Do Probiotics Prevent or Treat Human Disease?

A

a Critical Appraisal of the Literature

by Kim Whitaker

Abstract

Probiotics are a widely consumed dietary supplement used in the prevention and treatment of a range of human diseases. There is a need for a strong literature review in order to advise patients and the public about the benefits and risks of probiotic supplementation. It is hypothesized that probiotics are not a catchall treatment for human health and disease, but rather will prove to be beneficial in the treatment or prevention of some conditions, while ineffective in others. A literature search was performed using Medline, for the last 10 years, in search of English-language, human randomized controlled trials and meta-analysis using probiotics for various human health and disease conditions. Research was found on the use of probiotics in the treatment of gastrointestinal health, atopic conditions, bacterial vaginosis, and more recently metabolic syndrome and obesity. As hypothesized, probiotics were not globally effective in all areas of human health and disease. Probiotics were found to be effective in the treatment or prevention of some health conditions, ineffective in others, while still some areas were insufficiently studied and require more research. Particularly, in the area of obesity, insulin resistance and metabolic syndrome, research is still in its infancy; and although an important link between these areas and probiotics is shown, whether probiotics will represent a treatment choice in these multifactorial diseases requires more study.

Introduction

The human gut is home to an ecosystem of live microorganisms, consisting of thousands of species that confer a mutualistic benefit to human health, the most significant of which is modifying the human immune system. The gut is home to the majority of the human immune system located in mucosa-associated lymphatic tissue (MALT). This MALT system is a first-line defense against invading microbes, and it has been shown that the human gut microbiota represents an integral piece to this protection system. Furthermore, a healthy balance of gut microorganisms is known to regulate inflammatory cytokines, having an impact on both local inflammation, as well as systemic inflammation. Disruption to this ecosystem, termed dysbiosis, is linked with human health and disease processes. The most studied areas include infectious disease at the gut level (gastroenteritis), inflammatory diseases of the gut (inflammatory bowel disease), as well as more distant immune deregulations (atopic disease).

The link between dysbiosis and human health and disease has led to the development of the use of these commensal microorganisms, termed probiotics for prevention and treatment of human health and disease. Probiotics are defined as “live microorganisms which when administered in adequate amounts confer a health benefit on the host” (Salminen 1998). Probiotics have been studied for a wide range of health conditions, and the strains most often studied include various species of Lactobacillus and Bifidobacterium and the probiotic yeast Saccharomyces boulardii. Probiotics have become a widely used dietary supplement, available as capsules, tablets, and powders, as well as commercially available in yogurts and yogurt drinks. In the US, probiotics are among the top five most frequently used natural products for children (NCCAM 2011). In addition to supplementing live organisms, prebiotic oligosaccharides are also used to support the growth of probiotic organisms. Prebiotics are defined as “a selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microflora that confers benefits upon host well being and health” (Roberfroid 2007). To fulfill criteria as a prebiotic, these oligosaccharides must resist hydrolysis by gastric acid, resist absorption, resist fermentation by microbiota, and promote the growth and/or activity of commensal intestinal microbiota (Roberfroid 2007). A third category of supplements is called synbiotics. These products contain both probiotic organisms as well as the prebiotic oligosaccharides.

The mechanism of effectiveness of probiotics has not been fully elucidated, however may include modifying host gut microbiota from dysbiotic to synbiotic states, competitive adherence to the host epithelial lining crowding out dysbiotic organisms, and rebalancing of host immunity and reducing inflammatory cytokines, and rebalancing anti-inflammatory cytokines (Bermudez-Brito 2012).

The intestinal barrier is composed of a mucosal surface, antimicrobial protection including secretory IgA defenses, and epithelial tight junctions. Any disruption to this barrier, including damage to tight junction proteins such as cadherins, leads to “leaky gut function” and the ability of food antigens, and bacterial products to cross to the submucosa and induce an inflammatory response (Bermudez-Brito 2012). Probiotics have been shown to enhance gastrointestinal barrier function, by increasing expression of tight junction proteins, such as zonula occludens (ZO-2). Furthermore, by downregulating pro-inflammatory cytokines, damage to the intestinal epithelium can be reduced using probiotics (Bermudez-Brito 2012).

Probiotics have also been shown to induce release of defensins and antimicrobial proteins (AMPs) such as alpha and beta defensins, cathelicidins, C-type lectins. and ribonucleases. Furthermore, probiotics such as Lactobacilli and Bifidobacteria have been shown to inhibit human enteroviruses and pathogenic bacteria, including Salmonella, E. coli, Helicobacter pylori, Listeria monocytogenes, and Rotavirus (Bermudez-Brito 2010). By producing antimicrobial substances such as lactic acid and acetic acid, probiotics modify the epithelial environment to be more favorable for themselves, while outcompeting other bacteria/viruses that cannot withstand this acidic environmental modification.

