When it comes to bacteria, the strain matters.
In the past, whole bacterial genera or species have been associated with certain beneficial or harmful effects when it comes to human health (for example, consider the association of Cutibacterium acnes with the development of acne).
However, not all strains within each bacterial genus behave in the same way. This understanding is key when investigating the role or influence of various microbes in relation to the human body, and when it comes to understanding the efficacy and safety profile of probiotics used as food and cosmetic ingredients.
Here we will outline some of the key research underlying these findings and the implications for food and cosmetic products, as well as avenues for future work.
Bacteria: which strain?
Escherichia coli is one of the best-known species of bacteria in the scientific arena. First identified as a key gut microbe in 1885, this bacterium is taught about in school due to its involvement in disease and its role as the most popular model organism for life sciences research, and it continues to chase microbial researchers in one form or another through to PhD stage and beyond.
E. coli exists in different forms, namely pathotypes Enteropathogenic E. coli (EPEC), Enterotoxigenic E. coli (ETEC), Enteroinvasive E. coli (EIEC), Enterohemorrhagic E. coli (EHEC) and Enteroaggregative E. coli (EAEC), among others. These pathogenic strains are known to cause infections. For example, EPEC infects and causes the deaths of thousands of children per year [1], and EAEC is associated with cases of acute or persistent diarrhoea in both children and adults and has been implicated in the development of irritable bowel syndrome (IBS) [2]. However, E. coli also exists in the form of beneficial strains such as E. coli Nissle(ECn). Such strains are known to have beneficial effects on host health, highlighting that different strains of a single bacterial species can have differing effects – both positive and negative.
Another example is Bifidobacterium longum. Interestingly, certain strains can utilize human milk oligosaccharide (HMO) in breast-feeding infants, while a closely related Bifidobacterium longum strain is able to ferment carbohydrates but not HMO [3].
These observations suggest that even a small amount of genetic variation in microbes can be very significant for their function and virulence. The forces that control these variations are not known in full; however, diet, health conditions and therapeutic drugs are all factors to be considered here.
Beneficial strains in food
Lactobacillus and Bifidobacterium are the most abundant probiotics, with strains of each also representing the most common bacterial strains used in probiotic products offered to consumers in food form. Many different strains have been proposed to have probiotic benefits (the exact number of which changes often), but not all are equally known or studied.
Within these two probiotic bacterial types, the world’s best documented probiotic strain Lactobacillus rhamnosus GG (LGG; annotated with ‘GG’ for Sherwood Gorbach and Barry Goldin, who discovered the strain in 1985 in human intestinal microbiota) has been investigated in more than 300 clinical trials and over 1,000 scientific studies. For example, a great deal of research has been conducted in paediatrics where LGG has proven effective for the treatment of acute gastroenteritis and the prevention of antibiotic-associated diarrhea (AAD) [4–10].
Sticking with AAD, one group from the Netherlands published a review analyzing all available clinical studies focused on probiotics to investigate their ability to reduce or prevent AAD. Out of seven single or multiple-strain formulations, the strain LGG was shown to be the most effective. The researchers concluded that the best recommendations for this indication required the following strains: (1) LGG (daily dose 2 x 109 c.f.u.); or (2) a mixture of LGG, Lactobacillus acidophilus LA-5 and Bifidobacterium lactis BB-1 [11].
Beneficial strains in cosmetics
Let’s continue with Lactobacillus and Bifidobacterium. Although such probiotics have long been popular as food supplements, certain strains are now also gaining increasing attention for the skin microbiome, with the potential to work from the outside in.
Lactobacilli, for example, are generally anaerobic, so they are probably not going to grow well when applied directly to the skin. However, even as a dead preparation (a lysate – a preparation containing the lytic products of cells), specific strains of lactobacilli have been shown to have remarkable effects as a topical skin cosmetic.
Keratinocytes (the predominant cell type in the epidermis, the outermost layer of the skin) are one area where researchers have investigated and successfully demonstrated the benefits of Lactobacillus strains as probiotic aids for skin health. Two key examples focus on skin barrier function and skin repair.
Improved barrier function in skin models
In a cell culture of keratinocytes, the formation of so called ‘tight junctions’, which seal the space between the cells, was investigated in the presence of bacterial lysates of Bifidobacterium longum and various Lactobacillus strains. With the exception of L. fermentum, all strains investigated enhanced the tight-junction barrier within 24 h. Overall, B. longum and LGG were most efficacious with a dose-dependent effect over 4 days. These data demonstrate that probiotics and probiotic lysates can be beneficial for the tight junctions of the skin, but the effects are strongly strain dependent [12].
Improved skin repair
In another study on keratinocytes, the effect of different Lactobacillus lysates was investigated using a scratch assay. In this assay, a monolayer of keratinocytes was scratched and then incubated with the respective bacterial lysate. Re-epithelialization (the resurfacing of the wound with new epithelium) of the scratches was monitored and compared to an untreated control. While live LGG and Lactobacillus reuteri significantly increased the rate of re-epithelialization, LGG lysate was most efficacious in triggering increased proliferation and migration rates of the cells [13].
