Fighting Fire with Fire: Is it Time to Use Probiotics to Manage Pathogenic Bacterial Diseases?

Abstract

Probiotics, when considered in clinical practice, have traditionally been used for prophylaxis; however, there is growing data suggesting treatment benefits in numerous disease states. In this review, we focus on probiotics as treatment for and prevention of several acute and chronic infectious processes including Helicobacter pylori, Clostridium difficile, necrotizing enterocolitis, ventilator-associated pneumonia, vancomycin-resistant enterococci, and nonalcoholic fatty liver disease. It is inaccurate to generalize findings observed in a single probiotic species to all probiotics. This reasoning is due to the variability of colonizing abilities of native intestinal floras, probiotic or otherwise, secondary to different combinations, doses, and duration of treatments. Given these limitations, multiple animal and human studies have shown anti-inflammatory and selective antimicrobial effects of specific probiotics. Some studies suggest a role for probiotics as supplemental treatment, in combination with antibiotics, for the aforementioned disease processes. It is apparent from this review that the efficacy of probiotics is widely variable and multifaceted. More focused clinical and basic science research is necessary to better understand the treatment potential of various probiotics.

Probiotics are defined as “live microbial organisms which beneficially affect human health through the prevention of specific disease states.” [1] Probiotics have been commonly used to prepare fermented food products in many countries for hundreds of years, and have been shown to beneficially influence digestive functions and augment the immune system. Medically, probiotics have traditionally been used for prophylaxis; however, there is growing data suggesting treatment benefits in various disease states through anti-inflammatory and antimicrobial effects.

These organisms vary in their capacity to resist gastric and bile acids, colonize the lower intestinal tract, and influence cytokine secretions. Humans living in different settings and in different environments also have significant variations in native intestinal flora. It is challenging to directly study the effects of probiotics given these confounding variables, and it remains difficult to generalize findings observed in one probiotic species with varying combinations, doses, and durations of treatment.

As with any systemic literature review, it is necessary to draw on well-designed studies and avoid pseudoscience. An example of a failure to do so was demonstrated in the widespread public belief that shark cartilage could prevent angiogenesis and halt the growth of malignant tumors. In response, two separate studies were conducted showing no statistical difference in the growth of cancer cells or survival of patients with breast, colon, or prostate cancer [2]. The United States Food and Drug Administration responded with a court order, requiring manufactures to pay restitution fees to customers for making false claims without supporting evidence [3]. We aim to avoid these dangerous waters.

This brief review will focus on probiotics as treatment for multiple disease processes arising from Helicobacter pylori, Clostridium difficile, necrotizing enterocolitis, ventilator-associated pneumonia, vancomycin-resistant enterococci, and nonalcoholic fatty liver disease.

• 1) Helicobacter pylori

Helicobacter pylori is a gram-negative bacteria reported to infect the stomach and/or small bowel of at least half of the world’s population [4]. H. pylori is a known risk factor for atrophic gastritis, and gastric and duodenal ulcers. The World Health Organization classifies it as a Group 1 carcinogen for gastric cancer and MALT (mucosa-associated lymphoid tissue) lymphoma. The first-line treatment for H. pylori is the “triple therapy” of a proton pump inhibitor, clarithromycin, and amoxicillin [5]. However, growing bacterial resistance and side effects from the therapy, mainly diarrhea, increase the risk of treatment failure [6].

Michetti et al. (1999) were the first to use Lactobacillus acidophilus in human subjects as the sole treatment for H. pylori, for six weeks [7]. They measured a reduced urea [¹³C] breath test over time; however, with gastric mucosa biopsies, there was no demonstration of H. pylori clearance. Mukai et al. (2001) described the ability of L. reuteri to exhibit specific surface proteins inhibiting the binding of H. pylori in gastric mucosa [8]. Other studies have shown the release of autolysin for cell lysis with L. acidophilus [9] and antimicrobial peptides with Bifidobacterium [10] as potential mechanisms for H. pylori treatment in humans.

