.-G., Jun, C.-D., Rudra, D., & Im, S.-H. (2015). Lactobacillus helveticus suppresses experimental rheumatoid arthritis by reducing inflammatory T cell responses. Journal of Functional Foods, 13, 350–362. Kim, J.-Y., Park, B.-K., Park, H.-J., Park, Y.-H., Kim, B.-O., & Pyo, S. (2013). Atopic dermatitis-mitigating effects of new Lactobacillus strain, Lactobacillus sakei probio 65 isolated from kimchi. Journal of Applied Microbiology, 115(2), 517–526. Klatt, N. R., Canary, L. A., Sun, X., Vinton, C. L., Funderburg, N. T., Morcock, D. R., Quiñones, M., Deming, C. B., Perkins, M., Hazuda, D. J., Miller, M. D., Lederman, M. M., Segre, J. A., Lifson, J. D., Haddad, E. K., Estes, J. D., & Brenchley, J. M. (2013). Probiotic/prebiotic supplementation of antiretrovirals improves gastrointestinal immunity in SIV-infected macaques. The Journal of Clinical Investigation, 123(2), 903–907. Kwon, H.-K., Kim, G.-C., Kim, Y., Hwang, W., Jash, A., Sahoo, A., Kim, J. E., Nam, J. H., & Im, S.-H. (2013). Amelioration of experimental autoimmune encephalomyelitis by probiotic mixture is mediated by a shift in T helper cell immuneresponse. Clinical Immunology (Orlando, Fla.), 146(3), 217–227.

560

journal of functional foods 14 (2015) 549–561

Le Maréchal, C., Peton, V., Plé, C., Vroland, C., Jardin, J., BriardBion, V., Durant, G., Victoria Chuat, V., Loux, V., Foligné, B., Deutsch, S.-M., Falentin, H., & Jan, G. (2015). Surface proteins of Propionibacterium freudenreichii are involved in its anti-inflammatory properties. Journal of Proteomics, 113, 447–461. Lee, I.-C., Tomita, S., Kleerebezem, M., & Bron, P. A. (2013). The quest for probiotic effector molecules – Unraveling strain specificity at the molecular level. Pharmacological Research: The Official Journal of the Italian Pharmacological Society, 69(1), 61–74. Lee, N.-K., Kim, S.-Y., Choi, S.-Y., & Paik, H.-D. (2013). Probiotic Bacillus subtilis KU201 having antifungal and antimicrobial properties isolated from kimchi. Food Science and Biotechnology, 22(5), 1–5. Martínez Cruz, P., Ibáñez, A. L., Monroy Hermosillo, O. A., & Ramírez Saad, H. C. (2012). Use of probiotics in aquaculture. ISRN Microbiology, 2012, 916845. Min, S.-Y., Park, K.-S., Cho, M.-L., Kang, J.-W., Cho, Y.-G., Hwang, S.-Y., Park, M. J., Yoon, C. H., Min, J. K., Lee, S. H., Park, S. H., & Kim, H.