Probiotic Clinical Considerations: Where do they fit?

CORRESPONDENCE:

Kimberly A.B. Cauthon, PharmD, CGP, BC-ADM cauthon@uiwtx.edu

INTRODUCTION

There is a growing interest in probiotic use for health benefits and disease treatment strategies. Probiotics are defined as “live micro- organisms which when administered in adequate amounts confer a health benefit on the host.”1 The term probiotic comes from the Greek word “for life” and has been identified as bacteria or yeast in certain dietary supplements and foods. The most common pro- biotics available include bacteria Lactobacillus and Bifidobacterium, and yeast Saccharomyces boulardii. Probiotics as single species or combinations of multiple species are found in products over the counter including yogurt, dairy drinks, capsules, tablets, packets, and sachet powders. Each probiotic has unique qualities but there is little evidence supporting various species combinations when advertised for synergy.2 There is no known class effect regarding species and health benefits.2, 3 Table 1 (page 22) lists the types of probiotics found in many available products.

Probiotic Mechanisms of Action

Several characteristics of probiotics have been reported to play a role in health. These include the ability to 1) transit through and survive in the gastrointestinal (GI) tract, 2) colonize and reproduce in the gut by adherence, 3) modulate the host immune system and block pathogens, and 4) balance homeostasis of the gut flora. Other important characteristics include quality manufacturing practices that ensure shelf life stability and the development of probiotics that are not pathogens.2, 4

Probiotic Safety

Probiotic safety and research is limited. Adverse effects reported have been minimal and are primarily GI in nature. Didari et al. con- ducted a systematic review in 2014 of clinical studies using com- mon probiotic species that included Bifidobacterium, Lactobacillus, Saccharomyces boulardii, Streptococci, Enterococcus, Propionibacte- rium, and Escherichia coli species Nissle 1917. Their observations determined that “overwhelming existing evidence suggests that probiotics are safe;” however, there were some studies that re- ported adverse risks including fungemia, sepsis, and GI ischemia.5 This review highlighted an important connection between serious illnesses and certain high risk patient groups including those who were hospitalized, immunocompromised, post-operative, in the in- tensive care unit, and critically sick infants. For example, several cases of fungemia caused by S. boulardii were identified in critically ill patients who had central venous catheters.5 The National Insti- tutes of Health (NIH) acknowledges many studies demonstrate probiotic safety with certain species, but advises caution about ap- plying this to all probiotics.2,4

TABLE 2:

Yale / Harvard 2015 Workshop Probiotic Expert Recommendations6

Probiotic Quality

The majority of probiotic products are sold as dietary supplements which are not subject to Food and Drug Administration (FDA) approval before marketing. In order for a specific probiotic to be marketed as a drug for clinical treatment, more stringent studies must be performed to meet the FDA requirements. Many probi- otic advertisements make online statements regarding safety and health promotion, but they cannot make disease prevention claims without FDA regulation.2,4

Finding high quality commercial probiotics can be challenging. First, manufacturing processes may damage viable microorgan- isms.3 Second, clinical studies have raised concern regarding the species composition in current products along with the lack of universal quality assurance programs. The label or manufacturing process may state “generally recognized as safe” (GRAS), but this applies to food supplements and is not supported by FDA quality or safety standards as indicative of therapeutic benefit.2,4 Finally, many products available online need to be stored in a cool environ- ment which makes receiving probiotics in the mail subject to qual- ity concern.2,5

This article will focus on answering common questions regarding four broad clinical areas of suggested probiotic use: adult and pe- diatric diarrheal illness, genitourinary infections, atopic dermatitis, and upper respiratory tract infections. Each section will include a discussion of recent evidence from meta-analyses and systematic reviews. Additionally, recommended evidence ratings from the Yale/Harvard 2015 Workshop of probiotic experts will be included (Table 2).6

SHOULD PROBIOTICS BE RECOMMENDED FOR USE FOR GASTROINTESTINAL CONDITIONS, SUCH AS DIARRHEA, INFLAMMATORY BOWEL DISEASE, OR IRRITABLE BOWEL SYNDROME?