Many atopic conditions have been attributed to a “hygiene hypothesis” that has been further revised with a Th1/Th2 imbalance hypothesis. These theories attribute atopy to the lack of exposure of children in the industrialized world to infectious disease, parasitic infections, and symbiotic microorganisms (i.e., probiotics) while increasing susceptibility to atopy by suppressing development of the natural immune system. More specifically, the Th1 component of the immune system is suppressed, leading to an overdominant Th2 response, leading to allergic diseases and immune dysregulations. Th2-dominant responses lead to inflammatory cytokine production, including IL4, IL5, and IL13, with resultant IgE and eosinophil production. This relationship is supported by studies showing that nonatopic infants have better colonization of Lactobacillus and Bifidobacterium, whereas atopic infants have more Clostridium species.

Some strains of probiotics have been shown to exert anti-inflammatory effects, such as L. casei-inducing production of IL10 an anti-inflammatory cytokine. While other strains, such as L. reuteri, have been shown to be pro-inflammatory, via TNF-alpha and IL12, selection of appropriate strains for specific conditions is of paramount importance.

Given these mechanisms of action, probiotics have been studied for diseases of both gastrointestinal origin as well as systemic diseases. Probiotics have been studied for both diseases of infectious or dysbiotic origin, including bacterial vaginosis, gastroenteritis, antibiotic-associated diarrhea (AAD), postcolorectal cancer surgery (infection prevention), and diseases of inflammatory or immune dysregulatory origin, such as atopic dermatitis, seasonal allergic rhinitis (SAR), inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS) and functional abdominal pain (FAP), and neonatal necrotizing enterocolitis. More recently, probiotics have been studied for the major lifestyle diseases of Western society including obesity, type 2 diabetes, and metabolic syndrome due to the fact that people with these diseases demonstrate dysbiosis in their gastrointestinal tracts.

Animal models have shown a link between reduced Bifidobacterium and obesity as well as with high-fat diets. A reduction in colonization with Bifidobacterium has been simultaneously linked with increased inflammatory activity, increased fat mass, and insulin resistance (Esteve et al. 2011). It has been further shown that probiotic strains have anti-inflammatory activities, antidiabetic activities, and improved insulin sensitivity in their hosts. Therefore research is being conducted to elucidate the role of probiotics as a therapeutic tool in the prevention or treatment of obesity and diabetes.

The rapid growth in the use of probiotic supplements in the US, along with growing consumer interest, creates a need for strong research in probiotics for the prevention and treatment of specific health conditions. The goal of this review article is to analyze the research on probiotics and to demonstrate that probiotics are not a catch-all treatment for all diseases, but effectively treat or prevent some human diseases and are ineffective in others.

Methods

Medline was searched in July 2012 using the following search terms, and limited to English language, human clinical trials or meta-analysis, limited to the last 10 years.

“probiotics and therapeutic use”

“probiotics and obesity”

“probiotics and treatment outcome”

“probiotics and RCTs”

Papers were excluded where the primary research subject was not a therapeutic use of probiotics for human diseases or conditions. The primary research studies (n = 18) were then subdivided into the following categories for organizational purposes:

1. metabolic syndrome, obesity, and diabetes (n = 2)

2. gastrointestinal disease (n = 11 total)

   1. irritable bowel syndrome (IBS; n = 4)

   2. antibiotic-associated diarrhea (AAD; n = 1)

   3. neonatal necrotizing enterocolitis (NEC; n = 1)

   4. gastroenteritis/traveler’s diarrhea (n = 1)

   5. colorectal cancer surgery (n = 1)

   6. inflammatory bowel disease (IBD): Crohn’s (n = 1) and ulcerative colitis (n = 2)

1. bacterial vaginosis (n = 1)

2. atopic dermatitis (n = 2) and seasonal allergic rhinitis (n = 2)

Results

Luoto Kalliomaki et al. (2010) hypothesized that early use of probiotics will alter gut microbiota and immunologic health of infants, and reduce the development of obesity and reduce the risk of allergic disease. Pregnant mothers (n = 159) were randomized to receive either probiotic (1 × 10¹⁰ CFU Lactobacillus rhamnosus GG) or placebo once a week for 4 weeks before delivery, and following delivery for 6 months. The postdelivery probiotics were given direct to infants in water in non-breast-feeding mothers. Follow-up occurred after delivery, age 2 weeks, 3, 6, 12, and 24 months, and 4, 7, and 10 years. In this study, children who were defined as overweight at age 10 tended to be overweight at birth (p < 0.005), and mean BMIs over the 10-year follow-up showed constantly and increasing higher at every measure compared with normal-weight children (p < 0.001, ANOVA). This study found an initial phase of weight gain between fetal periods continuing until 24 to 48 months of age. A second growth phase occurred after 24 to 48 months, particularly in the already overweight children. When comparing the overweight children of the probiotic group with the placebo group, the BMI of children in the probiotic group was significantly lower at every measure, but most pronounced at age 4 years. However, there was no statistically significant difference (p = 0.063).