These studies provide evidence to support that probiotics, which are normally formulated as ingestible food products to support the gut microbiome and gastrointestinal health, may also be beneficial for skin health. However, the observed effects vary significantly between bacterial species, and so a detailed scientific evaluation of each bacterial strain used is needed.
A focus on C. acnes
The role of Cutibacterium acnes (formerly Propionibacterium acnes) in the pathogenesis of acne has been controversial. Contributing to this uncertainty is the fact that C. acnes is a dominant member of the resident microbiota of healthy human skin,
An important recognition, however, resulting from advances in genetic analysis, is the considerable diversity that exists within bacterial species, and the observation that particular subpopulations may be responsible for infections while others are non-pathogenic.
One study, for example, was undertaken to determine the population structure of C. acnes with emphasis on isolates from skin, and to test the hypothesis that the species includes evolutionary lineages that live in harmony with their host and others that have the capacity to induce acne [14]. The study population was observed to comprise three major divisions, one of which was strongly associated with moderate to severe acne, while others were associated with healthy skin or opportunistic infections.
Despite its role in the development of acne, in more recent years, it has become clear that C. acnes also contributes to skin health benefits in many ways. For example, by:
- Supporting the skin’s defences both directly, by producing the antimicrobial peptide cutimycin, and indirectly, with fermentation products
- Stimulating autophagy, an essential cellular process involved in everything from skin aging to cancer
- Inducing sebum production through its metabolites
- Ameliorating unusual cases of skin itching
- Acting as an important pillar in the skin’s antioxidant defense (in the case of certain strong anti-oxidant-producing strains) [15]
Again, results of a pilot study published in 2019 [16] revealed that not all strains are equal and each behaves differently. Imbalances in skin microflora, particularly those in relation to certain C. acnes strains, may trigger acne. However, although C. acnes was formerly thought to be the leading or fundamental cause of acne, it was found recently that some, but not all, strains of C. acnes are responsible for acne development and that some instill beneficial effects such as those listed above.
Although the underlying causes of acne are multifactorial, it was also long believed that what matters in acne is the C. acnes count on somebody’s skin. However, reducing C. acnes quantities is now known to not be the key to clearing acne…but rebalancing its distribution between acneic and non-acneic could be more helpful!
Application of non-acne-causing strains to the skin may therefore modulate the skin microbiome and lead to a reduction in acne – this understanding is now feeding into the development of safer and more effective acne treatments.
Safety
Given that some microbial strains can be beneficial while others are detrimental, it is crucial to remain aware of this when analysing and investigating the effects of resident bacteria on the skin and wary when introducing probiotics as food or cosmetic ingredients.
When it comes to the skin, different strains of C. acnes have varying levels of irritation potential. For example, research has shown that certain C. acnes strains induce different immunological responses and express different protein factors. [17]. The investigators found that acne-associated C. acnes strains induced two- to three-fold higher levels of IFN-γ and IL-17 in peripheral blood relative to C. acnes strains associated with healthy skin, which induced two- to four-fold higher levels of IL-10. These factors have varying anti-inflammatory and immunosuppressive effects, indicating varying modulation of the immune response.
Concluding remarks
So, it’s clear that strains really matter when we talk about the benefits, efficacy and safety profile of different bacterial species.
Combining the right selection criteria to identify a suitable strain in a genetically diverse strain library would be the best approach to obtain the perfectly suited strain for a given application.
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References
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3. Lawson, M. A. et al. Breast milk-derived human milk oligosaccharides promote Bifidobacterium interactions within a single ecosystem. ISME J. 14, 635–648 (2020).
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12. Sultana, R. et al. Strain-dependent augmentation of tight-junction barrier function in human primary epidermal keratinocytes by Lactobacillus and Bifidobacterium lysates. Appl. Environ. Microbiol. 79, 488–4894 (2013).
13. Mohammedsaeed, W. et al. Lactobacillus rhamnosus GG lysate increases re-epithelialization of keratinocyte scratch assays by promoting migration. Sci. Rep. 5, 16147 (2015).
14. Lomholt, H. B. & Kilian, M. Population genetic analysis of Propionibacterium acnes identifies a subpopulation and epidemic clones associated with acne. PLoS ONE 5, e12277 (2010).
15. C. acnes Assist. The simple addition of ‘good’ bacteria such as C. acnes is not a one-size-fits-all answer to skin problems. A careful approach to modulate the C. acnes community is required. Cosmet. Toilet. 136, 5 (2021).
16. Karoglan, A. & Paetzold, B. Safety and efficacy of topically applied selected Cutibacterium acnes strains over five weeks in patients with acne vulgaris: an open-label, pilot study. Acta Derm. Venereol. 99, 1253–1257 (2019).
17. Yu, Y. et al. Different Propionibacterium acnes phylotypes induce distinct immune responses and express unique surface and secreted proteomes. J. Invest. Dermatol. 136, 2221–2228 (2016).
