Which Probiotic for Which Disease? Part 1

Over a century ago, scientist Élie Metchnikoff proposed that certain bacteria in the human body are potentially beneficial and serve as a natural barrier against disease.¹ In recent years, there has been great interest in the use of probiotics to improve human health. The term probiotic has been defined as, “living microorganisms which, when consumed in adequate amounts, confer a health effect on the host.”² Probiotics can commonly be found in fermentation products, such as kimchi and sauerkraut, foods like yogurt and popsicles, and topical cosmetic preparations.³Lactobacillus and Bifidobacterium are two of the most commonly-used probiotics.⁴ Probiotics have already been used in patients with irritable bowel syndrome and may modulate mucosal immune responses, leading to a reduction in gastrointestinal inflammation.⁵ These live microbes could have wider applicability as evidenced by the gut–brain–skin axis theory postulated 80 years ago,⁶ and their use could be extended to dermatological conditions. Indeed, gut bacterial dysbiosis is associated with chronic inflammatory disorders of the skin.⁷ Thus, the microbiome can be considered a potential therapeutic target.

Additionally, oral probiotics have direct immunomodulatory properties. Roudsari and colleagues highlighted the beneficial role of ingested probiotic bacteria both on healthy and diseased skin.⁸ Their results indicate that oral consumption of probiotic microorganisms might reduce skin sensitivity. Several skin conditions are also associated with negative bacterial balance on the skin, for which topical probiotics can be used to balance the skin microbiome.⁹ Probiotics have been implicated or used in the treatment of atopic dermatitis, acne vulgaris, psoriasis, rosacea, and seborrheic dermatitis.¹⁰ Since many conventional treatments for these conditions are associated with negative side effects, the excellent safety profile of probiotics renders them attractive alternatives or adjunctive treatments.

However, there are many different strains of bacteria used in probiotic formulations, and different strains are used for different skin conditions. In this narrative review, we examine different probiotic studies and compare the effectiveness of selected strains for each of the following skin conditions: atopic dermatitis, acne vulgaris, psoriasis, rosacea, and seborrheic dermatitis. Some of the studies include probiotics taken with prebiotics. A prebiotic is a nondigestible food ingredient that selectively stimulates the growth and survival of beneficial bacteria in the colon, thereby improving host health.¹¹ The combination of a prebiotic and probiotic is called a synbiotic. Other studies include paraprobiotics (also called “postbiotics”) which are inactivated probiotics.¹²

Atopic Dermatitis

Atopic dermatitis (AD) is a chronic pruritic inflammatory skin disease that affects patients of all ages and has a severe impact on quality of life. The pathogenesis of AD is not fully elucidated, but it is clearly a multifactorial disease involving skin barrier dysfunction, immune dysregulation, and microbiome imbalance.¹³ The conventional approach includes topical corticosteroids, calcineurin inhibitors, antibiotics, immunosuppressants, and most recently a biologic agent, with many more in development. While generally more effective than placebos, these treatments are not without side effects, and increasing numbers of patients are seeking alternative and complementary therapies perhaps in consideration of both real and perceived risks.

It has long been observed that barrier defects in AD seem to go beyond the skin, involving the intestinal mucosa¹⁴ where indigenous intestinal microflora contributes to the mucosal barrier function and stabilizes intestinal permeability.¹⁵ It has also been postulated that microbiome composition or diversity are strongly associated with the development of allergic disease. Children who have a less diverse gut microbial flora in their early life may be more susceptible to development of allergic diseases.¹⁶ Furthermore, atopic children have also been reported to harbor more clostridia and fewer bifidobacteria and lactobacilli in their gut flora than non-atopic children.¹⁷ The decreased microbial exposure due to urbanization, the intensive use of antibiotics and vaccines, and improved infant sanitation are hypothesized to have led to the increased development of AD.¹⁸

Additionally, AD is associated with a shift in T helper (Th1/Th2) cytokine balance toward a Th2 response.¹⁹ Probiotics can inhibit the Th2 response and stimulate the production of Th1 cytokines. In addition, decreases in regulatory T cells have been reported in patients with AD, and their numbers are inversely correlated with IgE, eosinophilia, and interferon gamma levels.^20,21 Probiotics upregulate the generation of Tregs, which migrate to inflammation sites and suppress disease progression in mice.²² In addition, defects in skin barrier and less antimicrobial peptides lead to more Staphylococcus aureus on the skin of AD patients which have implications in triggering inflammation.²³