-Y. (2006). Antigen-induced, tolerogenic CD11c+,CD11b+ dendritic cells are abundant in Peyer’s patches during the induction of oral tolerance to type II collagen and suppress experimental collagen-induced arthritis. Arthritis and Rheumatism, 54(3), 887–898. Miquel, S., Martín, R., Rossi, O., Bermúdez-Humarán, L. G., Chatel, J. M., Sokol, H., Thomas, M., Wells, J. M., & Langella, P. (2013). Faecalibacterium prausnitzii and human intestinal health. Current Opinion in Microbiology, 16(3), 255–261. Mohammadmoradi, S., Javidan, A., & Kordi, J. (2014). Boom of probiotics: This time non-alcoholic fatty liver disease – A mini review. Journal of Functional Foods, 11, 30–35. Mokarram, R. R., Mortazavi, S. A., Najafi, M. B. H., & Shahidi, F. (2009). The influence of multi stage alginate coating on survivability of potential probiotic bacteria in simulated gastric and intestinal juice. Food Research International (Ottawa, Ont.), 42(8), 1040–1045. Mokrozub, V. V., Lazarenko, L. M., Babenko, L. P., ShynkarenkoSichel, L. M., Olevinska, Z. M., Timoshok, N. O., Pidgorskyi, V. S., & Spivak, M. Y. (2012). Effect of probiotic strains of lacto- and bifidobacteria on the activity of macrophages and other parameters of immunity in cases of staphylococcosis. Mikrobiolohichnyı˘ Zhurnal (Kiev, Ukraine: 1993), 74(6), 90–98. Müllner, K., Miheller, P., Herszényi, L., & Tulassay, Z. (2014). Probiotics in the management of Crohn’s disease and ulcerative colitis. Current Pharmaceutical Design, 20(28), 4556– 4560. Nikniaz, L., Ostadrahimi, A., Mahdavi, R., Hejazi, M. A., & Salekdeh, G. H. (2013). Effects of synbiotic supplementation on breast milk levels of IgA, TGF-β1, and TGF-β2. Journal of Human Lactation: Official Journal of International Lactation Consultant Association, 29(4), 591–596. Nishihira, J., Kagami-Katsuyama, H., Tanaka, A., Nishimura, M., Kobayashi, T., & Kawasaki, Y. (2014). Elevation of natural killer cell activity and alleviation of mental stress by the consumption of yogurt containing Lactobacillus gasseri SBT2055 and Bifidobacterium longum SBT2928 in a doubleblind, placebo-controlled clinical trial. Journal of Functional Foods, 11, 261–268. Pagnini, C., Saeed, R., Bamias, G., Arseneau, K. O., Pizarro, T. T., & Cominelli, F. (2010). Probiotics promote gut health through stimulation of epithelial innate immunity. Proceedings of the National Academy of Sciences of the United States of America, 107(1), 454–459. Pan, C.-Y., Wang, Y.-D., & Chen, J.-Y. (2013). Immunomodulatory effects of dietary Bacillus coagulans in grouper (Epinephelus coioides) and zebrafish (Danio rerio) infected with Vibrio

