In Colitis Patients, Skin Conditions Can Come From The Intestine

Cross section of healthy skin, showing layers of skin (red), the normal microbiome of skin bacteria (green) and several types of immune cells (purple). In the skin affected by colitis, the bacteria remain the same, but the number of immune cells is greater, creating inflammation. Image by Scharschmidt Lab.

A new study by UC San Francisco researchers reveals how intestinal inflammation can irritate not only the digestive system, but the skin as well. It’s a story in which the main players are specialized immune cells and the community of bacteria – called the microbiome – that resides in the gut and skin.

Scientists are becoming increasingly aware that disruptions to the gut microbiome can affect other parts of the body. These changes have been linked to an increased risk of diseases such as asthma, rheumatoid arthritis, multiple sclerosis.

In a study published May 31, 2022 in Cell Reports, a team of researchers investigated how colitis, or chronic inflammation of the colon, can cause a debilitating skin condition that looks like an infection but doesn’t actually contain a skin pathogen.

“What we learned is that the factors involved with gut inflammation actually cause the skin to react differently to familiar microbes,” says dermatologist Tiffany Scharschmidt, MD, senior author of the study. “The composition of bacteria on the skin has not changed. Instead, what changes is the skin’s immune response to them.”

Scharschmidt believes the discovery could help explain the skin disorder associated with colitis.

Many Microbes

Normally, invading pathogenic bacteria are attacked and expelled by immune cells, but the well-behaved microbial members of the body’s microbiome – called “commensals” – are tolerated by the immune system. This tolerance is formed very early during infancy.

Scharschmidt and his team are beginning to better understand how disruption of the immune microbiome environment in the gut can deprive the microbiome of tolerance in another distant organ – the skin. This phenomenon occurs in a variety of conditions, including colitis, which belongs to inflammatory bowel disease (IBD).

The research, spearheaded by graduate student Geil Moaning, PhD, focused specifically on inducing colitis in adult mice and observing how the immune system and microbiome in the gut and skin responded. The team found that this allowed neutrophils, a type of inflammatory immune cell, to infiltrate the skin. In mice, this neutrophil invasion, which has also been observed in humans with IBD-associated skin disorders, requires the activity of a molecule called IL-1, a protein that plays a role in regulating immune responses.

Turning the Table Against Tolerance

The second surprising finding was that colitis appears to abrogate early-life tolerance to certain skin commensal bacteria, causing the immune system to launch an inflammatory reaction directed against a previously absent microbe.

Understanding what’s going on in the skin is the first step to thinking of new ways to deal with the problem.

The body’s ability to tolerate a species of bacteria is maintained by balancing the work of two types of immune cells that have opposing functions. Regulatory T cells, or Tregs, promote tolerance, while effector T cells defend against molecules or microbes that do not belong to the body. Tolerance arises when Tregs suppress effector T cells.

The team looked at T cells that target the common skin bacterium Staphylococcus epidermidis, which is usually harmless. They found that colitis led to lower Treg ratios with their peer effector T cells. It is this Treg deficit, they conclude, that promotes skin inflammation.

The researchers then induced colitis in a group of mice whose T cells were unresponsive to IL-1. In contrast to the normal mouse response, the genetically altered mice did not experience neutrophil accumulation in the skin. The ratio of the two types of T cells is not affected, and there is no inflammation.

These results suggest that IL-1 plays a key role in removing the balance from tolerance and leading to the inflammatory response, according to Scharschmidt.

Therapy that can maintain a balanced T-cell response could be a promising therapy for future research and development, Scharschmidt said. “Understanding what happens in the skin is the first step towards thinking about new avenues for dealing with problems.”

This research was funded by the NIH grant DP2AI144968 and the Burroughs Wellcome Fund CAMS-1015631 grant.

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