Sikorska and Smoragiewicz found that various strains of Lactobacillus and Bifidobacterium isolated from a variety of sources inhibit in vitro growth of S. aureus.²⁴

However, some studies have failed to demonstrate beneficial effects of probiotics in AD.^25,26 The discrepancy may be explained by variations in disease subtype, as well as age; cultural, diet, genetic backgrounds; disease severity; allergic comorbidities; and study designs. Other factors may include different mechanisms of action, dosages of different strains, and combination of strains, as probiotic effects are likely largely strain-specific.²⁷ Meta analyses have shown that while probiotics can lower SCORAD values in those with AD, the results differ among probiotic strains.

Lactobacillus

Lactobacilli are commensal bacteria of the human gut microflora. Lactic acid bacteria have also long been used in a variety of fermented foods for both improving the taste and preserving properties of the foods.²⁸ The intestinal tract was found to be more frequently colonized by lactobacilli in nonallergic children than in allergic children.²⁹ This supports the idea that appropriate microbial colonization of the gut might lower the risk of developing atopic diseases.³⁰Lactobacillus species also showed the most potent inhibitory activity against the growth of Staphylococcus aureus, which has been identified as one of the causes of AD exacerbation.³¹

L. rhamnosus/LGG

Lactobacillus rhamnosus is a lactic acid-producing bacterium that is found in a large variety of habitats, including industrial dairy products, the oral cavity, intestinal tract, and vagina.³²Lactobacillus rhamnosus GG (LGG) is a specific strain of L. rhamnosus that was isolated in 1983 from the intestinal tract of a healthy human being by Sherwood Gorbach and Barry Goldwin, explaining its typical surname letters GG.³³ LGG is one of the most studied probiotic strains for the treatment for AD, particularly in infants. Many studies have shown that LGG administered to high-risk infants or their mothers can prevent or delay the development of AD in infants.³⁴ However, the effectiveness of LGG administration for the treatment of established AD is less clear. Gruber et al., Folster et al., and Brouwer et al. all found no significant differences in AD outcomes between infants who were treated with LGG vs placebo. However, the LGG group showed a greater reduction in SCORAD than did the placebo group, -26.1 vs-19.8 (P=0.036) after 4 weeks of treatment in specifically IgE-sensitized infants. Another study that looked at 31 infants also found a decrease in SCORAD after 1 month of LGG (treated: p = 0.008 vs placebo treated: p = 0.89).³⁵ However, a meta analysis³⁶ found that LGG was ineffective in improving AD. Overall, LGG efficacy has been studied the most in the infant population, and there are conflicting individual reports on whether it is actually effective in improving AD symptoms, with a meta analysis by Huang et al. concluding that LGG is not effective.

Other studies with non-LGG strains of L. rhamnosus show results that are promising but limited. SCORAD decreased significantly when 66 infants were given L. rhamnosus MP108 for 8 weeks compared to placebo.³⁷ A combination of L. rhamnosus (no strain specified) and Bifidobacterium lactis improved SCORAD in food-sensitized children.³⁸ Another study with 66 children showed that 56 percent of the probiotic group showed SCORAD improvement after six weeks of a combination L. rhamnosus 19070-2 and L. reuteri treatment compared to 15 percent of the placebo group (this was not significantly significant).³⁹ Another study found that both L. rhamnosus Lcr35 + prebiotic and the prebiotic alone significantly improved the manifestations of AD in children aged two years and over.⁴⁰

L. paracasei

Lactobacillus paracasei is another species of lactic acid bacteria that is commonly used in dairy product fermentation and is found in the human gut. It shares 90 percent of its genome with L. rhamnosus and L. casei.⁴¹ Its differences include that it is somewhat heat resistant and has high proteolytic activity.⁴² A study showed that L. paracasei was able to promote recovery of the skin barrier since it significantly reduced TEWL compared to the control, and it also significantly decreased in SP-induced vasodilatation, edema scores, and release of TNF-alpha.⁴³ There is some evidence that L. paracasei could be useful in treating AD for adults more than infants. In a study with 34 adults, 12 week treatment with heat-inactivated L. paracasei (paraprobiotic) showed skin severity scores that were significantly decreased from baseline at week 8 (P < 0.05) and at week 12 (P < 0.01) in the probiotic group but not in the placebo group.⁴⁴ However, another study with 133 infants found that while SCORAD values did decrease after 12 weeks of L. paracasei supplementation, there was no difference observed among the probiotic vs placebo groups.⁴⁵ Another recent study, again with infants, showed the same results.⁴⁶ Overall, it seems that there is limited evidence for L. paracasei for AD improvement among adults, none for AD improvement among infants.

