Synthetic sebum

Mouse model mimics human acne

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SAN DIEGO—“Eighty percent of individuals suffer from acne sometime during their life. Most get it during the teenage years,” according to Dr. George Liu, professor and chief of the Division of Pediatric Infectious Diseases at the University of California, San Diego’s medical school and formerly a faculty member at Cedars-Sinai Medical Center in Los Angeles.
While researchers once thought Propionibacterium acnes (P. acnes) bacteria—which are plentiful on everyone’s skin—cause acne, not everyone gets it or experiences it to the same degree. Recent genetic sequencing experiments showed that not all P. acnes are the same. There are different strains, some of which are abundant in acne lesions and some that are never found there.
Because researchers had no animal model that replicates the human condition, acne research and therapeutic development have lagged. Administration of P. acnes to mice does not cause long-term skin lesions, and the mouse immune system quickly removes the bacteria. Liu and a team of researchers from the UC San Diego School of Medicine, Cedars-Sinai and the University of California, Los Angeles, have developed a new mouse model that closely resembles human acne by adding one new factor—a synthetic sebum, the waxy skin secretion that increases in human adolescence. The model, described in a paper published in JCI Insight, enabled the researchers to directly compare “good” (health-associated) and “bad” (acne-associated) strains of P. acnes bacteria in a meaningful way.
“Sebum was thought to possibly contribute to either inflammation or P. acnes growth in acne, but published data were not conclusive,” Liu explained. “Our work points to the role of sebum contributing to P. acnes survival, but whether this is direct or indirect is still unclear.”
He added, “Since we know exactly which genes differ between these strains, next we can pinpoint exactly what it is about the acne-associated strains that allows them to cause skin lesions. And that information will help us develop new therapies that specifically block those acne-promoting factors, or tip the balance of a person’s skin chemistry in favor of the healthy strains.”
The team prepared synthetic sebum by using fatty acid, triglyceride, wax and squalene, a precursor compound to sterols, such as cholesterol and steroid hormones. A previous study described the “recipe” in ratios that resemble human sebum.
According to Liu, “When we started working with these bacteria and checked out the animal models others have been using over the years, we thought: ‘We’ve got to come up with something better than this.’ Acne typically occurs when a person hits their teenage years …What’s the difference between a child’s skin and a teenager’s skin? Increased sebum production. And we were surprised to find how such a simple addition made a big difference in our ability to study acne.”
The researchers injected mice with P. acnes and applied fresh sebum daily. Without the sebum, the mice had minimal lesions, and the bacteria were rapidly cleared from the site of administration. The sebum alone produced no effect on the skin, but applying both sebum and acne-associated strains of P. acnes, produced what appeared to be human acne, and the bacteria lived for weeks. These P. acnes strains also caused inflammation in the skin, as shown by elevated levels of inflammatory cytokine molecules.
When the researchers attempted the same procedure with health-associated strains of P. acnes—strains that are not found in human acne lesions—the results were very different. The same amount of bacteria was still present on the skin three days post-inoculation, regardless of the strain applied. However, lesions caused by acne-associated P. acnes strains scored about two times higher than lesions caused by health-associated strains in a measure that takes into account a lesion’s size, redness, dryness and degree of skin sloughing.
As Liu explained, “We showed that P. acnes provokes inflammation. P. acnes strains that caused severe acne in mice are more pro-inflammatory. Conversely, P. acnes strains that are associated with mild lesions are less inflammatory.”
Unlike people, the mice in these experiments were all genetically identical. According to Liu, that means that the differences in acne severity were due only to differences between the bacterial strains, not differences in the mice’s innate ability to react to the bacteria.
Next, the team hopes to improve upon its acne mouse model to achieve similar results when the bacteria are applied topically rather than administered by injection under the skin. The researchers also want to study genes unique to acne-associated P. acnes strains and determine how human sebum promotes these strains.
Liu noted that this information could help the team better understand who is at increased risk for acne and how to develop personalized therapies and vaccines that target the acne-promoting bacterial factors or sebum components. He concluded, “If the type of P. acnes determines if a person is likely to have moderate to severe acne, a personalized therapy would consist of swabbing a patient and determining what type of P. acnes grows on his or her skin. Based on that, the person could be treated topically with the health-associated P. acnes strain.”

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