Luoto, Laitinen, et al. (2010) conducted another study using perinatal probiotics with the hope of reducing risks of Western lifestyle diseases. Pregnant mothers (n = 256) were randomized to the treatment group or control group. The control group received intensive dietary counseling alone, or dietary counseling plus probiotics (L. rhamnosus and B. lactis 10¹⁰ CFU /d) from the first trimester of pregnancy to the end of exclusive breast-feeding. Pregnant women were followed three times during their pregnancy, and infants were followed at 1, 6, 12, and 24 months.

Luoto, Laitinen, et al. (2010) found that dietary counseling in combination with probiotics had a significantly decreased risk of gestational diabetes mellitus (OR = 0.27, p = 0.002), improved plasma glucose and insulin sensitivity. The infants showed no statistically difference in birth weights, length, weight gain, or growth over the study period. The normal growth rates provide evidence that the probiotics were safe for use in pregnant women; however, they did not provide any benefit to the children born to mothers consuming them.

The gastrointestinal mucosa of patients with IBS has increased permeability, and impaired gastrointestinal barrier function. Since, probiotic bacteria function to reduce inflammation and restore barrier function, Zeng et al. (2008) performed a single-blind randomized control trial to determine whether probiotics can in fact improve intestinal mucosal barrier function in diarrhea-predominant irritable bowel syndrome (D-IBS). The study recruited 30 patients with D-IBS defined as negative screening examinations, IBS symptoms with Gastrointestinal symptom rating scale (GSRS) greater than or equal to 4, for at least 2 months, compared with 12 asymptomatic controls. The D-IBS patients received probiotic fermented milk twice daily, 30 min. before meals for 4 weeks, composed of Streptococcus thermophilus (1.0 × 10⁸ CFU/ml), L. bulgaricus (1.0 × 10⁷ CFU/ml), L. acidophilus (1.0 × 10⁷ CFU/ml), and B. longum (1.0 × 10⁷ CFU/ml). Small intestinal permeability was measured at the beginning of the study using lactulose-mannitol test (See appendix for explanation), and found that 68.9% of D-IBS patients demonstrated increased small intestinal permeability, defined as L/M > 0.025, and increased colonic permeability compared with normal controls. Following administration of probiotics, the small bowel permeability decreased significantly at week 4 (P = 0.004) compared with controls. The colonic permeability was unimproved. Furthermore, clinical symptoms improved in the probiotic group compared with controls, measured by reduction in mean global IBS score (p = 0.004). In particular there was a significant decrease in the probiotic treatment group in abdominal pain and flatulence (p < 0.001, P = 0.010). Zeng et al (2008) further strengthened the impact of these results by real-time qPCR analysis showing decreased transcription of ZO-1 and occludin proteins in D-IBS patients compared with controls. These two proteins are components of the tight junctional complexes that form the tight epithelial barrier that is essential in controlling intestinal permeability. Visualization of this tight junctional complex in normal controls showed that staining was strong and continuous, and comparatively discontinuous in approximately 1/3 of patients with D-IBS.

Francavilla et al. (2010) conducted a study on 141 children with IBS or functional abdominal pain (FAP) who were randomized to receive either placebo or Lactobacillus rhamnosus strain GG (LGG) 3 × 10⁹ CFU, twice per day for 8 weeks. Episodes of pain were used as a functional measure of probiotic effectiveness, and it was found that the treatment group had decreased episodes of pain and severity of pain at 12 weeks (p < 0.01). Treatment success defined as decrease in at least 50% in the number of episodes and intensity of pain was achieved in 72% of probiotic treatment group vs. 53% of placebo group (p < 0.03). Parents also reported a statistically significant improvement in their children’s pain by 54% at week 12 and 70% at week 20 vs. 33% and 55% in the placebo group in the same time periods (p < 0.02 and p < 0.04, respectively). The intestinal permeability (IPT) test revealed that children with IBS treated with probiotics showed improvement, but not the children with FAP (p < 0.02). By demonstrating both decreased symptoms and decreased intestinal permeability in the probiotic treatment group the authors are trying to show support for the theory that probiotics are effective in IBS by improving intestinal permeability.

Guglielmettie et al. (2011) studied 122 patients with IBS and randomized them to a placebo group (n = 62) and treatment group (n = 60) that received B. bifidum MIMBb75 1 × 10⁹ CFU. The probiotic treatment group achieved a statistically significant reduction in subjective global analysis (SGA) of IBS symptoms (p < 0.0001), and pain/discomfort (p < 0.0001), and distension/bloating (P < 0.0001), urgency during treatment phase (p < 0.0001), and bowel movement satisfaction (p < 0.0001) when compared to placebo. By using a composite score, Guglielmettie et al. (2011) were able to demonstrate that the probiotic group significantly benefited from the use of Bifidobacterium bifidum MIMb75 compared with placebo. Overall, 57% of treatment group were classified as responders vs. 21% of the placebo group (p = 00001). Furthermore, 43% of patients in probiotic group achieved adequate relief compared to 8% of the placebo group (p < 0.0001). Both physical and mental health, were improved in the treatment group, showing that B. bifidum MIMBb75 significantly improved quality of life.