The administration of probiotics improves gut colonization with enteric flora. Theoretical benefits include restored gut barrier function, improved mucosal immunity, reduced inflammation, and improved bile acid metabolism.7 A variety of probiotic formula- tions have been studied for gastrointestinal conditions, but each report has a high degree of variability in species, dosing, and re- search endpoints.

Diarrhea - Recommended for Acute Infectious Diarrhea & Antibiotic Associated Diarrhea

Acute infectious diarrhea (AID) can be viral, bacterial, or parasitic in nature. These types of infections are most commonly treated with rehydration and anti-diarrheal agents. As adjunctive therapy, probiotics modify gut pH, compete with the infectious agent for nutrients, and may improve the immune response. The use of pro- biotics for the treatment of AID was evaluated in a 2010 Cochrane systematic review of 63 randomized controlled trials (RCTs). Most trials evaluated LGG and S. boulardii and included AID of any infectious origin. In addition, 18 trials specifically reported data from rotavirus infection in children. Overall, probiotics reduced the duration of diarrhea by a mean of 24.8 hours (95% CI, 15.9 to 33.6) and reduced the risk of diarrhea lasting 4 days or longer (RR 0.41, 95% CI 0.32 to 0.53).8

Broader studies of probiotics as adjuvant to rehydration for acute gastroenteritis in children have been found to decrease the dura- tion of symptoms. The European Society for Pediatric Gastroenter- ology, Hepatology, and Nutrition (ESPGHAN) supports with strong recommendation the use of LGG and S. boulardii for 5 to 7 days in otherwise healthy children. However, these recommendations are based upon low quality evidence, unclear randomization protocols and study blinding, and varying definitions of clinical endpoints.9 The Yale/Harvard 2015 Workshop expert panel also supports the use of LGG, S. boulardii, and L. reuteri with an “A” recommendation. The use of L. reuteri is given a weaker but also positive recommen- dation from ESPGHAN.6,9 Notably, ESPGHAN published a strong recommendation against the use of E. faecium SF 68 due to safety concerns with vancomycin resistance.9

Antibiotic-associated diarrhea (AAD) results from disruption of the normal gut microflora. Because discontinuation of antibiotics for a clinical condition is not usually recommended, prevention of AAD is a preferred strategy. Several recent meta-analyses evalu- ated the use of probiotics for prevention of AAD. Videlock et al. evaluated 34 placebo-controlled studies of probiotics and found a reduced risk of AAD (RR 0.53; 95% CI 0.44 to 0.63).10 Hempel et al. reviewed 63 studies and found a similar risk reduction (RR 0.58; 95% CI 0.50 to 0.68).11 Goldenberg et al. evaluated 23 trials of the use of probiotics to prevent AAD in patients up to 18 years of age, also demonstrating a lower risk of AAD (RR 0.46; 95% CI 0.35 to 0.61).12 All authors identified significant heterogeneity between studies. Participants in the Yale/Harvard 2015 Workshop sup- port the use of S. boulardii, LGG, and a combination of Lactobacillus/ Streptococcus thermophilus species for AAD with an “A” recommen- dation.6

Data are more variable on the use of probiotics for the prevention of C. difficile-related diarrhea.6 The American College of Gastroen- terology (ACG) does not support the use of probiotics for treat- ment or prevention of C. difficile diarrhea. They further caution against probiotic use among immunocompromised patients.13

Irritable Bowel Syndrome (IBS) - Weakly Supported

Irritable bowel syndrome (IBS) is defined by the ACG as “abdomi- nal discomfort associated with altered bowel habits.14 The Rome III criteria is often applied in the research setting. This criteria specifies IBS as the recurrence of abdominal pain or discomfort for at least 3 days per month over 3 months, and the presence of at least 2 of the following findings: onset of symptoms associated with a change in either stool frequency and/or appearance and im- provement of symptoms with defecation. Patients can be further categorized into four subtypes based upon bowel patterns: IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), mixed type (IBS-M), and unclassified (IBS-U).14

The pathophysiology of IBS is complex and not fully defined. A dis- ruption in the gut-brain connection leading to visceral hypersen- sitivity has been hypothesized as an underlying cause. Additional theories have implicated serotonergic, immunologic, genetic, and psychosocial contributors. Alterations in the gut microbiome and the function of the gut barrier have been the focus of recent inves- tigations.7

