by Adrienne Williamson , Medical Xpress
High fat diet feeding promotes an accumulation of mature adipocytes in the skin dermis and impairs skin’s resistance against S. aureus infection. (A). Mice were fed with standard diet (SD) or high fat diet (HFD) and skin sections were stained with hematoxylin and eosin to visualize how HFD alters skin structure. (B). SD or HFD mice were infected intradermally with S. aureus, and images for skin lesion was shown. Credit: Zhang et al.
The list of diseases and conditions complicated by obesity is a long one; it includes heart disease, cancer, diabetes and impaired wound healing, as well as skin infections. It is not always clear, however, in what way this complication is caused. New research from the School of Pharmaceutical Science at Xiamen University and the Gallo Lab at UC San Diego School of Medicine, published last month in Science Translational Medicine, has uncovered the mechanisms that link obesity and skin infections, and identified a treatment option that will soon be tested in a Phase 2 clinical trial.
The work is focused on discovering links between disease and the epithelial microbiome—that is, the normal bacteria that live on our skin—and how the skin’s defense system can be optimized to treat or prevent disease. In this study, the goal was to identify how obesity contributes to higher rates of atopic dermatitis. “Obesity is associated increased risk for skin infection, but how obesity impairs our immune system is not clear,” explains Dr. Ling-juan Zhang, School of Pharmaceutical Science at Xiamen University and lead researcher on the study. “We have found that when mice are fed a high fat diet and become obese, skin adipocytes (or fat cells) become enlarged and lose the ability to fight against bacterial invasion during an skin infection.”
The findings revealed that an increased number of mature adipocytes (fat cells) increases TGFβ signaling, which in turn decreases the number dermal adipocyte progenitors that produce an antimicrobial peptide called cathelicidin. This absence leaves the epidermis vulnerable to infection from common culprits like Staphylococcus aureus. In lean subjects (both mice and human in this study), the skin microbiome was successful in preventing Staph infections, as the number of mature fat cells was insufficient to disrupt the normal dermal fat functions that keep such infections at bay. “Normally, skin fat cells can rapidly respond to invading bacteria, and produce a molecule called antimicrobial peptide, which is the antibiotics produced by our own cells, to kill bacteria. However, upon obesity, the enlarged skin fat cells lose the ability to produce antimicrobial peptides, and this is mediated by a cell signaling protein transforming growth factor beta or TGFβ, which is produced by the enlarged fat cells and negatively impacts antimicrobial peptides during obesity,” says Dr. Zhang.
Dr. Richard L. Gallo, lead researcher at Gallo Lab at UC San Diego School of Medicine, explained the importance of this research to Medical Xpress: “Atopic Dermatitis is a chronic inflammatory skin disease which affects up to 20% of children and up to 3% of adults worldwide, posing a significant burden on patients’ quality of life. People suffering from atopic dermatitis have red, itchy skin. In many cases this rash will disrupt sleeping and severely impact quality of life. Also, people with atopic dermatitis are more susceptible to infections of the skin and are more likely to have other allergies and asthma.”
Model proposed for how diet induced obesity impairs the antimicrobial defense function of dermal fat. High fat diet feeding leads to a profound loss of the reactive adipogenesis response that is necessary to defense against S. aureus skin infection. The PPARγ agonist ROSI or a TGFβ receptor inhibitor (SB) restored the ability of the obese mice to defend against infection. Credit: Zhang et al.
Next, the team hoped to find a treatment option that would work safely and effectively for most patients. Prevention, as always, is better than cure. Dr. Zhang explains: “Our study shows how an unhealthy diet and obesity can impact the skin’s ability to fight against bacterial infection, and will help to educate individuals on the importance of a healthy diet and life style that includes regular exercises to prevent accumulation of enlarged fat cells that may negatively impact the antimicrobial function of our skin.”
For obese individuals already experiencing atopic dermatitis, the team is in search of effective treatment options. They turned again to the skin microbiome of healthy individuals for clues. “We are currently investigating new therapies, including new agents to block TGFβ action and stem cell therapy, to treat obesity-associated skin infection,” says Dr. Zhang. “Stem cells that can turn into healthy fat cells maybe used as potential therapy to regenerate healthy fat cells that can produce antimicrobial peptides in the obese skin to help to fight against infection.”
“Fat is not all ways bad, and healthy adipocytes are necessary for our body to fight against infection,” Dr. Zhang explains. “Luckily, fat cells are highly plastic and regulatable, and the antimicrobial activity of obese fat cells can be restored through interventions, such as switching to a healthy diet, regular exercise and targeted drugs or therapies.”
That’s where the Gallo Lab’s focus comes in. “The skin microbiome, sometimes called the skin flora, is the term for the millions of microorganisms that live on and in our body’s largest organ and protective barrier,” Dr. Gallo explains. Obese mice, inoculated with S. aureus, were treated with bacterial genes found in typical dermal microbiota. When the animal trial proved successful, the Gallo Lab team moved to human subjects. “A total of 54 adults were treated in a double-blind, placebo-controlled human trial. The technique used is a transformational approach to treating disease since we specifically chose the bacteria for use based on specific bacterial genes that were missing from the microbiome of atopic dermatitis patients.”
The research is good news for pharmaceutical researchers desperate to find a path around antibiotic resistance, as well, an increasingly problematic result of antibiotic overuse and the nature mutation of bacteria. “Modulating the skin microbiome can lead to a new class of live therapeutics for skin diseases beyond atopic dermatitis. This approach is a dramatic improvement over broad-spectrum antibiotics that destroy pathogenic bacteria but also kill beneficial bacteria by ‘friendly fire,'” Dr. Gallo says. “This paper shows how a bacteria that is found on healthy human skin can be used safely to treat people with atopic dermatitis. … The exciting part of the work is that this is the first time the approach of targeted bacteriotherapy has been used for a skin disease, and the trial shows it is safe and helped most of the patients who received it.”
From here, the therapy moves forward on its path toward clinical use. “With this as a proof of principle we can now expand the size of the study to include more patients and to apply this approach to more diseases. We have also expanded our screening platform to look at other skin diseases and are excited to advance these programs into the clinic,” says Dr. Gallo.
The technology described in the study has been licensed by MatriSys Bioscience, a San Diego based biotechnology company. Dr. Gallo is cofounder and a member of the MatriSys scientific advisory board. MatriSys plans to conduct a Phase 2 clinical trial with 150 patients over a 12-week treatment period.
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