2212-4055/12 $58.00+.00 © 2012 Bentham Science Publishers
Probiotics as an Alternative Strategy for Prevention and Treatment of Human Diseases: A Review
Soghra Khani
1, Hamideh M. Hosseini
2, Mohammad Taheri
3, Mohammad R. Nourani
4and Abbas A. Imani Fooladi
*,51
Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran
2
School of Pharmacy, Student's Research Committee, Tabriz University of Medical Science, Tabriz, Iran
3
Diagnostic laboratory Science and Technology Research Center, Paramedical School, Shiraz University of Medical
Science, Shiraz, Iran
4
Chemical Injury Research Center (CIRC), Baqiyatallah University of Medical Sciences, Tehran, Iran
5
Applied Micobiology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
Abstract: Probiotics are live microbial food supplements or their components, which have been shown to have beneficial
effects on human health.
Probiotics can be bacteria, molds, or yeasts, but most of them fall into the group known as lactic acid bacteria and are normally consumed in the form of yogurt, fermented milk, or other fermented foods.
Data from clinical trials have shown contrasting effects and should be interpreted with caution. A large variety of potential beneficial effects have been reported including improvement of intestinal tract health, enhancing the immune system, reducing symptoms of lactose intolerance, decreasing the prevalence of allergy in susceptible individuals, reducing risk of certain cancers, treating colitis, lowering serum cholesterol concentrations, reducing blood pressure in hypertensives, and improving female urogenital infections and Helicobacter pylori infections. The aim of this article is to present a review of the current expanding knowledge of applications of utilizing probiotic microorganisms in the prevention and treatment of several diseases.
Keywords: Human disease, prevention, probiotic.
INTRODUCTION
Probiotics, (according to the FAO/WHO) are defined as
“Live microorganisms which when administered in adequate amounts confer a health benefit on the host” [1-3].
The history of probiotics started at the beginning of 20
thcentury with a hypothesis first presented by Nobel Prize winning Russian scientist Elie Metchnikoff, who claimed that the long, healthy life of Bulgarian peasants resulted from their consumption of fermented milk products. He further reported that the organisms presented in yogurt are necessary to protect the intestine from the damaging effects of other harmful bacteria [4].
The essential criteria for classifying microorganisms as ideal probiotic preparations include: be generally recognized as safe (GRAS), be resistant to bile, hydrochloric acid and pancreatic juice, have anti-carcinogenic activity and stimulate the immune-system, have reduced intestinal permeability, produce lactic acid, be able to survive both the acidic conditions of the stomach and the alkaline conditions of the duodenum, be able to survive gastric transport, exhibit antagonistic activity against bacterial pathogens, be able to
*Address correspondence to this author at the Applied Micobiology Research Centers, Baqiyatallah University of Medical Sciences, Tehran, Iran; Tel/Fax: +98-21- 88068924;
E-mails: [email protected], [email protected]
adhere and colonize the intestinal epithelium of the hosts, be viable during processing, transporting, and storage and result in clinically demonstrable health outcomes [5, 6]. The most common organisms in probiotic preparations are Lactobacillus, Bifidobacterium, Escherichia, Enterococcus, Bacillus, and Streptococcus. Some fungal Saccharomyces strains have also been used [7, 8]. Commensal bacteria in gut flora that play key roles in human health include probiotic genera such as Lactobacillus and Bifidobacterium [9].
Human foods containing probiotics include fermented milks, cheeses, fruit juices, wine, cereals, and sausages that may be prepared with single or multi cultures [10].
Commercial probiotics can be dispensed as a powder, liquid, gel, paste, granule, capsule, or sachet [6].
Current dosages of probiotic administration range from 10
8through to 10
11colony forming units (CFU) per day [11].
ACTIONS OF PROBIOTICS
Probiotics can exert alterations in gut microbial milieu
through several mechanisms that result in stabilized host
health (Fig. 1). It is important to note that each species and
strain of these microbes has unique properties and it own
effective actions, so that knowledge is required to select an
appropriate strain for treatment. Data obtained from previous
studies has shown that ingestion of probiotics abates
pathogen microorganism concentrations in the gastrointes-
tinal tract as a result of nutrition and site binding competition between the commensal species and the pathogenic one.