Silk et al. (2008) studied the use of a prebiotic (trans-galactooligosaccharide mixture) that was shown in previous studies to promote the colonization of Bifidobacteria. The study randomized 44 patients with IBS to 3 groups receiving 3.5 g/prebiotic, 7g/d prebiotic, or 7g/day placebo for 4 weeks. Silk et al. (2008) demonstrated that 4-week treatment with prebiotics resulted in dose dependent increase in Bifidobacterium colonization (p < 0.05 and p < 0.001) for 3.5g/d and 7.0g/d. Simultaneously, the study found significantly lower proportions of Bacteroides (p < 0.005) and C. perfringens histolyticum (p < 0.05) after administration of 7.0g/d of prebiotics. Clinical response to 3.5g/d prebiotic included significant improvement in flatulence (p < 0.05), bloating (p < 0.05), composite Likert scale (p < 0.05), and SGA (p < 0.05). In comparison, treatment with 7.0g/d prebiotic had a significantly greater effect on Composite Likert scale (p < 0.05), anxiety scores (p < 0.05) and quality of life (p < 0.05).

Szajewska et al. (2006) conducted a meta-analysis to evaluate the effectiveness of probiotics in the prevention of AAD in children. By combining the data from 6 RCTs (n = 766 children), the study found that probiotics reduced the risk of AAD in children from 28.5% (placebo) to 11.9% (probiotic treatment).

Lin et al. (2008) conducted a prospective, randomized double-blind controlled trial in 7 NICUs in Taiwan. The study treated very low birth weight (VLBW) preterm infants (<1500 g, <34 weeks) and randomized them to receive breast milk, or breast milk with added Infloran probiotic (L. acidophilus 10⁹ CFU and B. bifidum 10⁹ CFU) twice daily added to breast milk (n = 443). The probiotic treatment group had lower incidence of death and stage 2 or more NEC (p < 0.02; Lin et al. 2008).

Htwe et al. (2008) studied 100 children with acute watery diarrhea in Myanmar. Diarrhea was defined as more than 3 stools per day. In this area, diarrhea is typically caused by enteropathogenic and enterotoxigenic E. coli, in addition to Salmonella, Shigella, and cholera. The children were randomized so that half received oral rehydration solution (ORS) with additional S. boulardii 250 mg twice per day for 5 days, and the control group received ORS alone. The study demonstrated that S. boulardii showed a decrease in the duration of diarrhea (p < 0.05) and reduced frequency of defecation on day 2 (p = 0.019), and by day 3 the probiotic group was twice as likely to reduce defecation frequency to less than 3 per day than the control group. Furthermore, by day 3, 76% of the treatment group was passing solid stools, whereas only 24% of the control group were passing solid stools by this time (p < 0.005).

Liu et al. (2010) conducted a randomized controlled trial of 100 patients with colorectal carcinoma undergoing radical colectomy to determine if preoperative and postoperative treatment with probiotics would decrease the rates of infection postoperatively. The treatment group (n = 50) received L. plantarum, L. acidophilus, and B. longum, a total dose of 2g/d, 2.6 × 10¹⁴ CFU/d. The probiotics were given 6 days preoperatively and 10 days postoperatively. In addition, both treatment and control groups received antibiotic prophylaxis of 500 mg metronidazole and 1g ceftriaxone, given 1 hour before induction and continued for 48 hours postoperatively. The study found the probiotic group had lower rates of bacterial translocation (p < 0.01), and by day 10 lower rates of intestinal permeability than the placebo group (p = 0.04) as measured by lower lactulose/mannitol ratios. Furthermore, the study found the probiotic group had lower rates of infection complication when compared with the control group (p < 0.05).

Rhaimi et al. (2007) conducted a meta-analysis on the efficacy of probiotics for maintaining remission and prevention of relapse of Crohn’s disease. The meta-analysis included 8 trials, with a total of 320 patients with Crohn’s disease, randomized to receive either probiotics or placebo. The authors were unable to show that probiotics maintain remission, or prevent relapse in patients with chronic Crohn’s disease (Rhaimi et al. 2007).

Furrie et al. (2005) conducted a pilot trial on the use of B. longum and prebiotic inulin oligofructose (Synergy 1) in active ulcerative colitis (UC) in order to induce remission or improve disease state. The patients (n = 18) were treated with the synbiotic treatment twice daily for 4 weeks. The study found increased levels of mRNA expression of inducible defensins (p = 0.0078) in rectal biopsies of UC patients receiving probiotic and prebiotic treatment. TNF-alpha and IL-1 alpha, and CRP levels were significantly decreased in the treatment group compared with controls. The treatment group also demonstrated a 42-fold increase in colonization of Bifidobacterium compared with 4.6-fold increase in the control group. The authors examined clinical effectiveness by measuring sigmoidoscopy score (SS), clinical activity index (CAI), and bowel habit index (BHI). The results found SS decreased by 1.3 points, where the placebo group increased and BHI also improved in the treatment group (reduction 20.4%), compared with an increase in the placebo group (increase 70.4%; Furrie et al. 2005) while CAI showed mixed results. Histopathology demonstrated resolution of acute inflammatory processes, resolution of crypt abscesses, and regeneration of epithelium.

