647 Bidirectional Gut-Skin Axis
recent findings suggest that changes in the skin can also trigger alterations in the gut
microbiome (Figure 2).22,6 This concept not only affirms the existence of the gut-skin axis,
in which changes in the gut microbiome affect the skin, but also introduces a reciprocal
skin-gut axis, where alterations in the skin impact the gut and the gut microbiome.6
Research by Dokoshi et al. (2024) demonstrated that dermal injury to the skin directly
influences the composition and behavior of the gut microbiome in a murine model.6 Skin
damage, whether through injury or artificial digestion of dermal hyaluronan, alters host
defense gene expression in the colon, specifically causing an increase in the expression
of Regenerating Islet-Derived Protein 3 (Reg3) and Mucin 2 (Muc2), which ultimately
disrupts the gut microbiome and enhances bacterial penetration of the intestinal
lining.6 Researchers hypothesize that the hyaluronan fragments released as a result of
skin injury or artificial digestion act as damage-associated molecular pattern molecules
(DAMPs) in response to skin inflammation.6 Through the activation of receptors
such as CD44 and Toll-like receptor 4 (TLR4), these fragments engage components
of the innate immune system.161–163 This activation likely leads to the production of
pro-inflammatory cytokines, including interleukin-6 (IL-6), as observed in recipients
of FMT from wounded mice.6 The elevated levels of IL-6 amplify the inflammatory
response and may contribute to downstream inflammatory effects, impacting distant
tissues such as the colon.6
Furthermore, the release of these hyaluronan fragments induced expression of the host
defense genes Muc2 and Reg3 in colon epithelial cells, both of which contribute to
maintaining the spatial separation between the microbiome and the host epithelium.6
REG3 protein specifically contributes to protection against damage, cell proliferation,
antibacterial defense and the prevention of bacterial translocation.164 Meanwhile, MUC2
mucin forms a polymeric net-like mucus layer anchored to epithelial cells, continuously
replenishing the inner mucus layer from beneath.165 This inner layer is impervious to
bacteria, keeping them away from the epithelial cells.165
Therefore, skin injury appears to have a potentially detrimental effect on the gut
microbiome, leading to the loss of beneficial bacteria, an increase in pathogenic bacteria
and an overall decrease in total bacterial diversity.6 The relative abundance of certain
bacterial species, such as Lachnospiraceae bacterium A4 and Akkermansia muciniphila,
was found to increase in the gut microbiomes of mice with skin wounds.6 Additionally,
skin wounding was associated with the upregulation of genes involved in the choline
catabolic process and cobyrinic acid synthase activity, which enhanced bacterial survival
and the activity of opportunistic pathogens like B. thetaiotaomicron.6 Conversely, there was
a decrease in the expression of genes beneficial to the intestine, such as those involved
in propionate catabolic processes, which are important for suppressing inflammatory
responses.6 The observed increase in mucin and REG3 likely contributes to the overall
loss of bacteria, while also enabling the surviving organisms to penetrate further into the
mucus layer and colonic epithelium.6
Further research is required to fully elucidate the roles of these genes in this process, as
well as the characteristics of the bacteria that penetrate the intestinal epithelium. Previous
studies by the same researchers found that skin wounds increase susceptibility to colitis
in mice, and that skin inflammation activates intestinal stromal fibroblasts, promoting
colitis and altering the gut microbiome.166 They concluded that skin-derived hyaluronidase
expression could activate intestinal stromal fibroblasts, modify the fecal gut microbiome,
promote reactive adipogenesis and increase colon inflammation.166 It is important to note
recent findings suggest that changes in the skin can also trigger alterations in the gut
microbiome (Figure 2).22,6 This concept not only affirms the existence of the gut-skin axis,
in which changes in the gut microbiome affect the skin, but also introduces a reciprocal
skin-gut axis, where alterations in the skin impact the gut and the gut microbiome.6
Research by Dokoshi et al. (2024) demonstrated that dermal injury to the skin directly
influences the composition and behavior of the gut microbiome in a murine model.6 Skin
damage, whether through injury or artificial digestion of dermal hyaluronan, alters host
defense gene expression in the colon, specifically causing an increase in the expression
of Regenerating Islet-Derived Protein 3 (Reg3) and Mucin 2 (Muc2), which ultimately
disrupts the gut microbiome and enhances bacterial penetration of the intestinal
lining.6 Researchers hypothesize that the hyaluronan fragments released as a result of
skin injury or artificial digestion act as damage-associated molecular pattern molecules
(DAMPs) in response to skin inflammation.6 Through the activation of receptors
such as CD44 and Toll-like receptor 4 (TLR4), these fragments engage components
of the innate immune system.161–163 This activation likely leads to the production of
pro-inflammatory cytokines, including interleukin-6 (IL-6), as observed in recipients
of FMT from wounded mice.6 The elevated levels of IL-6 amplify the inflammatory
response and may contribute to downstream inflammatory effects, impacting distant
tissues such as the colon.6
Furthermore, the release of these hyaluronan fragments induced expression of the host
defense genes Muc2 and Reg3 in colon epithelial cells, both of which contribute to
maintaining the spatial separation between the microbiome and the host epithelium.6
REG3 protein specifically contributes to protection against damage, cell proliferation,
antibacterial defense and the prevention of bacterial translocation.164 Meanwhile, MUC2
mucin forms a polymeric net-like mucus layer anchored to epithelial cells, continuously
replenishing the inner mucus layer from beneath.165 This inner layer is impervious to
bacteria, keeping them away from the epithelial cells.165
Therefore, skin injury appears to have a potentially detrimental effect on the gut
microbiome, leading to the loss of beneficial bacteria, an increase in pathogenic bacteria
and an overall decrease in total bacterial diversity.6 The relative abundance of certain
bacterial species, such as Lachnospiraceae bacterium A4 and Akkermansia muciniphila,
was found to increase in the gut microbiomes of mice with skin wounds.6 Additionally,
skin wounding was associated with the upregulation of genes involved in the choline
catabolic process and cobyrinic acid synthase activity, which enhanced bacterial survival
and the activity of opportunistic pathogens like B. thetaiotaomicron.6 Conversely, there was
a decrease in the expression of genes beneficial to the intestine, such as those involved
in propionate catabolic processes, which are important for suppressing inflammatory
responses.6 The observed increase in mucin and REG3 likely contributes to the overall
loss of bacteria, while also enabling the surviving organisms to penetrate further into the
mucus layer and colonic epithelium.6
Further research is required to fully elucidate the roles of these genes in this process, as
well as the characteristics of the bacteria that penetrate the intestinal epithelium. Previous
studies by the same researchers found that skin wounds increase susceptibility to colitis
in mice, and that skin inflammation activates intestinal stromal fibroblasts, promoting
colitis and altering the gut microbiome.166 They concluded that skin-derived hyaluronidase
expression could activate intestinal stromal fibroblasts, modify the fecal gut microbiome,
promote reactive adipogenesis and increase colon inflammation.166 It is important to note