Therapeutic options for IBS range from dietary changes that in- crease fiber intake and restrict gluten or FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) to pharmacologic treatments. Traditional use of antispasmodics and antidepressants has expanded to several symptom-specific options for IBS-D (alosetron, eluxadoline) and IBS-C (linaclotide, lubiprostone).14, 15, 16 The possible contribution of an altered gut microbiome has prompted the investigation of antimicrobial agents (e.g., rifaximin, metronidazole) and probiotics as potential therapeutic options.14, 15

The ACG supports a “weak” recommendation for the use of pro- biotics for IBS.14 A similar grade is noted by the Yale/Harvard 2015 Workshop expert panel with a “B” recommendation for B. infantis and VSL #3.6 The ACG guideline cites literature that identifies a positive impact of probiotics on “global symptoms” in- cluding abdominal pain, flatulence, and bloating.14 The guideline does not support any recommendation for a particular probiotic over another due to variable data. A 2014 meta-analysis found probiotics were associated with a lower risk of IBS symptoms per- sisting after treatment when compared with placebo (RR 0.79; 95% CI 0.70 to 0.89).17 The probiotics most commonly included Lacto- bacillus, Bifidobacterium, Escherichia, and Streptococcus species, but products varied widely in formulation and dosing. These probiotics appeared to be well tolerated; however, further evidence suggest- ed a higher risk for adverse events including abdominal pain and bloating, versus placebo (RR 1.21; 95% CI 1.02 to 1.44).17

Many unanswered questions about the clinical role of probiotics for IBS remain. A trial of probiotics seems to be a reasonable op- tion, particularly for patients complaining of abdominal pain, flatu- lence, and bloating. However, the optimal probiotic formulation and dose have not been determined, requiring further studies for clarification.

Inflammatory Bowel Disease (IBD) - Recommended for Ulcerative Colitis

Inflammatory bowel disease, including ulcerative colitis (UC) and Crohn’s disease (CD), is often characterized by features of abdomi- nal pain and diarrhea. Conventional therapeutic interventions fo- cus on acute management of symptoms followed by maintenance of remission utilizing various anti-inflammatory and immune mod- ulating agents.18,19 Although pathophysiology of the two condi- tions is not well understood, a recent interest in the gut microflora immune and inflammatory response has stimulated investigations into the role of probiotics.

Studies of probiotics in UC have focused primarily on the use of VSL#3 and E. coli Nissle species. Their use has been targeted for induction and maintenance of remission. In a meta-analysis, Fujiya et al. found that probiotics appeared as effective as mesalazine for prevention of remission (RR 1.00; 95% CI 0.79 to 1.26).20 The Yale/ Harvard 2015 Workshop expert panel assigned a “B” recommen- dation for the induction of remission and an “A” recommendation for maintenance of remission.6

The prevention of pouchitis, an inflammatory condition occurring after an ileal pouch-anal anastomosis procedure for UC appears to be another promising therapeutic use. A recent systematic review showed that probiotic formulation VSL#3 (containing several Lac- tobacilli and Bifidobacterium species plus S. thermophilus) prevented pouchitis and maintained remission at higher rates than placebo.21 Participants in the Yale/Harvard 2015 Workshop support the use of VSL #3 with an “A” recommendation.6

The evidence regarding the use of probiotics in CD is limited. Stud- ies of probiotics for CD have yielded conflicting data, offering a “C” recommendation from the expert panel at the Yale/Harvard 2015 Workshop.6 The ACG recommends that further investigation of probiotics is necessary before supporting use in CD.18

SHOULD PROBIOTICS BE RECOMMENDED IN FEMALE GENITOURINARY TRACT INFECTIONS: BACTERIAL VAGINOSIS, VULVOVAGINAL CANDIDIASIS, & RECURRENT URINARY TRACT INFECTIONS?