Lactobacillus fermentum (LF) + L. paracasei

Lactobacillus fermentum has the ability to protect the host against food-derived infections and oxidative damage.⁴⁷ Specifically, the strain Lactobacillus fermentum ME-3 has been identified as an antimicrobial and antioxidative probiotic. Eight weeks of taking 2 × 10^10 CFU/g /d of L. fermentum was found efficacious in improving the SCORAD index compared to the placebo group in 56 infants.⁴⁸ Another study took it a step further by comparing Lactobacillus fermentum alone and Lactobacillus paracasei alone with the mixture of the two probiotics and found that while all three groups showed significantly improved SCORAD scores compared to the placebo group (P<0.001), the combination of the two probiotics was superior to either alone in treating moderate to severe AD.⁴⁹ Overall, this preliminary evidence shows that L. fermentum may be effective in improving AD symptoms and that L. fermentum + L. paracasei may be even better.

L. acidophilus L-92

Lactobacillus acidophilus L-92 is a type of lactic acid-producing bacteria with a wide range of paraprobiotic activities. It has been reported that paraprobiotic L-92 is useful in the treatment of perennial allergic rhinitis. Oral administration of L. acidophilus L-92 in 50 Japanese children led to significant amelioration of AD symptoms.⁵⁰ Another study with 50 AD patients who were given L. acidophilus treatment for 24 weeks showed that the L. acidophilus L-92 group showed significant decreases in IGA and SCORAD compared to the placebo group.⁵¹ Furthermore, it was suggested that sustained ingestion of L. acidophilus resulted in suppression of scratching behavior and maintenance of remission status of skin symptoms. There was also a significant increase in transforming growth factor-Β and IL-12 in the probiotic group. This study suggested that L-92 suppresses type-2-helper-T Cell-dominant inflammation by activating regulatory T cells and Type 1 helper T cells.

Finally, in a study with 59 children ages six months to three years who had a concomitant food allergy, a significant decrease in SCORAD was observed in the group given L. acidophilus L-92 treatment after 24 weeks but not in the placebo group.²⁸ However, no significant difference was observed between the two groups. Significant decreases in serum TARC and total IgE levels were observed in the L. acidophilus group compared with the placebo group, which reflects the suppression of skin inflammation.

Gerasimov et al. studied the effects of L. acidophilus DDS-1, Bifidobacterium lactis UABLA-12, and fructo-oligosaccharide in children aged 12–36 months with moderate to severe AD.52 ^A significant decrease in scoring of atopic dermatitis (SCORAD) index was found in the probiotic group. Overall, L. acidophilus has potential but the evidence is limited and mainly confined to studies done in Asia.

L. salivarius

L. salivarius is a lactobacillus strain found in the GI tract that has been relatively well studied in pediatric and adult populations. It exerts a range of therapeutic properties including suppression of pathogenic bacteria and has been used to improve oral hygiene⁵³ and treat irritable bowel syndrome⁵⁴ and pancreatic necrosis.⁵⁵ One study with 38 adult AD subjects showed a reduction in their SCORAD scores after 16 weeks of L. salivarius LS01 treatment and a significant decrease in the staphylococci load compared with the placebo group.⁵⁶ This suggests that the manipulation of intestinal flora with the L. salivarius LS01 strain could help to prevent the emergence of allergy symptoms. Moreover, L. salivarius LS01 showed the ability to reduce the production of Th2 cytokines, maintaining the production of Th1 cytokines stable. Furthermore, L. salivarius LS01 supplementation for 16 weeks significantly decreased SCORAD index and itch intensity in 43 children and that those benefits persisted 1 month after the supplementation ceased, probably due to permanent changes in the fecal flora of AD subjects.^57,58 L. salivarius PM-A0006 + prebiotic resulted in a significantly improved SCORAD index (P=0.024) compared to the prebiotic alone (Fructo-Oligosaccharide). Overall, L. salivarius shows promise as a supplemental AD treatment, especially given its antimicrobial and immune modulation properties.

