638 JOURNAL OF COSMETIC SCIENCE
by two anaerobic bacterial phyla: Bacteroidetes and Firmicutes.32 Key genera involved in this
production include Bifidobacterium, Eubacterium, Lactobacillus and Prevotella.33 Roseburia, a
genus within the Lachnospiraceae family, is a key producer of butyrate in the gut.27 These
SCFAs serve critical functions including blood pressure regulation, post-infarction heart
healing, anti-inflammation and gut barrier function by serving as an energy source for
intestinal epithelial cells.34
Varied amounts of SCFAs enter the bloodstream, influenced by factors such as dietary fiber
intake, microbial fermentation rates and the extent of colon absorption. Once absorbed,
SCFAs interact with G-coupled-protein receptors such as free fatty acid receptor 2 (FFAR2,
also known as GPR43), the free fatty acid receptor 3 (FFAR3, also known as GPR41) and
the free fatty acid receptor GPR109a. These are expressed in tissues including adipocytes,
intestinal epithelial cells, pancreatic beta-cells, the spleen and immune cells such as M2
macrophages, neutrophils, eosinophils and mast cells.32,35 Regarding the skin, SCFAs can
dampen immunoglobulin E (IgE) allergic inflammatory responses, increase cholesterol and
ceramide concentrations in the stratum corneum, repress transepidermal water loss for the
maintenance of the epidermal barrier and inhibit histone deacetylation of keratinocytes to
further suppress inflammation.31 Therefore, SCFAs may directly affect the skin or alter the
skin’s commensal bacteria. However, further research is needed to determine the clinically
significant amount of SCFAs that must reach the bloodstream to impact the skin.30
Other gut microbial metabolites associated with skin conditions include tryptophan
metabolites.36 In the gut, commensal colon-inhabiting microbes like Clostridium, Bacteroides,
Bifidobacterium and Lactobacillus convert tryptophan to indole and its derivatives, such as
indole-3-aldehyde (IAId), indole-3-lactic acid (ILA), indole-3-propionic acid (IPA), indole-
3-acetic acid (IAA), indole-3-acrylic acid (IA) and tryptamine, all of which play key roles
in maintaining intestinal immune balance and barrier function.37,38 IPA in specific has
demonstrated the ability of enhancing intestinal barrier function in vitro and murine
models.39 Furthermore, products of this indole pathway, like indole-3-carbaldehyde (I3A),
can activate the aryl hydrocarbon receptor (AhR), which is widely expressed in skin cells
like fibroblasts, keratinocytes, Langerhans cells, melanocytes, sebocytes, mast cells and
lymphocytes.40–45 The effects of AhR stimulation are dependent on the dose and the specific
ligand, influencing different transcriptional pathways and inducing various biological
responses.40 AhR activation in the skin has been shown to enhance the production of key
skin barrier proteins, improving skin hydration and reducing water loss, while also causing
the upregulation of metalloproteinases and suppression of type I collagen and fibronectin
expression, thereby improving wound healing and decreasing scar formation.46 In addition,
another bacterial metabolite of tryptophan is indole pyruvate (IPyr) and it exerts a protective
effect on keratinocytes exposed to UVB.47
Finally, amine derivatives—such as trimethylamine (TMA) and trimethylamine N-oxide
(TMAO) —produced by the gut microbiome have been associated with skin health.36 These
amine derivatives are products of the intestinal microbiome’s degradation of quaternary
amine group-containing molecules, such as choline, L-carnitine or phosphatidylcholine
found in eggs, liver and dairy.48 TMA is generated by bacterial genera such as Clostridium,
Proteus, Shigella and Enterobacter and is then transported to the liver where it is oxidized
to produce TMAO.49 Further research is required to fully understand the implications of
TMA and TMAO in skin health. However, in general, elevated levels of these metabolites
have been associated with skin disorders such as psoriasis, systemic lupus erythematosus
and hidradenitis suppurativa.49–51

639 Bidirectional Gut-Skin Axis
The neuroendocrine connection between the gut microbiome and the skin arises from
the ability of the gut microbiome to stimulate neural pathways through the production
of neurotransmitters.25 Research has demonstrated that neurotransmitters produced by
certain microorganisms affect the skin in various ways. These include gamma-aminobutyric
acid (GABA), dopamine, serotonin and acetylcholine, with effects such as itch restriction
(GABA), inhibition of hair growth (dopamine), modulation of melatonin (serotonin) and
the enhancement of barrier function (acetylcholine).52–55
Different dietary components have been linked to skin effects, with the gut microbiome
playing a hypothesized role in mediating these effects. These include gluten, which is known
to cause skin rashes in some cases of celiac disease.56 Although genetics are the greatest
determinant in celiac disease, research suggests that intestinal dysbiosis, particularly low
levels of Bifidobacterium and Ruminococcus, may contribute to the condition, suggesting that
the gut microbiome may in part modulate symptoms.57 Polyphenols, which are naturally
occurring compounds found in fruits, vegetables and cereals, have demonstrated anti-
inflammatory effects on both the gut and the skin.58,59 These effects are hypothesized to
result from interactions with the gut microbiome however, further research is required to
fully elucidate these mechanisms.58 Investigating dysbiosis of the gut microbiome in patients
with inflammatory skin conditions is therefore a valuable approach for understanding this
relationship.
THE GUT-SKIN AXIS AND ACNE
Acne vulgaris is a chronic inflammatory skin disease that affects an estimated 80–90% of
adolescents, particularly in developed countries.60 It affects the skin’s pilosebaceous units
and is characterized by excessive sebum production, abnormal follicular keratinization,
proliferation of Cutibacterium acnes and pro-inflammatory activity within the cutaneous
microbiome in the face, neck, chest or back regions.25 Despite the multifaceted nature of
acne, its association with gut microbiome dysbiosis has been a prominent field of research
and interest since 1961.61 Elements of the standard Western diet (SWD), particularly high
levels of hyperglycemic carbohydrates, dairy and saturated fats including trans-fats and
deficient ω-3 polyunsaturated fatty acids (PUFAs), have been associated with acne.62–64
These dietary elements elevate insulin and Insulin-like Growth Factor (IGF-1) levels,
disrupting sebaceous gland function and exacerbating acne, as well as increasing the
activity of the mechanistic Target of Rapamycin Complex 1 (mTORC1) pathway, which
enhances sebum production and inflammation.65 The SWD has also been shown to cause
dysbiosis in the gut microbiome.66
In conjunction, research has established that acne patients typically have gut microbiomes
with reduced diversity compared to non-affected individuals. Specifically, they exhibit
increased levels of Bacteroides and a lower abundance of Firmicutes, along with significant
reductions in the genera Proteus, Clostridium, Bifidobacterium, Butyricicoccus, Coprobacillus,
Lactobacillus and Allobaculum, as well as the families Lachnospiraceae and Ruminococcaceae
(Table III).67,68 Coprobacillus produces the SCFA butyrate, which plays an important role in
maintaining intestinal epithelial barrier integrity.69 Interestingly, older research suggests
that elevated levels of circulating lipopolysaccharide endotoxin from Escherichia coli (E. coli
LPS) are common in acne patients, indicating that intestinal permeability may be linked
to the pathogenesis of acne.61,70