vulnificus. Aquaculture International: Journal of the European Aquaculture Society, 21(5), 1155–1168. Park, J. H., & Kim, I. H. (2014). Supplemental effect of probiotic Bacillus subtilis B2A on productivity, organ weight, intestinal Salmonella microflora, and breast meat quality of growing broiler chicks. Poultry Science, 93(8), 2054–2059. Park, M.-K., Ngo, V., Kwon, Y.-M., Lee, Y.-T., Yoo, S., Cho, Y.-H., Hong, S. M., Hwang, H. S., Ko, E. J., Jung, Y. J., Moon, D. W., Jeong, E. J., Kim, M. C., Lee, Y. N., Jang, J. H., Oh, J. S., Kim, C. H., & Kang, S.-M. (2013). Lactobacillus plantarum DK119 as a probiotic confers protection against influenza virus by modulating innate immunity. PLoS ONE, 8(10), e75368. Patel, S., & Goyal, A. (2013). Evolving roles of probiotics in cancer prophylaxis and therapy. Probiotics and Antimicrobial Proteins, 5(1), 59–67. Peterson, C. T., Sharma, V., Elmén, L., & Peterson, S. N. (2014). Immune homeostasis, dysbiosis and therapeutic modulation of the gut microbiota. Clinical and Experimental Immunology, 179, 363–377. Pothlichet, J., & Quintana-Murci, L. (2013). The genetics of innate immunity sensors and human disease. International Reviews of Immunology, 32(2), 157–208. Qin, C., Xu, L., Yang, Y., He, S., Dai, Y., Zhao, H., & Zhou, Z. (2013). Comparison of fecundity and offspring immunity in zebrafish fed Lactobacillus rhamnosus CICC 6141 and Lactobacillus casei BL23. Reproduction (Cambridge, England), 147(1), 53–64. Rajput, I. R., Li, L. Y., Xin, X., Wu, B. B., Juan, Z. L., Cui, Z. W., Yu, D. Y., & Li, W. F. (2013). Effect of Saccharomyces boulardii and Bacillus subtilis B10 on intestinal ultrastructure modulation and mucosal immunity development mechanism in broiler chickens. Poultry Science, 92(4), 956–965). Rask, C., Adlerberth, I., Berggren, A., Ahrén, I. L., & Wold, A. E. (2013). Differential effect on cell-mediated immunity in human volunteers after intake of different lactobacilli. Clinical and Experimental Immunology, 172(2), 321–332. Rasmussen, S. B., Reinert, L. S., & Paludan, S. R. (2009). Innate recognition of intracellular pathogens: Detection and activation of the first line of defense. APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica, 117(5–6), 323–337. Rizzo, A., Losacco, A., & Carratelli, C. R. (2013). Lactobacillus crispatus modulates epithelial cell defense against Candida albicans through Toll-like receptors 2 and 4, interleukin 8 and human β-defensins 2 and 3. Immunology Letters, 156(1–2), 102– 109. Schenten, D., & Medzhitov, R. (2011). The control of adaptive immune responses by the innate immune system. Advances in Immunology, 109, 87–124. Shao, C., Tian, G., Huang, Y., Liang, W., Zheng, H., Wei, J., Wei, C., Yang, C., Wang, H., & Zeng, W. (2013). Thymosin alpha-1transformed Bifidobacterium promotes T cell proliferation and maturation in mice by oral administration. International Immunopharmacology, 15(3), 646–653. Shi, S.-H., Yang, W.-T., Yang, G.-L., Cong, Y.-L., Huang, H.-B., Wang, Q., Cai, R. P., Ye, L. P., Hu, J. T., Zhou, J. Y., Wang, C. F., & Li, Y. (2014). Immunoprotection against influenza virus H9N2 by the oral administration of recombinant Lactobacillus plantarumNC8 expressing hemagglutinin in BALB/c mice. Virology, 464–465, 166–176. Smelt, M. J., de Haan, B. J., Bron, P. A., van Swam, I., Meijerink, M., Wells, J. M., Faas, M. M., & de Vos, P. (2013). Probiotics can generate FoxP3 T-cell responses in the small intestine and simultaneously inducing CD4 and CD8 T cell activation in the large intestine. PLoS ONE, 8(7), e68952. Soukoulis, C., Yonekura, L., Gan, H.-H., Behboudi-Jobbehdar, S., Parmenter, C., & Fisk, I. (2014). Probiotic edible films as a new strategy for developing functional bakery products: The case of pan bread. Food Hydrocolloids, 39, 231–242.