L. salivarius + B. breve

Iemoli et al. studied a specific combination of L. salivarius LS01 and B. breve BR03 in adults.⁵⁹ Patients receiving probiotics showed a significant improvement in clinical parameters (SCORAD, P < 0.0001 and DLQI, P < 0.021) compared with baseline. Probiotics reduced microbial translocation (P < 0.050), immune activation (P < 0.001), improved Th cell 17/T-regulatory cell (Treg) (P < 0.029) and Th1/Th2 (P < 0.028) ratios. None of these changes was observed in the placebo group. The study concluded that this specific mixture of probiotics (LS01 and BR03 strains) might be beneficial for clinical and immunologic alterations in adults with AD.

L. salivarius + tara gum and S. thermophilus

Another combination of probiotics include L. salivarius LS01 as well as adding tara gum and Streptococcus thermophilus ST10. S. thermophilus is a fermentative facultative anaerobe found in fermented milk products and generally used in the production of yogurt.⁶⁰ Tara gum is a natural additive obtained by grinding the endosperm of the seeds of Caesalpinia spinosa, often used as a thickening agent in foods such as ice cream.⁶¹S. thermophilus ST10 and tara gum create a gelling complex that adheres to intestinal mucus and improves barrier function.⁶² The addition of tara gum and S. thermophilus ST10 seems to improve the overall efficacy of the L. salivarius strain in treating AD, in particular shortening the time required for the onset of the positive effects. SCORAD index improved after only 1 month of treatment. Overall, these studies show that while L. salivarius LS01 is likely efficacious on its own, the addition of B. breve or tara gum + S. thermophilus may improve the efficacy even more.

Lactobacillus sakei

L. sakei is another probiotic bacteria that is often used in sausage fermentation and found in foods like kimchi and sauerkraut.⁶³ It has in the past been found to treat sinusitis.⁶⁴ In 75 children with atopic eczema, L. sakei KCTC 10755BP administration for 12 weeks was associated with significantly decreased SCORAD scores (P=0.01) and lower pretreatment-adjusted serum levels of CCL17 (chemokine ligand 17) and CCL27 (P =.03 for both).⁶⁵ However, L. sakei remains one of the lesser studied probiotic strains for use in AD in humans.

L. plantarum

Lactobacillus plantarum is a probiotic found in the human gut and saliva, as well as many fermented foods including kimchi, sauerkraut, pickles, and sourdough. It has been shown to suppress AD-like skin lesions, high serum IgE levels and epidermal thickening and also to diminish the accumulation of eosinophils and mast cells in topical inflammatory sites in NC/ Nga mice model induced by house dust mites.⁶⁶ One strain-specific study with 104 children⁶⁷ showed that L. plantarum CCFM8610 was able to improve SCORAD index by increasing serum IL-10 but that Bifidobacterium bifidum CCFM16 was not. Another study⁶⁸ with 83 children who took L. plantarum CJLP133 supplementation for 14 weeks found that SCORAD scores at week 14 were lower in the probiotic group than in the placebo group (p = 0.044), and the mean change in the SCORAD score from weeks 2 to 14 was 9.1 in the probiotic group, which was greater than the mean change of 1.8 in the placebo group (p = 0.004). Overall, there is limited evidence regarding L. plantarum as an efficacious treatment but it is a contender.

Speaking of Bifidobacterium, a study of 90 infants found that Bifidobacterium breve M-16V and a galacto-/fructooligosaccharide mixture did not significantly benefit compared to the placebo.⁶⁹

Synbiotics + multiple strains

There is more evidence showing that a combination of probiotic strains supplemented with prebiotics can lead to significantly improved AD symptoms. A study with 320 children younger than 12 years old with AD suggest that supplementation with multistrain synbiotics (Lactobacillus casei, Bifidobacterium lactis, Lactobacillus rhamnosus, Lactobacillus plantarum, fructooligosaccharide, galactooligosaccharide, and biotin) helps to improve AD symptoms.⁷⁰ More than 80 percent of children experienced SCORAD improvement.

Another study showed that a mixture of B. bifidum + L. acidophilus + L. casei + and L. salivarius mixture tested in 40 children effectively reduced the SCORAD index and serum cytokines interleukin (IL)-5, IL-6, interferon (IFN)-γ, and total serum IgE levels.⁷¹

Another study with 10^9 CFU each of Bifidobacterium lactis, B longum, and Lactobacillus casei in 50 children with AD led to a 19.2-point greater mean reduction in SCORAD compared with control patients.⁷²

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