Probiotics attach to intestinal epithelial cell receptors by various proteins such as mucus binding proteins, anchorless housekeeping proteins, surface large proteins, LPXTG motif proteins, transporter proteins, and glycolipids. They stabilize tight junction integrity and block transporting of pathogens and their substances across the paracellular route [12].
Furthermore, to enhance the mucus barrier, probiotics overexpress MUC2 and MUC3 [13].
In addition to prevention of pathogen colonization, probiotics create an unfavorable environment through secretion of antimicrobial factors such as bacteriocin, NO, defensin, and H
2O
2. To attenuate pathogen growth, probiotics remove essential nutrition and alter local pH by acetic acid, lactic acid, and fatty acid production. Probiotics can also interact with toxins derived from pathogens [12].
Since the gastrointestinal tract has the largest lymphoid compartment, the presence of commensal bacteria affects the immunity mechanism of the host. The function of cells and components involved in innate and adaptive immunity such as APCs, NK cells, B and T cells, cytokines and antibodies are modulated by probiotics. DNA derived from the probiotics attaches to Toll-like receptors, blocks NF-B, and stabilizes the IB factor [14]. Metabolites produced by probiotics immediately inhibit heat shock protein degradation mediated by proteasomes, resulting intestinal cell protection [15]. Furthermore, probiotic bacteria are able to prevent apoptosis in a cytokine dependent manner following anti-apoptotic Akt/protein kinase B activation and MAPK signaling by blocking by IFN-, TNF- and IL 1- [16].
Several studies have reported the potent abilities of numerous probiotics or their substances in the stimulation of
humeral immune system to secret specific antibodies, especially sIg A [17].
EFFECTS OF PROBIOTICS IN HEALTH MAINTENANCE AND DISEASE PREVENTION
Probiotics seem to have promise in the prevention or treatment of several diseases. The following section describes some beneficial effects of probiotic preparations in the prevention, prophylaxis and treatment of human diseases.
Table 1 summarizes some mechanisms contributing in disease.
Diarrhea
Functions of the intestinal compartment can be interfered with by many different diarrheal causes. Probiotics have a potent effect on attenuation of the incidence or duration of certain diarrheal diseases. The most important role of probiotics in inhibiting infection is their ability to compete with pathogenic viruses or bacteria for attachment to sites on epithelial cells [7, 18-20]
Data obtained from the pediatric population suggest that probiotics benefit viral diarrhea through increasing antibody (as IgA) secretion and lowering viral shedding, suggesting an immunological mechanism [7].
They also decrease the intestinal pH, release bactericidal components such as organic acids (lactic, acetic, butyric acid), H
2O
2and bacteriocines, regulate nitric oxide synthesis, attach to the mucosal surface of epithelial cells, compete for fermentable substrates, produce gut-protective metabolites (arginine, glutamine, short-chain fatty acids and conjugated linoleic acids), induce toxin degradation, modulate intestinal motility and mucus production, and prevent selected intracellular mechanisms involved in viral replication (such as MEK, PKA, p38 MAPK) [21, 22].
Fig. (1). Schematic illustration of several mechanisms involved in probiotic action to protect host health.(
: Probiotic bacteria,
: Pathogen, : NO molecule, :Bacterial toxin, : H
2O
2molecule).
Data obtained from an early meta-analysis showed dose- related efficacy of lactobacilli strains against gastroenteritis [23]. A further study reported correlation of both strain- dependent and dose-dependent (at least 10 billion/day is necessary) with probiotic efficacy [24]. Several recent clinical trial studies were summarized in Table 2.
Viral Diarrhea
Several clinical studies have reported that probiotics can shorten the duration of viral diarrhea (Table 2). Using Lactobacillus GG to treat acute infectious diarrhea, especially rotavirus diarrhea, in infants and children produced the most consistent effect [20].
Traveler’s Diarrhea
Residents of developed countries traveling to subtropical and tropical zones suffer increased traveler’s diarrhea incidence (3 times or more). Drinking a Lactobacillus GG strain significantly decreased the prevalence of diarrhea in travelers [25].
A meta-analysis showed that probiotics significantly prevent traveler's diarrhea [26]. Several clinical trials were reported in Table 2.
Antibiotic Associated Diarrhea
Antibiotic associated diarrhea (AAD) occurs in 11-40%
of children upon administration of broad-spectrum antibiotics and about 5-25% of adult patients; 25% of the latter are caused by Clostridium difficile [27].