journal of functional foods 14 (2015) 549–561

Standen, B. T., Rawling, M. D., Davies, S. J., Castex, M., Foey, A., Gioacchini, G., Carnevali, O., & Merrifield, D. L. (2013). Probiotic Pediococcus acidilactici modulates both localised intestinaland peripheral-immunity in tilapia (Oreochromis niloticus)). Fish & Shellfish Immunology, 35(4), 1097–1104. Steed, H., & Macfarlane, S. (2009). Mechanisms of prebiotic impact on health. New York: Springer Science+Business Media, LLC. Suarez, C. J., Parker, N. J., & Finn, P. W. (2008). Innate immune mechanism in allergic asthma. Current Allergy and Asthma Reports, 8(5), 451–459. Sugimura, T., Jounai, K., Ohshio, K., Tanaka, T., Suwa, M., & Fujiwara, D. (2013). Immunomodulatory effect of Lactococcus lactis JCM5805 on human plasmacytoid dendritic cells. Clinical Immunology (Orlando, Fla.), 149(3), 509–518. Takeda, S., Kawahara, S., Hidaka, M., Yoshida, H., Watanabe, W., Takeshita, M., Kikuchi, Y., Bumbein, D., Muguruma, M., & Kurokawa, M. (2013). Effects of oral administration of probiotics from Mongolian dairy products on the Th1 immune response in mice. Bioscience, Biotechnology, and Biochemistry, 77(7), 1372–1378. Talpur, A. D., Munir, M. B., Mary, A., & Hashim, R. (2014). Dietary probiotics and prebiotics improved food acceptability, growth performance, haematology and immunological parameters and disease resistance against Aeromonas hydrophila in snakehead (Channa striata) fingerlings. Aquaculture (Amsterdam, Netherlands), 426–427, 14–20. Toomer, O. T., Ferguson, M., Pereira, M., Do, A., Bigley, E., Gaines, D., & Williams, K. (2014). Maternal and postnatal dietary probiotic supplementation enhances splenic regulatory T helper cell population and reduces ovalbumin allergeninduced hypersensitivity responses in mice. Immunobiology, 219(5), 367–376. Touchefeu, Y., Montassier, E., Nieman, K., Gastinne, T., Potel, G., Bruley des Varannes, S., Le Vacon, F., & de La Cochetière, M. F. (2014). Systematic review: The role of the gut microbiota in chemotherapy- or radiation-induced gastrointestinal mucositis – Current evidence and potential clinical applications. Alimentary Pharmacology & Therapeutics, 40(5), 409–421.

561

Tripathi, M. K., & Giri, S. K. (2014). Probiotic functional foods: Survival of probiotics during processing and storage. Journal of Functional Foods, 9, 225–241. Tuthill, C., Rios, I., & McBeath, R. (2010). Thymosin alpha 1: Past clinical experience and future promise. Annals of the New York Academy of Sciences, 1194, 130–135. Vieira, A. T., Teixeira, M. M., & Martins, F. S. (2013). The role of probiotics and prebiotics in inducing gut immunity. Frontiers in Immunology, 4, 445. Vlasova, A. N., Chattha, K. S., Kandasamy, S., Liu, Z., Esseili, M., Shao, L., Rajashekara, G., & Saif, L. J. (2013). Lactobacilli and bifidobacteria promote immune homeostasis by modulating innate immune responses to human rotavirus in neonatal gnotobiotic pigs. PLoS ONE, 8(10), e76962. Vujkovic-Cvijin, I., Dunham, R. M., Iwai, S., Maher, M. C., Albright, R. G., Broadhurst, M. J., Hernandez, R. D., Lederman, M. M., Huang, Y., Somsouk, M., Deeks, S. G., Peter, W., Hunt, P. W., Lynch, S. V., & McCune, J. M. (2013). Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Science Translational Medicine, 5(193), 193ra91. Wang, S., Zhu, H., Lu, C., Kang, Z., Luo, Y., Feng, L., & Lu, X.(2012). Fermented milk supplemented with probiotics and prebiotics can effectively alter the intestinal microbiota and immunity of host animals. Journal of Dairy Science, 95(9), 4813–4822. Weiss, G., Christensen, H. R., Zeuthen, L. H., Vogensen, F. K., Jakobsen, M., & Frøkiær, H. (2011). Lactobacilli and bifidobacteria induce differential interferon-β profiles in dendritic cells. Cytokine, 56(2), 520–530. Ying, D., Schwander, S., Weerakkody, R., Sanguansri, L., Gantenbein-Demarchi, C., & Augustin, M. A. (2013). Microencapsulated Lactobacillus rhamnosus GG in whey protein and resistant starch matrices: Probiotic survival in fruit juice. Journal of Functional Foods, 5(1), 98–105. Zhang, C.-N., Li, X.-F., Xu, W.-N., Jiang, G.-Z., Lu, K.-L., Wang, L.-N., & Liu, W.-B. (2013). Combined effects of dietary fructooligosaccharide and Bacillus licheniformis on innate immunity, antioxidant capability and disease resistance of triangular bream (Megalobrama terminalis). Fish & Shellfish Immunology, 35(5), 1380–1386.