Tong et al. (2007) identified and systematically reviewed 14 randomized trials (N = 1671) of different probiotic microorganisms, mainly Lactobacillus and Bifidobacterium species, on H. pylori colonization both in vitro and in vivo [11]. Pooled eradication rates were achieved in 83.6 % of patients with probiotic supplementation, and 74.8 % without (OR = 1.84, 95 % CI = 1.34–2.54). The overall occurrence of total side effects, most prominently diarrhea, was 24.7 % with probiotics and 38.5 % without (OR = 0.44, 95 % CI = 0.30–0.66). Szajewska et al. (2010) also conducted a meta-analysis to investigate the effects of Saccharomyces boulardii as supplementation to triple therapy on H. pylori eradication rates [12]. Five randomized controlled trials (N = 1307) were analyzed [13–17]. Compared with placebo or no intervention, S. boulardii, given along with triple therapy, significantly increased the eradication rate of H. pylori (RR = 1.13, 95 % CI = 1.05–1.21) and reduced triple therapy-related side effects (RR = 0.46, 95 % CI = 0.3–0.7), especially diarrhea (RR = 0.47, 95 % CI = 0.32–0.69). (Note: Saccharomyces is not considered a true “probiotic” by definition, as it is not normally found in the human gastrointestinal tract [18].

To date, there remains no clear Level 1 evidence to support the role of probiotics as a supplement to traditional triple drug therapy for H. pylori. However, species of Lactobacillus, Bifidobacterium, and S. bouolardii have shown promising signs in both increased eradication rates and decreased medication-associated side effects in human subjects.

• 2) Clostridium difficile

Clostridium difficile is an anaerobic gram-positive, spore-forming bacterium. The pathophysiology of C. difficile has been shown to distort the native flora to establish itself in the colon and proliferate. C. difficile bacterial overgrowth causes fluid secretion and extravasation, inflammation, and mucosal damage, resulting in diarrhea and toxic megacolon in the most severe cases. It is believed that over 90 % of C. difficile associated diarrhea (CDAD) occurs during or after antibiotic use, and approximately 30 % of cases will recur [19]. Standard treatment is oral vancomycin or metronidazole [20].

McFarland et al. (1994) reported that all patients receiving a four week treatment of oral vancomycin or metronidazole with S. boulardii (N = 57) were significantly less likely than placebo (N = 67) to experience a recurrence of CDAD (RR = 0.59; 95 % CI = 0.35-0.98) [21]. Surawicz et al. (2000) analyzed 168 patients with active CDAD taking low to high-dose vancomycin or metronidazole [22]. For four weeks, half also received S. boulardii or placebo. The authors did show a significant difference in recurrent CDAD with high-dose vancomycin and S. boulardii versus placebo (RR = 0.33; 95 % CI 0.10-1.06). However, there was no difference between the two groups for those having their initial presentation of CDAD, nor was there a difference between groups when patients were treated with low-dose vancomycin or metronidazole. Lawrence et al. (2005) treated 15 patients with known recurrent CDAD with oral vancomycin [23]. Half also received Lactobacillus rhamnosis GG (LGG). A nonsignificant reduction in the rate of CDAD rate was seen among those receiving LGG (16.7 % versus 50 %), but without statistical significance (RR = 2.63; 95 % CI = 0.35-19.85). In a 2006 meta-analysis of the use of probiotics for the treatment of CDAD, analyzing six randomized controlled trials, S. boulardii was the only effective probiotic agent for reducing the recurrence of CDAD [24].

Regarding the prevention of C. difficile in high-risk populations, Hickson et al. (2007) reported giving 100 g of L. casei, L. bulgaricus, and S. thermophilus twice daily during and for one week after the course of antibiotic therapy. This strategy resulted in a significant decrease in both antibiotic associated diarrhea and C. difficile infection [25]. The numbers needed to treat were five to prevent antibiotic associated diarrhea and six for C. difficile infection.

In a 2008 Cochrane review of the use of probiotics with oral vancomycin or metronidazole for the treatment of CDAD in adults, the authors concluded, “There is insufficient evidence to recommend probiotic therapy as an adjunct to antibiotic therapy for CDAD.” [26] However, there is evidence that S. boulardii may provide benefit as a supplement to antibiotic treatment for recurrent CDAD.