Michael de Vrese et al. suggested that administration of probiotic strains, especially Lactobacillus Rhamnosus strain GG (LGG) and Saccharomyces boulardii, before and during antibiotic treatment and also during triple therapy for H.
pylori eradication reduced the frequency and/or duration of diarrhea, but it was not always effective [18].
Several meta-analyses have shown reduced incidences of AAD in probiotic treated patients [28].
Helicobacter pylori
Helicobacter pylori is the most common chronic bacterial infection in man; it can lead to gastric ulcers, gastric cancer, lymphoma, and several non-gastrointestinal disorders.
Results obtained from several in vitro studies have suggested that some strains of Lactobacilli or culture supernatant are capable to inhibit H. pylori and alleviate the deletion rate of H. pylori (Table 2).
In addition, pre-treatment and administration of probiotic in in vivo models was shown to avoid or reduce H. pylori infections.
Several mechanisms are involved in H. pylori counteraction by probiotics. The probiotics induce H. pylori aggregation and compete with them to attach to binding sites on gastric epithelial cells. In addition, high amounts of dendritic receptor specific interacellular adhesion molecule 3-grabbing non integrin and CpG sequences in the probiotic decrease H. pylori colonization. Additionally, inflammatory response modulatory effects such as differential regulation of cytokine production recognized by Toll-like receptors, IgA secretion improvement, enhancement of DC function, mucin release stimulation from epithelial cells, and down- regulation of H. pylori virulence factor production are factors contributing to preventing infection development.
Therefore, probiotics can be used in patients with antibiotic adverse reactions as an alternative therapy [29, 30].
Vaginosis
Vaginosis can be caused by various organisms, and in many cases, the causative agent may not be identified.
Lactobacilli predominate in the healthy vagina, and vaginosis is caused by a shift in vaginal flora from hydrogen peroxide-producing Lactobacillus species to anaerobes that raise the vaginal pH (Table 2) [31].
Several studies suggest that Lactobacilli probiotics can be used to treat urinary tract infections.
Table 1. Summarizes Some Mechanisms Contributing in Disease
Disease Probiotic Mechanisms
IBD IL-10, IL-12, IL-2 TGF-, and T regulation in peripheral blood, TNF-
Diarrhea sIgA secretion, viral shedding, pH, production of organic acids, NO and H2O2, microbial colonization, hydrolysis of toxin Cancer ROS reactivity and mutation, absorb carcinogens on cell wall, DNA damage, modulate enzymes involved in xenobiotics
detoxify
Vaginosis pH, production of H2O2, pathogen colonization.
Kidney stone Express oxalyl CoA decarboxylase and formyl CoA, Transferase, Oxalate degradation Lactose intolerance Produce lactase, hydrolyse lactose to glucose and galactose
Control of cholesterol Assimilate and degrade cholesterol molecules, Deconjugate cholesterol to the bile acid
Hypertension Production of antihypertensive substances such as cell wall components and - amino butyric acid Hepatic Disease hyperamonemia, inflammatory and oxidative stress, toxin uptake, TNF- and NK cell in liver
Allergy
Modulate the toll-like receptors and the proteoglycan recognition proteins of enterocytes, leading to activation of dendritic cells and Th1 responses, Stimulation of Th1 cytokines and suppress Th2 responses, of IFN- production and IgE and antigen- induced TN F-, IL-5, and IL-10 secretion
One study showed that consumption of yogurt containing L. acidophilus decreased the incidence of Candida yeast infections [32].
Inflammatory Bowel Disease
Inflammatory Bowel Disease (IBD), including ulcerative colitis and Crohn’s disease, is a group of bowel disorders characterized by unpredictable and spontaneous periods of
Table 2. Several Recent Clinical Trials Done on Infectious DiseaseClinical Trials Participants/Duration Treatment Outcome Ref.
