643 Bidirectional Gut-Skin Axis
to achieve systemic health benefits, including enhanced skin health, by modifying the
gut microbiome.92 The most notable therapeutic application of this strategy involves the
development of live biotherapeutic products (LBPs). LBPs, which can be either naturally
occurring or genetically modified, are oral or topical treatments containing live bacteria
or fungi designed to treat, prevent, or cure diseases.93,94 Because LBPs are therapeutic
in nature, they are subject to stringent regulatory and clinical standards. In contrast,
nutricosmetic products are non-living oral supplements intended for cosmetic benefits and,
as such, are generally subject to less rigorous regulation.95 Despite this, nutricosmetics have
the potential to offer immediate commercial opportunities for improving health and well-
being by leveraging their specific beneficial effects.
THERAPEUTIC APPLICATIONS
Various clinical trials are investigating microbiome engineering techniques to address
different health conditions. These include LBPs, fecal microbiome transplants (FMTs),
phage therapy, dietary interventions, personalized nutrition and synbiotics (a combination
of probiotics and prebiotics).96 In the realm of microbiome research, probiotics refer to live
microorganisms that benefit the host by enhancing immune function and outcompeting
harmful bacteria. Complementary to these, prebiotics are non-digestible compounds that
selectively promote the growth of beneficial microbes, contributing to improved host health.
Postbiotics, or paraprobiotics, consist of non-viable microbial cells and their metabolic
by-products, which have significant immunomodulatory effects. Lastly, synbiotics combine
both prebiotics and probiotics in a single supplement and function to support immune
health and restore balance to the microbiome.97
Unlike conventional probiotics, LBPs are specifically designed to treat certain diseases or
conditions and must undergo clinical trials to evaluate their safety and effectiveness.93,94
Therefore, in the context of skin conditions, LBPs offer an alternative to topical and
oral antibiotics by selectively targeting pathogenic microorganisms while preserving
beneficial microbiota, thereby aiding in the reestablishment of microbiome equilibrium.93
Consequently, research and clinical trials exploring LBPs have gained momentum in the
past decade.98
In the case of AD, numerous studies have explored the use of LBPs as an effective treatment.
These often include Lactobacillus-containing LBPs, specifically L. fermentum, L. paracasei, L.
plantarum, L. rhamnosus, L. salivarius, L. sakei and various mixtures thereof.99–102 However,
meta-analyses conclude inconsistent results, as many studies show that LBPs improve
Scoring Atopic Dermatitis (SCORAD), though not always to a clinically significant degree.
This variability highlights the need for further research.102 Most studies in this area have
focused on infants and children with AD. Some research has also targeted pregnant women
at high risk of having infants who develop AD for example, one study administered
L. rhamnosus strain GG (ATCC 53103) supplements daily from 4 weeks before delivery
until 6 months postpartum.103 In the intervention group, 26% of children developed AD
compared to 46% in the placebo group, demonstrating the treatment’s effectiveness.103
Additional research into adult-type AD exhibited that B. animalis subspecies lactis LKM512
was antipruritic (effective in alleviating itch) through the mechanism of increasing the
expression of the antipruritic and antinociceptive metabolite kynurenic acid (KYNA).84 An
additional study demonstrated that supplementation with a mixture of B. longum CECT

644 JOURNAL OF COSMETIC SCIENCE
7347, B. lactis CECT 8145 and L. casei CECT 9104 significantly decreased the SCORAD
index and reduced the use of topical steroids in patients with AD, although the exact
mechanism remains unclear.104
The largely hypothesized mechanism of action of these LBPs involves immune system
modulation. Preclinical trials using L. sakei WIKIM30 showed alleviation of AD symptoms,
due to the induction of Treg differentiation and altering the gut microbiota.105 Furthermore,
a study that utilized L. fermentum treatment in AD-induced mice demonstrated significant
reductions in serum IgE, tissue mast cells, eosinophils and T-helper 2 (Th2) related
cytokines.105 The treatment also led to increases in anti-inflammatory cytokines, such
as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), as well as changes
in amino acid levels, including methionine, phenylalanine, serine and tyrosine, and in
SCFAs such as acetate, butyrate and propionate.106 The proposed mechanism for these
Lactobacillus-containing LBPs is their ability to reduce T-helper 1 (Th1) and T-helper 17
(Th17) cytokines, in addition to Th2 cytokines, while simultaneously increasing IL-10 and
CD4+CD25+ regulatory T cells. This immune modulation is thought to influence the gut
microbiota and alleviate AD symptoms.106,107
In addition, supplementation with the LBP L. rhamnosus SP1 LSP1 has been shown to
be effective in treating adult acne.108 A prevalent hypothesis suggests that L. rhamnosus-
containing LBPs may enhance microbial diversity, increase SCFA production and normalize
gene expression related to insulin signaling in the skin.109 Additionally, an LBP containing
Bacillus species demonstrated improvement in acne lesions and reduced sebum excretion
rates.110 Notably, a blend of L. acidophilus, L. delbrueckii subspecies bulgaricus and B. bifidum
showed efficacy comparable to 100 mg of daily minocycline, a commonly used antibiotic
for acne treatment.111 Therefore, in addition to microbiome balance, the hypothesized
mode of action through which LBPs may treat acne is via immunomodulation and anti-
inflammatory effects. Specifically, LBPs are thought to generate regulatory dendritic cells
and CD4+ Foxp3+ T cells, leading to B and T helper cell hyporesponsiveness without
apoptosis, along with suppression of cytokine production.112
In addition, LBPs for acne may be effective through the reduction of oxidative stress. The
elevated local burden of lipid peroxidation associated with acne increases the demand for
antioxidants from the bloodstream. LBPs may address this issue by reducing systemic
oxidative stress and modulating inflammatory cytokine release within the skin.113,114
Specifically, a reduction in interleukin-1 alpha (IL-1α), observed under certain experimental
conditions, could offer therapeutic benefits for acne.115 Furthermore, similar to internal
antibiotics, LBPs have the potential to alter microbial communities in areas beyond the GI
tract, potentially enhancing their effectiveness in acne management.116
Research into the effects of LBPs in relation to rosacea is relatively limited. However, studies
have shown that oral supplementation with E. coli Nissle 1917, in combination with conventional
topical treatments such as tetracycline, steroids and retinoids, resulted in significantly greater
symptomatic improvement in rosacea patients compared to those who received only topical
treatments.117 Hence, E. coli Nissle 1917 is able to strengthen the intestinal epithelial barrier
and inhibit pathogenic bacterial growth by interacting with immunomodulatory and anti-
inflammatory mechanisms, suggesting its mode of action for rosacea treatment.117 Similarly, a
treatment regimen for rosacea that included a Bifidobacterium-containing LBP was associated
with a higher rate of clinical remission compared to conventional treatments alone.118 A case
of scalp rosacea was also effectively managed with a low dose of doxycycline combined with
an LBP containing B. breve BR03 and L. salivarius LS01.119