D’Inca et al. (2010) conducted a study to determine if rectal administration of L. casei DG would improve colonic microbiota and inflammatory activity including cytokine balance and toll-like receptor (TLR) expression in UC patients. The study took 26 patients with mild UC, defined by the authors as “2-3 stools daily, blood in < 50% stools, hyperemia with indistinct vascular pattern of colonic mucosa, a chronic inflammatory infiltrate of the lamina propria, and a mild architectural disorder or an acute inflammatory infiltrate with mucosal injury and crypt abscesses but no ulcerations.” The patients were divided into three groups and treated for 8 weeks, all groups received 2.4g/d 5-ASA. Group 1 received 5-ASA alone (n = 7), group 2 received oral L. casei DG (8 × 10⁸ CFU/d) twice daily (n = 8), group 3 received rectal L. casei GG (8 × 10⁸ CFU/d) twice daily.

The study found that in patients with UC. there were fewer Lactobacillus species and Enterobacteriaceae species were elevated. Patients treated with rectal L. casei DG had increased Lactobacillus spp. and decrease Enterobacteriaceae and similarly had reduced TLR4 mRNA levels in (p < 0.0004), These trends were not observed in the groups receiving 5-ASA or oral probiotics. Similarly, IL-10 levels (anti-inflammatory cytokine) showed a significant increase and IL-1 beta and TNF-alpha (pro-inflammatory cytokines) showed a significant decrease in rectally treated patients compared with 5-ASA alone (p = 0.05, p = 0.04, p = 0.05 respectively). Furthermore, UC patients treated rectally with L. casei DG also showed clinical improvement in histological disease severity scores, which directly correlated with reduced TLR4 mRNA levels (p = 0.024).

Wang et al. (2010) conducted a double-blind, randomized, placebo-controlled trial to determine the efficacy of vaginal suppositories containing either placebo (n = 62) or 8 billion CFU probiotics (n = 58), consisting of Lactobacillus rhamnosus (6.8 billion CFU), thermophiles (0.8 billion CFU) for 14 days with follow-up at 30 and 60 days in women who had 2 or more episodes of bacterial vaginosis in the previous year but were currently uninfected.

Wang et al. (2010) demonstrated that the probiotic treatment group had lower rates of recurrence of BV through 2 months follow-up (15.8% probiotics vs. 45% placebo; p < 0.01). Between 2 and 11 months BV recurrence was lower in the probiotic vs. control group (10.6% vs. 27.7% respectively; p = 0.04).

Clinically, the probiotic treated group reported reduced symptoms of vaginal discharge, lowered vaginal pH, and reduced presence of clue cells within 2 months of treatment time. Incidence of vaginal discharge and odor between 2 and 11 months was 3 times higher in the control vs. treatment group (Wong et al. 2010).

Nermes et al. (2010) conducted a randomized controlled trial for 3 months on 39 infants with atopic dermatitis comparing a placebo group (n = 20) with a probiotic group receiving oral L. rhamnosus GG (LGG) at 5 × 10⁷ CFU/g (n = 19). The authors examined the effect on skin and gut microbiota and in particular Bifidobacterium:Clostridium ratio and associated humoral immune responses.

Nermes et al (2010) found at 3 months that the number of Ig-secreting cells in the probiotic-treated infants decreased to statistical significance, specifically IgA (p = 0.044) and IgM (p = 0.036), while memory B cells increased (p = 0.009). Decrease in Ig-secreting cells may correlate to improved intestinal permeability and resultant decreased antigen exposure and sensitization. However, this needs to be confirmed in future studies, as there was no statistical significance in SCORAD assessment in severity of atopic dermatitis.

Ivory et al. (2008) conducted a double-blind, placebo-controlled trial for 5 months with 10 seasonal allergic rhinitis (SAR) sufferers who received Lactobacilli milk drink, and 10 SAR sufferers who received placebo. This trial was not designed to draw clinical conclusions but provided insight into the immune response to Lactobacillus casei Shirota (LcS).

Ivory et al. (2008) found that treatment of SAR patients for 5 months with LcS reduced IL5, IL6, IFNgamma, and IgE compared with placebo group. This modification of allergen-induced inflammatory response demonstrates that LcS may be of benefit in patients with SAR.

Lee et al. (2008) conducted a meta-analysis on pediatric atopic dermatitis (PAD) pooling data from 6 prevention trials (n = 1581) and 4 treatment trials (n = 299). The authors found a significant risk reduction (61%) associated with prenatal and/or postnatal probiotics for prevention of PAD. Analysis confirmed probiotic treatment prenatally to be critically important.

Lee et al. (2008) found that although some treatment trials did show some improvement in SCORAD of PAD, the meta-analysis combining the included treatment studies did not show statistically significant difference in PAD when treated with probiotics. Furthermore, the analysis found treatment studies to have more variability in design and smaller sample sizes, and therefore proposed higher-quality treatment trials using probiotics in the treatment of PAD in order for an effective meta-analysis to be conducted.