Acute Diarrhea
R, B, CT 684 patients/7 d L. rhamnosus GG No significant difference in duration [33]
R. DB, PC 224 infants/10 d L. rhamnosus GG No significant difference in duration
or frequency of diarrhoea [34]
R, PC 50 children/5 d L. reuteri duration and frequency of diarrhoea [35]
R. DB, PC 113 children/NA E. coli Nissle 1917 frequency of diarrhea [36]
R. DB, PC 64 children/5 d S. boulardii, L. rhamnosus,
L. acidophilus, B. longum duration of diarrhea and fever
by S. boulardii [37]
Traveler Diarrhea
R. DB, PC 174 adult/1 d before
Till 3d after travel non viable L. acidophilus No effect in incidence of diarrhea [38]
R. DB, PC 245 adult/1-3w L. rhamnosus GG incidence of diarrhea [39]
R. DB, PC 820 adult/1-2w L. rhamnosus GG No significant incidence of diarrhea [40]
R. DB, PC 92 adult/2w L. acidophilus, l. bulgaricus,
B. bifidium, S. thermophilus incidence of diarrhea [41]
ADD
R. PC 240 children & adults/during
Ab therapy L. rhamnosus
(st, E/N, Oxy and Pen) risk of any diarrhea [42]
R. DB, PC 239 patients/Ab therapy + 1w L. plantarum gastrointestinal symptoms [43]
DB, PC 78 children/during Ab therap B. longum, L. rhamnosus,
L. plantarum No significant diarrhea rate,
frequency of stools per day [44]
R. DB, PC 214 patients/14 d Lactobacillus Maintains their bowel habits,
no effect on rate of AAD [45]
H. Pylori
OR 90 symptomatic children/4w S. boulardii after 10 d triple therapy side effects incidence [46]
R. DB, PC 83 children/7 d Lactobacillus GG plus triple therapy No significant alter the rate
of eradication or side effects [47]
R 78 adults/14 d Bifi. DN-173 010 stomatitis and constipation [48]
DB, PC 40 dyspeptic adults/28 d L. reuteri Suppress H. pylori infection,
dyspeptic symptom [49]
DB, PC 124 dyspeptic adults/2w S. boulardii adverse effect [50]
DB, PC 206 symptomatic adults/7 d Lactobacillus spp., Bifidobacterium spp.,
S. thermophilus plus Lactopheri eradication rate, adverse effect [51]
Vaginosis
OCT 40 female patients/2y L. rhamnosus Restore the physiological vaginal pH,
control BV symptoms [52]
R. DB, PC 95 women after treatment
vaginosis and Candidiasis/5 d L. gasseri, L. casei, L. fermentum,
P. acidilactici recurrences, vaginal colonization [53]
R. DB, PC 120 women//7 d L. rhamnosus, L. acidophilus, S. thermophilus BV recurrence and G vaginalis [54]
R. DB, PC 65 HIV-infected women/6m L. rhamnosus GR-1, L. reuteri RC-1 beneficial vaginal pH, not
enhanceing the cure of BV [55]
R, PC 24 women with VB/2w L. crispatus CTV-05 No find grade 3 or 4 AE,
no deep epithelial disruption [56]
R, randomized; DB, double-blind; PC, placebo-controlled; d, day; W, week; M, month; NA, not available; Ab, antibiotic therapy; OR, open-randomized; OCT, open clinical trial;
BV, bacterial vaginosis; AE, adverse effects.
remission and relapse. Despite expanded studies, the causes of such diseases are unknown.
Recent clinical and experimental observations noted that probiotics have been extensively used to prevent and treat inflammatory bowel diseases (Table 3). The mechanism of action includes changes in the normal flora in the gut, stimulation of the host immune responses, and reduction of the oxidative reactions due to the organisms’ antioxidant properties and antioxidant enzyme production. These results have been demonstrated principally using animal models and human trials [57].
Cancer
Mutation or improper activation of genes that contribute to regulating cell growth and division can lead to cancer.
One of the events that can increase the occurrence of abnormal cells is chemical exposure.
Several studies have observed that carcinogens, co- carcinogens, or pro-carcinogens produced by the general population of intestinal bacteria can promote colon cancer occurrence. In contrast, other findings have described that probiotic bacteria may aid in avoiding colon cancer (Table 3) [58].
Mechanisms involved in colon cancer avoidance by probiotics include detoxification of food carcinogens;
modification of physicochemical conditions in the intestine that attenuate populations or metabolic activities of bacteria that may produce carcinogenic compounds; generation of antitumourigenic or antimutagenic compounds; production of short-chain fatty acids like butyrate, acetate and propionate, that decrease the pH of colonic contents, which may contribute to cancer prevention; incitement of the immune system to better defend against cancer cell proliferation; prevention of DNA damage in certain colonic cells, and other mechanisms that prevent adherence, colonization of pathogenic bacteria in the intestinal wall, and entry of pathogens and allergens into the bloodstream by increasing mucus secretion, tightening the mucosal barrier, and producing bacteriocins and antitoxins [5, 59].