The female genitourinary tract is predominantly colonized by Lac- tobacilli (LAB) species. Changes in the vaginal microbiota can lead to genitourinary tract infections including bacterial vaginosis (BV), vulvovaginal candidiasis (VVC), and recurrent urinary tract infec- tions (UTIs). This disruption or “vaginal dysbiosis” can be caused by the use of broad spectrum oral antibiotics, changes in sexual part- ners, menopause, diabetes, obesity, poor hygiene, and elevated vaginal pH. This most likely occurs through intestinal colonization by pathogenic bacteria which enter the vagina from the rectum.2,22 The mechanisms of action (correction of dysbiosis) proposed for the predominant LAB species found in the genitourinary tract in- volves 1) lowering the pH by producing lactic acid and hydrogen peroxide, 2) producing bacteriocins toxic to pathogenic bacteria, and 3) blocking pathogenic bacteria adhesion to the genitourinary epithelium. Collectively, this decreases genitourinary colonization of pathogenic bacteria and maintains a healthy balance.22, 23, 24

Several studies using either oral or intravaginal probiotics for the treatment or prevention of genitourinary infections have been performed. Studies have used two approaches: primary therapy using probiotics alone (either single species or a combination of species) or additive therapy to conventional treatment. Inter- pretation of data from several well organized RCTs is challenging because variations were used in study design, probiotic species, treatment length, and patient follow-up.23, 24, 25

Bacterial Vaginosis - Probiotic Recommended as Adjuvant

BV is one of the most frequent vaginal infections in the world and results from the overgrowth of bacteria in the genitourinary tract, most commonly Gardnerella, Atopobium, and Prevotella. The over- growth of these bacteria can raise the pH creating vaginal dys- biosis. Symptoms include pruritus, vaginal discharge, and dysuria. BV is typically treated with metronidazole or clindamycin, either orally or intravaginally. However, failure and recurrence rates are estimated at 30-40%.2, 23

One of the first reported meta-analyses of RCTs regarding the ef- fects of probiotics for the treatment of BV was published in 2014 by Huang et al. This study included 1,304 individuals from 12 RCTs with a primary outcome specifically for BV cure rate. Authors con- cluded that “probiotics show a beneficial effect in patients who are suffering from BV” [RR 1.53; 95% CI 1.19 to 1.97]. They further ex- amined a subgroup of the 9 highest quality studies and determined that probiotics either orally or intravaginally were effective either alone or in combination with conventional antibiotics for the treat- ment of BV [RR 1.60; 95% CI 1.16 to 2.22].24 A literature review by Homayouni et al. in 2014 included several of these studies and reported similar conclusions.25

Many experts state the preferred probiotic delivery route should be intravaginal but online searches suggest this type of product is limited.22, 24, 25 Several oral products are available, but the viability of probiotics to survive the gut and finally enter the GU tract was not thoroughly investigated in clinical trials. Timing of GU colo- nization after oral administration was not consistent and further studies are recommended.24, 25

Considerable heterogeneity was found among the type of probi- otic used in the meta-analyses.24 For example, Ya et al. randomized 117 Chinese women with BV to vaginal probiotic capsules (Pro- balac Vaginal: containing 108 CFU of L. rhamnosus, L. acidophilus, and Streptococcus thermophilus) versus placebo. Patients used pro- biotics for 7 days on and then omitted for 7 days, alternating this schedule for 30 days. Conversely in a different study, Bradshaw et al. randomized 268 women with BV to oral metronidazole 400 mg BID for 7 days followed by vaginal pessary use daily contain- ing L. acidophilus KS400 ≥ 107 CFU and 0.03 mg of estriol for 12 days, versus oral metronidazole 400 mg BID for 7 days followed by vaginal pessary placebo for 12 days. The women in this study were followed for 180 days.24

The Yale/Harvard 2015 Workshop expert panel offered a recom- mendation level “C” regarding probiotics for BV treatment.6 How- ever, given the general safety of probiotics, they should be consid- ered as adjuvants either orally or intravaginally for women with BV.3, 24, 25 In several studies, L. rhamnosus and GR-1 and L. reuteri RC-14 were found effective for the treatment of BV when added to standard metronidazole therapy.6,22,24,25 Similar probiotics may be found online and include UltraFlora (oral) by Metagenics, Fem- Dophilius (vaginal) by Jarrow, and Terbiotics (oral) by Klaire Labs. (See Table 3, page 26) These products have not been approved by the FDA.