Ouwehand et al. (2009) studied 47 children with birch pollen allergy, including the symptoms of rhinitis and conjunctivitis. Patients with asthma, habitual probiotic/prebiotic use, and recent antibiotic use were excluded from the study. Patients were randomized for treatment with either placebo or 5 × 10⁹ CFU of 1:4 ratio of L. acidophilus:B. lactis. Patients were examined before, during, and after birch pollen season (March, May, June).

The study found reduced nasal symptoms, lack of nasal eosinophil infiltration, and dampened increase in fecal IgA in the treatment group when compared with the placebo group. At the beginning of the season (March) there was a decrease in IL6 and TNFalpha but not statistically significant midseason (May).

Summary Table

Discussion

According to the CDC (Ogden et al. 2012), nearly one-third of US adults are obese. Obesity-related conditions are among the leading causes of preventable death. The research behind the use of probiotic therapies for obesity, type 2 diabetes, and metabolic syndrome is still in its early stages. There is indeed a link between gut dysbiosis and inflammation (Esteve 2011; Diamant 2010). Animal studies have shown that obesity and high-fat diets are linked with reduced levels of the probiotic Bifidobacterium, and a secondary increase in inflammatory activity, increased fat mass, and insulin resistance (Esteve et al. 2011). Human studies have also shown obesity and type 2 diabetes to be associated with reduced levels of Bacteroides, and weight loss shows alteration in gut microbial balance more similar to lean humans (Esteve et al. 2011). Reduced levels of Bifidobacteria do have effects on increasing intestinal permeability, endotoxemia, and inflammation. Furthermore, gut dysbiosis is associated with increased energy uptake from the diet, modifying host gene expression, endotoxemia and inflammation (Esteve et al. 2011). Dysbiotic microorganisms have been shown to increase lipoprotein lipase (LPL) activity in adipose tissue, increasing adiposity and fat storage. By contrast, the probiotic organism L. paracasei has been shown to reverse this effect and the host has significantly less body fat. (Esteve et al 2011).

There is a link with inflammation and obesity and type 2 diabetes. Gut bacteria can upregulate inflammation through TLR4, which has an association with high-fat diet induced insulin resistance (Musso 2010). High-fat, high-carbohydrate meals induce postprandial elevated LPS and activation of TLR4, and other inflammatory signals such as NF-kappaB, and SOCS-3 (suppressor of cytokine signaling-3, an adipokine involved in insulin resistance).

Despite these links between high-fat, high-carbohydrate diets, dysbiotic organisms, inflammatory responses, and the resultant obesity and/or insulin resistance, it has not yet been proved whether or not probiotics represent a viable stand-alone treatment option for the prevention or modification of early obesity. Nor has it been proved what strain in particular may (or may not) be of benefit. Future research is needed for these claims to be elucidated and to determine the role of the inflammatory state that characterizes obesity and the role of gut microbiota in controlling energy balancing gut hormones on the developing metabolism of children. What is confirmed is that perinatal and postnatal treatment of mothers has been shown to reduce gestational diabetes, and has marginal response in decreasing fetal growth rates at 4 years (Luoto et al. 2010).

While awaiting larger, well-designed RCTs to examine possible benefits of probiotics on metabolic disease and obesity, we can continue to recommend healthful dietary choices high in fiber, fruits, and vegetables and low in fat and refined carbohydrates, as well as moderate use of antibiotics and breast-feeding of infants to encourage healthy gut ecology and its potential link with metabolic diseases (Musso 2010).

Abdominal pain and altered bowel habits are one of the most common presenting symptoms to family physicians (Holten and Wetherington 2003). IBS is a diagnosis of exclusion, without positive diagnostic results and is the most common chronic gastrointestinal illness. However, more serious bowel disorders must be ruled out, such as gastrointestinal cancer, inflammatory bowel disease, and diverticular disease. According to figures provided by Holten and Wetherington (2003), Americans spend $8 billion annually on IBS-related costs, significantly affecting quality of life and workplace productivity. IBS is characterized by alternating constipation and diarrhea, with pain or discomfort relieved by defecation. The pathophysiology of IBS is linked with abnormal gastrointestinal motility, psychological factors (50% associated with depression, anxiety, panic disorder, social phobia, somatization disorder, and dysthymia), and immune activation.

Zeng et al. (2008) provided strong evidence for the use of probiotics in directly affecting “leaky” gut in D-IBS patients. The authors were able to demonstrate that IBS patients do in fact have disruptions to mucosal barrier, and the patients show clinical improvement following intake of probiotics. The authors are drawing an indirect conclusion that the effectiveness of the probiotics lies in this intestinal barrier dysfunction. However, to further strengthen this study, the authors could have repeated the qPCR analysis and TEM imaging following administration of probiotics, to directly show that improvement in transcription of tight junctional complexes and TEM imaging of the improved barrier. Of note is that this is rather invasive procedure requiring intestinal biopsy and may represent a limitation to performing this step in showing the link between probiotics and intestinal barrier function.