One clinical study showed an increased recurrence-free period in subjects with bladder cancer [60].
Hepatic Disease
Hepatic encephalopathy (HE) is a liver disease with unknown pathogenesis. It is believed that gut-produced ammonia plays a key role in its pathogenesis.
Several studies (Table 3) have demonstrated the strong efficacy of probiotics in the treatment of hepatic encephalopathy by decreasing total ammonia in the portal blood, reducing inflammation and oxidative stress in the hepatocyte following increased clearance of ammonia and other toxins and finally attenuating uptake of toxins [61, 62].
A study of 97 patients observed the beneficial effect of a synbiotic (mixture of a probiotic and prebiotic) on minimal liver encephalopathy with a decrease in ammonium levels as well as the improvement of symptoms of hepatic encephalopathy [63].
Hypertension
High levels of blood cholesterol, diabetes, improper modulation of rennin, imbalanced sexual hormones, and obesity are risk factors causing hypertension [64].
Studies suggest that consumption of certain lactobacilli, or their formulation, may reduce serum cholesterol and improve lipid profiles, subsequently attenuating the risk of hypertension (Table 3) [65].
Kidney Stones
Elevated levels of oxalate in urine are a risk factor for kidney stones. Oxalate usage by intestinal microbes restricts its absorption. Patients fed probiotics demonstrated low levels of oxalate in their fecal excretion; therefore, probiotic formulations that contain bacteria can degrade oxalate in vitro, thus reducing oxalate fecal excretion in patients. This study suggests that modification of the gut flora with probiotic bacteria may improve gastrointestinal tract oxalate levels and may attenuate oxalate absorption [66, 67].
Lactose Intolerance
Data from numerous studies (Table 3) have shown that the appropriate strains of lactic acid bacteria in fermented milk products can relieve symptoms of lactose intolerance by secretion of bacterial lactase into the intestine and stomach [5, 68].
Control of Blood Cholesterol and Hyperlipidemia
One of the most potent risk factors for developing coronary heart disease is a high level of total blood cholesterol or other blood lipids. Assimilating, binding, and degradation functions are three useful mechanisms for attenuating absorption of dietary cholesterol.
Probiotic strains (Table 3) can remove the cholesterol for their own metabolism and degrade it to its catabolic products. Bile acid deconjugation of cholesterol is an indirect way to decrease the level of total blood cholesterol [5, 69 and 70].
Allergy
Allergy is defined as a hypersensitivity reaction initiated by specific antibody-mediated or cell-mediated immunologic mechanisms. The prevalence of allergic diseases have increased considerably in recent decades, especially in countries with western lifestyle that characterized by high standard of hygiene, reduced exposure to microbes in daily environments, reduced consumption of fermented food, irrational use of antibiotics and other drugs [99-101]. Here are some of clinical trial studies on anti-allergic effects of probiotics.
A randomized prospective double blind controlled trial study found out a probiotic (Lactobacillus casei DN-114 001) supplementation decreased the number of rhinitis episodes in children with allergic rhinitis [102].
In another randomized placebo-controlled trial,
administration of probiotic supplementation containing
specific strain (Lactobacillus GG) to pregnant mothers with atopic eczema, allergic rhinitis or asthma and postnatally for 6 months to their infants can be effective in prevention of early atopic disease in children at high risk [103].
Previous studies have demonstrated that consumption of probiotic supplementation can reduce the incidence of atopic
dermatitis, cow’s milk allergy and the severity of allergic manifestations [104, 105].
One study showed that a Lactobacillus rhamnosus lysate may be better choice for prevention and treatment of atopic diseases [106].
Table 3. Several Recent Clinical Trials Done on Non-Infectious Disease
Clinical Trials Participants/Duration Treatment Outcome Ref.