Vulvovaginal Candidiasis - Insufficient Evidence to Recommend

Vaginal dysbiosis may also lead to an overgrowth of Candida spe- cies with the most common type as Candida albicans.22 VVC symp- toms include vaginal discharge, dysuria, and pruritus. Many stud- ies report the use of either oral or intravaginal LGG, L. rhamnosus, L. reuteri, and L. acidophilus for use in women with a history of re- current VVC.2,6,26 However, most studies to date have had small sample sizes, lacked statistical significance, or had high attrition rates.26 Although probiotics are considered safe for use in most women, the use of probiotics for the primary treatment or added to conventional therapy has not been supported.3,22 Furthermore, probiotics for VVC should not be used as primary treatment be- cause LAB does not compete with Candida colonization. Only con- ventional anti-infectives will eliminate Candida thus allowing LAB to establish homeostasis.22

Recurrent Urinary Tract Infections - Weakly Supported

Urinary tract infections are common including infection of the kid- ney, ureter, urethra, or bladder. The most common pathologic bac- teria is E. coli, a gram positive cocci.27, 28 UTIs can be asymptomatic or symptomatic with cloudy urine, pyuria, urgency, frequency, and hematuria. Ascending infection may cause flank pain, fever, and chills. Mortality increases among the elderly and immunocompro- mised with UTIs.

Historically, probiotic research targeting UTIs increased in the 1980’s. Authorities confirmed that vaginal dysbiosis, including the depletion of healthy LAB, leads to an increased rate of UTI recur- rence in many patients. In the development of probiotics and in- vitro research studies, attempts to displace gram-positive cocci ad- hesion were made by adding L. reuteri RC-14 to L. rhamnosus GR-1. Many studies showed promising results, but the quality and design of several clinical trials were questioned.27

In response, a 2010 Cochrane systematic review by Schwenger et. al evaluated probiotics (any formulation) versus placebo (no thera- py) for prevention of UTIs in susceptible patients. They included 9 studies with 735 individuals and measured rates of UTI recurrence with probiotic or placebo. These studies were also challenged by high risk of bias, small sample sizes, and insufficient methodologi- cal detail. The authors reported that “a benefit could not be ruled out due to insufficient data” and more research in this area is need- ed. It has been further discussed that BV infection may increase the risk of recurrent UTIs.29 Due to the promising use of probiot- ics for the treatment of BV, a plausible link between probiotics and prevention of both BV and UTIs may emerge in the near future.

SHOULD PROBIOTICS BE RECOMMENDED FOR THE PREVENTION OR TREATMENT OF ATOPIC DERMATITIS?

Recommended in Specific Clinical Situations

Atopic dermatitis (AD) is widely considered an inflammatory skin condition in all ages, but infants and children are more commonly affected. Clinical conditions vary in severity and frequent exacer- bations are reported. Patients report itching, pain, and discomfort, which can significantly affect activities of daily living and sleep quality. AD standard therapy includes emollients and topical ste- roids.

The underlying pathophysiology of AD involves a complicated cel- lular immune response between the skin as a barrier and the bac- teria that normally colonize the surface. Given the role of probiot- ics with respect to GI immune response and inflammation, and the general safety of probiotics, studies have demonstrated a possible role in AD.30, 31, 32 Interestingly, it has also been reported that chil- dren who have slow development of both LAB and Bifidobacterium in the GI tract were found to be more susceptible to allergies.32

Specific use of probiotics LAB and Bifobacterium for the prevention of Pediatric Atopic Dermatitis (PAD) is recommended by the Yale/ Harvard 2015 workshop experts.6 Additionally, the World Allergy Organization (WAO) performed a systematic review in 2015 pro- viding conditional recommendations for the prevention of PAD in high risk infants. Infants at risk were defined by having any biological parent or sibling with a history of allergic rhinitis, asthma, eczema, or food allergy.33 The WAO further recommended for this risk group oral probiotic use by the mother during pregnancy and breastfeeding, and in infants who were not breastfed. The most significant risk reduction in PAD was reported when probiotics were used during pregnancy (RR 0.72, 95% CI 0.61 to 0.85) and when given to infants (RR 0.81, 95% CI 0.70 to 0.94).33