The other three studies all demonstrated clinical improvement in symptoms of IBS patients using three different pro-/prebiotic sources: L. rhamnosus GG (LGG), B. bifidum, and prebiotic trans-galactooligosaccharide (Francavilla 2010; Guglielmettie et al. 2011; Silk et al. 2008, respectively).

Francavilla et al. (2010) showed decreased episodes and intensity of abdominal pain as well as decreased intestinal permeability.

Guglielmettie et al. (2011) found decreased pain, discomfort, distension, bloating, urgency and bowel movement satisfaction, thereby significantly improving quality of life.

The prebiotic treatment (Silk et al. 2008) increased levels of Bifidobacterium and decreased Clostridium, restoring microbial balance. Furthermore, the study showed improved flatulence, bloating, and SGA using the prebiotic mixture. When using the 7g dose of prebiotic, quality of life and anxiety levels were also improved.

A common side effect of antibiotic use is AAD, which has a prevalence of 11% of children. Of these cases, 10% to 20% are caused by C. difficile infection (CDI; Alam and Mushtaq 2009).

Meta-analysis found that probiotics reduce the risk of AAD in children, and that for every 7 patients who would develop AAD, 1 fewer will develop if also being treated with probiotics (Szajewska et al. 2006).

Necrotizing enterocolitis (NEC) is a disease of the gastrointestinal tract of premature neonates and is one of the leading causes of morbidity and mortality in this population (Thompson and Bizzarro 2008). NEC occurs in 5% to 15% of very low birth weight infants (VLBW), defined as <1500g. In-hospital-case fatality rates are approximately 16% to 20%, but can be higher in VLBW infants (NEC guideline team 2010).

The study demonstrated reduced rates of death and stage 2 or more NEC and that in treating 20 patients with probiotics, 1 case of NEC was prevented (Lin et al. 2008).

Hwte et al. (2008) demonstrated the benefit of S. boulardii in reducing the duration of acute watery diarrhea, frequency of defecation, and consistency of stools in children with typically E. coli infectious diarrhea. Future research could elucidate the benefit for travelers in taking S. boulardii prophylactically to prevent the frequency and/or severity of E. coli, cholera, Shigella, and Salmonella infectious gastroenteritis.

Postoperative infection is a major risk factor affecting morbidity and mortality for patients diagnosed with colorectal cancer who undergo gastrointestinal surgery. Liu et al. (2010) found pre and postoperative treatment with probiotic reduced infection complication (p < 0.05), bacterial translocation (p < 0.01), and lower rates of intestinal permeability (p < 0.04). This research demonstrates that prophylactic probiotics in addition to prophylactic antibiotics represent a viable infection control mechanism for colon resection.
Inflammatory bowel disease (IBD) is typically diagnosed as Crohn’s disease (CD) or ulcerative colitis (UC). CD is a chronic inflammatory disease that most often affects the small bowel, although it can occur anywhere along the digestive tract from mouth to anus. The disease has ongoing cycles of relapse and remission, with over 70% of Crohn’s disease patients requiring surgical resection at some point in their lives (Rahimi 2007). As there is no cure for Crohn’s disease, the main goal of management is prevention of relapse. UC is a chronic relapsing inflammatory disease affecting the distal colon, characterized by bloody diarrhea.

At this time a case cannot be made for the use of probiotics with CD patients. Meta-analysis shows that probiotics do not reduce relapse or maintain remission in CD. However, studies for the use of probiotics with UC are more promising. A pilot trial (Furrie et al. 2005) showed very promising results using Synergy 1 (Bifidobacterium longum and prebiotic inulin oligofructose) on decreasing inflammatory cytokines, increasing defensins, and increasing colonization of Bifidobacterium. Furthermore, sigmoidoscopy scores, bowel habit index and histopathology demonstrated disease resolution. Large-scale studies are needed to confirm results. Use of rectal suppositories of Lactobacillus casei DG showed very promising results in decreasing TLR4, inflammatory cytokines, increasing IL10 (anti-inflammatory cytokines), and improvement in histological disease severity.

Bacterial vaginosis (BV) affects almost one third (29%) of women in the US (Allsworth and Peipert 2007). Anaerobic bacteria, including Gardnerella vaginalis, Mycoplasma hominis, Prevotella, and Peptostreptococcus, colonize the vagina due to disruption in normal flora (Lactobacillus; Wang et al. 2010). Complications of bacterial vaginosis include pelvic inflammatory disease, infertility, atopic pregnancy, miscarriage, and preterm labor (Wong et al. 2010).

Wong et al. confirmed that vaginal probiotic suppositories are effective in reducing recurrence of BV, reducing symptoms of BV as well as cultures of dysbiotic organisms, in particular Gardnerella vaginalis, with minimal side effects. When compared with metronidazole gel, probiotic vaginal suppositories have similar effectiveness and both have approximately 15% recurrence rates, however, the probiotics have a much safer side-effect profile than metronidazole (Wong et al 2010).

Atopic dermatitis affects 10% to 20% of Western children and is attributed to abnormal immune responses in the gut, overactivation of inflammatory pathways, leading to intestinal permeability and resultant local hypersensitivity reactions to food allergens, as macromolecules are able to “leak” across intestinal epithelia.