IBD
R, PC, DB 35 CD patients/3m B. longum Improving clinical symptoms [71]
R, PC, DB 75 CD children/2y L. rhamnosus GG No prolonging of time relapse [72]
R. DB, PC 147 UC patients/12w VSL#3 in UCDAI scores andinduce remission [73]
R. DB 90 UC patients/2w E. coli Nissle 1917 remission Time [74]
R. DB, PC 32 UC patients/52w L. acidophilus La-5,
B. animalis subsp. lactis BB-12 Non significant effect [75]
Cancer
R, PC, DB 100 CRC/6 d pre and 10 d
Postoperatively L. plantarum, L. acidophilus, B. longum blood enteropathogen, faecal bacterial variety
Improved peristalsis, diarrhea [76]
R, PC, DB 31 CRC/3 d pre and 2 d
Postoperatively B. longum, L. johnsonii (La1) concentration of pathogens (La1)
Modulates local immunity (La1) [77]
R, PC, DB 37 colon cancer/12w L. rhamnosus GG, B. lactis and inulin colorectal proliferation & necrosis [78]
RCT 102 bladder cancer/1y L. casei plus epirubicin 3-year recurrence-free survival rate [79]
RCT 23 bladder cancer/NA L. casei Prevent the recurrence of superficial bladder cancer [80]
Hepatic Disease
R, PC, DB 36 patients/6m L. acidophilus, L. bulgaricus,
B. lactis, S. thermophiles the ammonia levels in ammonia levels > 50 mmol/L [81]
R 25 paitients/2m yogurt Significant rate of MHE reversal [82 ]
O, RCT 190 cirrhotic patients/1m S. faecalis, C. butyricum,
B. mesentricus/Lactulose/both All are equally effective in the treatment of MHE [83]
R, PC, DB 60 cirrhotic patients/90 d B. longum with FOS NH serum, improved biochemical and
neuropsychological tests [84]
Hypertension
R, DB, PC 40 HNB subject/4w L. helveticus elevated blood pressure [85]
R, PC 39 mild hypertensive/21w L. helveticus cystolic and diastolic BP [86]
R, DB, PC 94 hypertensive/10w L. helveticus cystolic and diastolic BP [87]
R, DB, PC 70 healthy/8w L. acidophilus, S. thermophilus cystolic and diastolic BP [88]
R, PC, DB 46 borderline hypertensive L. helveticus cystolic BP [89]
Lactose Intolerance
Pilot study 5 adults/17 d VSL#3 Non significant effective [90]
Study 11 adults/2w B. longum, B. animalis Alleviates symptoms [91]
SB, R 130 children/2w live and killed probiotics breath hydrogen test [92]
R, PC 60 patient/10 L. reuteri or tilactase vs placebo of mean peak H2 excretion
Improve gastrointestinal symptoms [93]
Hypercholestrolemia
R, PC 24 men/21d fermented milk (Wild Lactobacillus) Hypocholesterolemic effect [94]
R, PC 29 woman/21w L. acidophilus145, B. longum 913 HDL-cholesterol, LDL/HDL ratio [95]
PC 20 Swicc mice/42 d L. casei NCDC-19, S. boulardii LDL and serum cholesterol [96]
R 36 H.C rats/21days L. acidophilus total serum cholesterol, VLDL+IDL+LDL [97]
R, CT 14 healthy cases/6w L. acidophilus, B. lactis serum total cholesterol [98]
R, randomized; DB, double-blind; PC, placebo-controlled; d, day; W, week; M, month; Y, year; NA, not available; Ab, antibiotic therapy; O, open; RCT, randomized clinical trial;
CD, Crohn's disease; UC, ulcerative colitis; UCDAI, Ulcerative Colitis Disease Activity Index; CRC, colorectal cancer, MHE, minimal hepaticencephalopathy; HNB, high normal blood pressure; SB, single-blinded.
According to current data, recommending probiotics as preventive treatment for atopic dermatitis, allergic sensitization, and asthma is not reliable [107, 108].
Conduction with a mixture of 4 probiotics and prebiotics in a randomized, double-blind, placebo-controlled trial study was shown incidence of eczema and atopic eczema decreased during the first 2 years of life but not so distinct [109].
However, the results obtained from several trials have been contradictory with regard to the type of probiotic used, dosing, period of administration and host genetics [110].
One study concluded that oral therapy with the probiotic mixture (VSL#3 and Lactobacillus casei strain Shirota) can cause reduction of anaphylactic symptoms in a food allergy model [111].
HIV and Immunomodulation
Individual species of LAB bacteria exert different immunomodulator actions may stimulate the immune response.