• 3) Necrotizing Enterocolitis

Necrotizing enterocolitis (NEC) is a life-threatening infection, most commonly affecting premature infants in their first few weeks of life [27]. NEC occurs in one to three per 1000 live births, with an incidence of approximately 6–7 % in very low birth weight infants of less than 1500 g [28]. Early recognition and aggressive treatment of this disorder has improved clinical outcomes. Treatment strategies include the use of trophic feedings, breast milk, and cautious advancement of feeds in addition to probiotic agents. Probiotics are a promising therapy for establishing normal intestinal flora in the preterm infant and in preventing NEC. Recent clinical trials have shown benefit in the use of probiotics for the prevention of NEC, helping to reduce the incidence of this destructive disease in preterm infants.

Bin-Nun et al. (2005) conducted a prospective randomized trial of 155 premature infants with a birth weight less than 1500 g receiving a standard formula with a probiotic-supplement containing Bifidobacterium infantis, S. thermophilus, and B. bifidus. [29] They demonstrated a significant reduction in NEC incidence in the treatment group, compared to controls (4 % versus 16.4 %; P = 0.03). The authors also reported a decrease in the severity of NEC in infants with probiotic supplementation. In 2008, Lin et al. conducted a multicenter trial of probiotics with a total enrollment of 443 infants [30]. The incidence of death or NEC was significantly lower (P = 0.002) in those infants given B. bifidum and Lactobacillus acidophilus in breast milk (or in a mixed feeding with breast milk and formula), twice daily for six weeks.

A meta-analysis by Deshpande et al. (2010) of 38 studies, showed that probiotics reduced the incidence of and mortality from NEC in preterm neonates [31]. A 2011 Cochrane review of 16 randomized trials similarly showed that enteral probiotic supplementation significantly reduced the incidence of and mortality from severe NEC and mortality [32].

In summary, routine supplementation of probiotics to prevent NEC is strongly supported by numerous relatively large prospective randomized trials. Nevertheless, the barriers to application of these recommendations in this high-risk population include the unavailability of consistent, high quality-controlled, and reliable probiotic products.

• 4) Ventilator-Associated Pneumonia

Hospital acquired pneumonia (HAP) is the second most common healthcare-related infection in the United States, and is associated with substantial morbidity and mortality [33]. In the postoperative setting, the incidence of HAP ranges from 1.5–15 %, with variable risk to the patient based on comorbidities [34]. Ventilator-associated pneumonia (VAP) typically occurs within 48–72 hours of intubation and placement on mechanical ventilation. The highest risks groups include trauma and burn Intensive Care Unit (ICU) patients. VAP has an incidence of approximately 30 % and a mortality close to 50 % [35]. Studies suggest that probiotics may help reduce the incidence of VAP both locally and systemically through selective colonization and possibly immunomodulation [36].

Morrow et al. (2010) conducted a prospective randomized double-blinded placebo-controlled trial of 138 mechanically ventilated patients at high risk of developing VAP [33]. Patients in the treatment arm received 10⁹ colony-forming units of Lactobacillus rhamnosus GG, twice daily. After five years, the researchers found that daily use of probiotics not only decreased VAP infections by about 50 % compared to placebo, but also reduced the amount of antibiotics needed in comparison to placebo-treated patients. A secondary outcome also demonstrated a significant delay in the time of onset of microbiologically confirmed VAP.

A meta-analysis conducted by Siempos et al. (2010), conducted prior to the Morrow et al. study above, found that in patients undergoing mechanical ventilation, the incidence of VAP was significantly lower in those treated with probiotics, compared to controls [37]. Other substantial findings were a nonsignificant decrease in ICU days in the probiotic group, and a significant decrease in colonization with Pseudomonas aeruginosa, in the probiotic group compared to controls. The remaining secondary outcomes included nonsignificant decreases in all-cause mortality, duration of mechanical ventilation, number of patients experiencing diarrhea, and probiotic-induced bacteremia. An additional review of the literature by Schultz et al. (2011) on the prevention of VAP, reported that three out of eight studies showed a significant reduction in VAP in the probiotic group, with no effect on mortality [38].

The majority of these studies show a consistent pattern of reduced risk from VAP in patients treated with probiotics, but a general consensus as to which probiotic to use, the optimal timing and duration of therapy, and methods of delivery, has not been reached. These factors need to be sorted out prior to generation of any guidelines for the prevention of VAP in critically ill patients.

• 5) Vancomycin-Resistant Enterococci

The first reports of the occurrence of vancomycin-resistant enterococci (VRE) in Europe began to appear in the mid-1980s, with increased prevalence over the past 10–15 years [39, 40]. Infection with VRE may present in the form of urinary tract infections, endocarditis, catheter-related infections, wound infections, and bacteremia [41].