Abnormal immune responses lead to disruption of intestinal microbiota and host responses to abnormal microbial toxins and antigens, further overactivating the gut inflammatory response.

Allergic responses are Th2 dominant resulting in IL4, IL5, and IL6 production, leading to IgE synthesis. IFNgamma is linked to eosinophil activation. IL5 is an eosinophil activator strongly correlated with pathogenesis of SAR and eosinophil degranulation in nasal mucosa is found in sufferers of rhinitis. IL6 works synergistically with IL5 and accompanies eosinophil response. IL6 also amplifies Th17 leading to up regulatory Th17 cells that are linked with inflammatory conditions, and pro-inflammatory cytokines IL1, IL6, TNFalpha.

The ability of probiotics to normalize intestinal permeability, correct immune dysfunction and gut inflammation as well as their antimicrobial function has led them to be researched for use in patients with atopic dermatitis.

Ivory et al. (2008) were able to show that the probiotic LcS is effective in rebalancing the Th1/Th2 system, which is known to be imbalanced in both atopic dermatitis and allergic rhinitis. However, future studies need to investigate the relationship between LcS and SAR and to determine dosing and length of treatment time.

Nermes et al. (2010) showed a decline in Ig-secreting cells and increase in memory B cells in probiotic-treated patients with AD. Supporting the theory that probiotics have a positive impact on the immune derangements prevalent in atopic conditions. One concern in the study design was that the probiotics (Nermes et al 2010) were delivered as casein hydrolysate, and the control group received the same base. Most milk allergies consist of allergens to whey or casein or both, and 26.3% of the probiotic group (n = 5) and 45% of the placebo group (n = 9) had seropositivity to tested allergens that included milk, egg, and gliadin. By administering the probiotics in a base of a commonly encountered allergen represents a confounding variable to this study.

Ouwehand et al. (2009) found that treatment of SAR before, during, and after the allergic season reduced nasal symptoms, reduced nasal eosinophil infiltration, and dampened the increase in fecal IgA in the treatment group when compared with the control group.

Clinically, probiotics have been shown to be effective in the prevention of PAD, particularly with prenatal treatment with probiotics. Improvements in study design are needed to fully elucidate the role of probiotics in the treatment of PAD. Although some studies have shown probiotics to be effective in treating PAD, meta-analysis does not confirm this due to high variability in study design and small sample sizes (Lee et al. 2008). There is a need for more studies on the use of probiotics in the treatment of PAD. The authors recommend the following criteria for effective study design in order to conduct an effective meta-analysis in future on the use of probiotics in the treatment of PAD:

1. inclusion criteria of stable AD, and threshold improvement in score before study to be considered meaningful and provide points of reference

2. subgroup stratification based on IgE status

3. quality control probiotics

4. elimination of confounding variables such as use of corticosteroids, antigen-elimination diets, concomitant antibiotics (2 week lead-in period)

Conclusion

Probiotics should not be used as a catch-all treatment in promoting human health, nor in the prevention and treatment of all human disease conditions. Probiotics are a novel treatment approach that research has shown to be effective in the treatment of bacterial vaginosis, acute ulcerative colitis, irritable bowel syndrome, infectious gastroenteritis, and antibiotic-associated diarrhea. Probiotics administered prenatally have been shown to be effective in the prevention of gestational diabetes mellitus and the prevention of atopic dermatitis in infants of treated mothers. Furthermore, prophylactic treatment of seasonal allergic rhinitis reduces symptom severity, prophylactic treatment of very low birth weight infants reduces the incidence of neonatal necrotizing enterocolitis and death, and prophylactic treatment in colorectal cancer surgery prevents infectious complications.

The research shows the use of probiotics in the treatment of Crohn’s disease to be ineffective. It should also be noted that although prenatal treatment with probiotics does prevent the risk for pediatric atopic dermatitis, probiotics have not yet shown to be effective in the treatment of pediatric atopic dermatitis; further well-designed studies are needed. Similarly, while probiotics have shown to be effective in treating infectious gastroenteritis in children, studies have not yet shown how probiotics may be used in prevention of acute gastroenteritis in travelers.

While the newest area of probiotic research does show a link between dysbiosis, inflammation and obesity and type 2 diabetes, probiotics are not proven to be a stand-alone treatment option for weight loss, or control of insulin resistance. Rather, lifestyle factors continue to be the recommendation of choice; meanwhile, the link between inflammation, dysbiosis, and metabolic syndrome needs further study.

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Appendix

As a graduate from McMaster University in 2000, Kim Whitaker pursued a career in Naturopathic Medicine at the Canadian College of Naturopathic Medicine, from which she graduated in 2004. For six fulfilling years, Kim ran a clinic in Toronto, Ontario, and was a member of the clinical faculty at the Canadian College of Naturopathic Medicine. In 2010, Kim returned to school for her doctor of medicine degree at Saba University School of Medicine, and concurrently achieved her master’s in hyperbaric medicine. Kim continues to practice as a naturopathic doctor while she completes her MD training.

drkimwhitaker@me.com