The American Academy of Dermatology published review by Baquerizo et al. reports several meta-analyses regarding the risk reduction of PAD with the use of prenatal and/or postnatal probi- otics. In an analysis of 16 trials with probiotics (LAB and Bifobac- terium) the risk of PAD was reduced by 20-24% (RR 0.79). This review recommends starting LAB orally for the mother during the last 2 weeks of pregnancy and continuing for the first three months post-delivery. The review did not state if the probiotics should be taken by the mother or the infant during post-delivery.30 Other recommendations suggest L. rhamnosus orally for the mother dur- ing the last 4 weeks of pregnancy and for the first 6 months of breastfeeding with a transition to oral probiotics to the infant con- tinuing until age 2.34

With respect to the treatment of AD, probiotic use has been sup- ported by clinical trial evidence. The Yale/Harvard 2015 workshop experts support a level “A” recommendation for the use of LGG and B. lactis in the treatment of AD associated with cow’s milk al- lergy.6 In addition, a recent 2014 meta-analysis of 25 clinical trials (n=1,599) by Kim et al. assessed the treatment of all AD using pro- biotics. The endpoint of the study included any change in the Scor- ing of Atopic Dermatitis (SCORAD) symptoms scale. For all ages the SCORAD decreased by a mean of 4.51 points (95% CI -6.78 to

-2.24). The most significant symptom reduction was found among patient ages 1-18 (-5.74, 95% CI -7.27 to 14.20) and was not found effective in infants <12 months. Considerable heterogeneity was found among all studies; however, probiotic species reported most beneficial included LAB or a combination of LAB with Bifidobacte- rium.32

SHOULD PROBIOTICS BE RECOMMENDED FOR THE PREVENTION OR TREATMENT OF UPPER RESPIRATORY TRACT INFECTIONS?

Weak support

Upper respiratory tract infections (URTIs) include viral and bac- terial infections such as colds, sinusitis, and pharyngitis. Several systematic reviews have recently assessed probiotic effectiveness in prevention of or shortening duration of URTIs.35, 36, 37 Probiot- ics may prevent URTIs by reducing the colonization of pathogenic bacteria in the GI tract, removing bacterial toxins, and enhancing humoral immune responses.38, 39

Probiotics may be more effective than placebo for prevention of URTIs in adults according to a Cochrane meta-analysis published in 2015 that included twelve RCTs (n=3,720).35 Fewer patients in the probiotic group versus the placebo group were diagnosed with one episode of URTI (OR 0.53; 95% CI 0.37 to 0.76). The mean du- ration of the URTI was less in the probiotic patient group (mean difference -1.89 days; 95% CI -2.03 to -1.75). While probiotics in this review seemed to be more effective than placebo, the quality of evidence in these studies was low.35

Another meta-analysis reported similar results in 2014. In this review of 20 clinical trials (n= 3,350) the duration of URTI symp- toms with probiotic use of Lactobacillus or Bifidobacterium ver- sus placebo suggested shorter illness courses.36 The duration of probiotic therapy use ranged from three weeks to seven months and patients in the probiotic intervention group had shorter ill- ness by ½ - 1 day compared to placebo (weighted mean difference -0.77; 95% CI -1.5 to -0.04). The probiotic group had less work or school absenteeism (mean difference -0.17; 95% CI -0.31 to -0.03). Similar to the Cochrane meta-analysis, clinical trial design varied and although probiotics were more effective than placebo, the quality of evidence was low.35, 36

SUMMARY

Although there are many studies regarding the use of probiot- ics for a wide variety of conditions, there is no consensus on the most appropriate species, dose, and products to recommend. The Yale/Harvard 2015 workshop experts provide important guid- ance through their published evidence ratings for certain clinical conditions.6 Some products are included in Table 3 for consider- ation. These products have not been fully evaluated by the FDA with quality and safety studies. In the age of increasing antibiotic resistance and the emerging role of the gut microbiome in health, further research is encouraged in the development of probiotics going forward.

*Yale/Harvard 2015 Workshop grade applies to the species type and clinical condition. It does not represent a rating for the product example listed. “A” recommendation is based on strong, positive, well-conducted, controlled studies in the primary literature, not abstract form. “B” recommendation is based on positive, controlled studies but the presence of some negative studies. “C” recommendation is based on some positive studies but clearly an inadequate amount of work to establish the certainty of “A” or “B”.

** Product examples are commonly found in stores or online, but do not represent all available products on the market. These products have not been fully evaluated by the FDA and are not intended to diagnose, cure, treat, or prevent any disease.

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