Manley et al. (2007), in a randomized prospective clinical trial of culture-proven VRE, used Lactobacillus rhamnosus GG (LGG) effectively for the first time to treat gastrointestinal VRE in renal patients [42]. All 12 patients that consumed 100 g of yogurt with active LGG cleared VRE in four weeks, compared to only one out of 11 patients in the control group given pasteurized yogurt (P = 0.001). Although this was a small study, it offered adequate results demonstrating a potential strategy to eradicate VRE colonization in a cost effective and relatively harmless way.

A recent study by Szachta et al. (2011) further bolstered the Manley study [43]. This was a randomized single-blind placebo-controlled study focused on the ability of LGG to eliminate the carrier state of VRE in children, with a secondary goal to evaluate the effect of the probiotic on the Lactobacillus pool in the gastrointestinal tract. Patients were randomized to receive LGG or placebo for three weeks, while serial fecal samples were monitored for VRE and semi-quantitative counts were obtained for Lactobacillus species. A statistically significant difference in VRE reduction between the LGG group and the placebo group was seen after three weeks, with over 62 % of the children in the treatment group negative for VRE colonization versus 24 % in the placebo group (P = 0.002). The authors concluded that LGG supplementation temporarily eliminates the VRE carrier state and increases gastrointestinal counts of Lactobacillus in high risk children versus placebo.

Although these studies were conduced with small sample sizes, they demonstrated that probiotics have been shown to reduce the risk of VRE colonization. The current expense for placing a patient on VRE isolation is estimated at $270 per day. Probiotics, in contrast, can be used safely and effectively to minimize risk from VRE at nominal costs.

• 6) Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) has recently become the most common cause of chronic liver disease in the United States, and is estimated to affect as many as 23 % of adults [44]. NAFD is thought to progress via a multi-hit hypothesis – involving chronic inflammation and oxidative stress causing the recruitment of liver macrophages via cytokine release, leading to lobular inflammation and fibrosis, which ultimately results in irreversible cirrhosis [45]. The only definitive treatment of severe end stage disease is liver transplantation.

Li et al. (2003) studied 48 obese mice with NAFD given a high-fat diet alone or with the probiotic mix VSL#3 (a combination of Bifidobacteria, Lactobacilli, and Streptococcus thermophilus), with non-obese mice as controls [46]. Treatment with VSL#3 was shown to improve liver histology by reducing total hepatic fat content and decreasing serum alanine aminotransferase (ALT) levels. Treatment also reduced the activity of Jun N-terminal kinase and Nuclear Factor-kB, subsequently improving insulin resistance. Cani et al. (2009) used an animal model with mice placed on a high-fat diet to show that increases in bacterial endotoxins, pro-inflammatory cytokines, and intestinal permeability, were all significantly reversed with Bifidobacteria treatment [47]. To date, there remains little prospective data or even good retrospective evidence that probiotics are efficacious in treating NAFLD in humans. Loguercio et al. (2005) have suggested beneficial clinical outcomes, with VSL#3 treatment in 22 subjects with NAFLD showing improved plasma levels of routine liver tests (AST, ALT, GGT, total proteins, albumin, and total bilirubin), but no significant changes in TNF-α, IL-6, and IL-10 [48]. This study did not include liver histology or quantitative measure of hepatic steatosis as endpoints of therapy.

Given the lack of randomized controlled trials, a 2007 Cochrane summary concluded, “There is no evidence to support or refute probiotics for patients with NAFLD.” [49]

Conclusion

It is apparent in review of the available literature, that the efficacy of probiotics as treatment for these disease states is multifaceted, and more standardized research is necessary. Studies support the role of probiotics as adjunctive therapy to bolster treatment and reduce antibiotic-associated side effects. Still, to date, it appears that probiotics have a more effective role in prophylaxis than for treatment of the disease processes discussed. The future role for probiotics may in fact be a major change from the current dogma of multiple antibiotics to treat many of our current maladies. Providing probiotics to stabilize, colonize, and support the gut-associated microbiota should result in better long term outcomes. Before this paradigm shift in “fighting fire with fire” may take place, more controlled prospective randomized clinical trials are needed, evaluating the effect of very specific bacterial species on outcome parameters deemed important to the clinician.