Some of immunomodulations including amplified mucus production, macrophage activation, stimulation of secretary IgA, decreased proinflammatory cytokine production, induced anti-inflammatory cytokines, increased peripheral immunoglobulin production and stimulated phagocytosis have occurred during in vivo studies on probiotics [112].
LAB directly influences antigen presenting cells such as dendritic cells, monocytes, macrophages, and B-cells, without being the origin of antigen [113].
Several Studies reported that phagocytic activity in polymorphonuclear and/or macrophage increases after supplementation with some probiotic strains (L. casei, B.
lactis, L rhamnosus) or a combination of L. acidophilus and B. animalis ssp. lactis or a combination of those two strains with L. paracasei [114].
Incitation of cytokines and maturation markers in APC due to LAB presence together with the any type of antigen can be a determinant factor ensuring T-cell response. In comparison, LAB incitement of monocyte/macrophage responses to Gram-negative bacteria has shown that LAB
preferentially induces IL-12 expression whereas Gram- negative bacteria such as E. coli mainly induce IL-10 production.
A study conducted by Mohamadzadeh et al. showed that L. gasseri, L. johnsonii and L. reuteri were able to induce secretion of IL-12 which consequently skews T-cell polarization toward Th1 and Tc1 cells [115].
It is generally confirmed that IL-12 induces IFN- expression in human NK cells. IFN- production by NK cells is necessary to induce Th1 responses in lymph nodes.
In addition to the described effects, temporary activation of NF-B pathways is an important mediator in regulation of cytokines, chemokines and receptor expression following inflammatory and immune responses, was stimulated by commensal bacteria (such as probiotics) in enteric epithelial cells [116].
Several studies from in vitro systems, animal models, and humans suggest that probiotics can enhance both specific and nonspecific immune responses [117-120].
Yogurt containing a novel strain, L. rhamnosus CAN-1, may act as an important functional food and also provide adjunct benefits for nutrition and immune function for people living with HIV [121].
Several studies suggested that probiotic microorganisms could be able to delay damage of immune system or help to preserve its function in HIV infected patients [122-124].
New Field in Probiotic Studies
In addition to studies of probiotic effects on man health and diseases, other type of studies termed "designer probiotic" or
"path-biotechnology" were performed to provide a new generation with improved characteristics. In this field, one of the interested genes in microorganisms is modified to obtain appropriate activity such as tolerance to bile and acid during gastero-intestinal tract transition, resistance to osmo-, cryo-, baro- and oxidative stresses during bioprocess and cell surface adhesion improvement. Furthermore, using these microorganisms as vaccines and drug delivery systems are interested fields for researchers. Table 4 summarizes few examples of these kinds of studies [125].
Table 4. Examples of Resistant Strains Construction
Gene Protein Probiotic Function Ref.
Sod A manganese- superoxide dismutase L. gasseri Oxidative stress resistant [126]
MnKat manganese catalase L. plantarum Oxidative stress resistant [127]
MnKat manganese catalase L. casei BL23 Oxidative stress resistant [128]
MnKat manganese catalase L. casei Oxidative stress resistant [129]
BetL betain uptake L. salivarius Osmo-, cryo, baro stress resistant [130]
BetL betain uptake B. breve Osmo-, cryo, baro stress resistant [131]
spaCBA pilin protein L. rhamnosus Improve cell surface adhesion [132]
TTFC C subunit of tetanus toxin L. plantarum, L. lactis Vaccine [133]
IL-10 interleukin-10 L. lactis Drug delivery [134]
CONCLUSION
There is a large amount of promising data on the preventive and therapeutic effects of probiotics in several diseases.
Nevertheless, due to some contraries among results of different trial studies on probiotics effects, they should be considered with caution.
The direct effects of probiotics in GI tract are well documented such as enhancing the mucus barrier, upregulation of immunoglobulins such as IgA, downregulation of inflammatory cytokines, creating an unfavorable environment through secretion of antimicrobial factors such as bacteriocin, NO, defensin, and H
2O
2.
Genetic changes imposed on probiotics provide the new generation which offers novel applications in treatment and/or prevention of multiple diseases.
ACKNOWLEDGEMENT
We thank Dr. Barbara Lee Smith Pierce (University of Maryland, University College Scientific and Medical Editing, Baltimore, USA) for editorial work in the preparation of this manuscript.
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