The Gut-Skin Connection
Exploring Leaky Gut Through a Hidradenitis Suppurativa Study
The Skin-Gut Axis Revolution
Imagine suffering from painful, recurring skin abscesses that dramatically impact your quality of life, with medical science offering limited explanations for what causes them. This is the daily reality for millions living with hidradenitis suppurativa (HS), a chronic inflammatory skin condition that has long puzzled researchers and clinicians alike 1 3 .
Recently, a fascinating new theory has emerged that connects skin health to our digestive system—the gut-skin axis—suggesting that problems in our intestines might manifest as inflammation on our skin.
At the forefront of this investigation stands a crucial biological question: could a "leaky gut" be contributing to the relentless inflammation seen in HS? This article explores how scientists are testing this theory by examining soluble CD14 (sCD14), a key immune marker in the blood that may indicate whether bacterial fragments are escaping from the gut and triggering inflammation throughout the body 5 . Join us as we unravel the story behind a pioneering scientific investigation that seeks to answer whether this elusive gut-skin connection truly exists.
What Is Hidradenitis Suppurativa?
Hidradenitis suppurativa (HS), sometimes known as acne inversa, is a chronic, inflammatory skin condition that causes deep, painful lesions to form in areas where skin rubs together, such as the armpits, groin, and under the breasts 1 3 . These aren't ordinary pimples—they're deep-seated abscesses that can persist for weeks or months, often draining pus with a strong odor, forming tunnels under the skin, and leaving behind significant scarring 1 .
1-4%
of the population affected by HS
Prevalence
The condition typically begins after puberty and affects approximately 1-4% of the population, with women being three times more likely to be diagnosed than men 1 .
Underlying Mechanisms
While the exact cause remains unknown, researchers believe HS involves a combination of genetic, immune, and environmental factors 3 . The process begins when hair follicles become blocked and rupture, spilling their contents into the surrounding skin tissue and triggering an intense inflammatory response 1 . This is followed by an abnormal immune reaction that leads to the painful nodules and abscesses characteristic of the condition.
The Gut-Skin Axis: An Emerging Frontier
The concept that our gut health might influence our skin condition dates back nearly a century, but it's only in recent years that scientific evidence has begun to accumulate supporting what researchers now call the "gut-skin axis" 1 . This theory proposes that the health and balance of our gastrointestinal system directly affects the health and appearance of our skin.
Gut Microbiome
At the center of this theory lies the gut microbiome—the vast community of trillions of bacteria and other microorganisms living in our intestines. When this microbial community falls out of balance (a state known as dysbiosis), it may contribute to systemic inflammation that manifests in various organs, including the skin 1 . In people with HS, studies have indeed shown changes in gut bacteria composition that differ from healthy individuals 5 .
HS and IBD Connection
The gut-skin connection becomes particularly compelling when we consider the strong clinical association between HS and inflammatory bowel disease (IBD), especially Crohn's disease 5 . Crohn's disease is known to involve significant impairment of the gut epithelial barrier, commonly referred to as "leaky gut" 5 . This relationship led researchers to wonder: could a similar barrier defect be present in HS patients, allowing bacterial products to enter the bloodstream and trigger skin inflammation?
The gut microbiome plays a crucial role in the gut-skin axis theory
Soluble CD14 and Leaky Gut: Connecting the Dots
To understand the science behind the leaky gut theory in HS, we first need to meet the key players in this biological drama:
Lipopolysaccharide (LPS)
Lipopolysaccharide (LPS) is a component of the outer membrane of gram-negative bacteria that normally reside in our gut. When the intestinal barrier is compromised, LPS can "leak" into the bloodstream, where it functions as a potent trigger for inflammation 5 .
Soluble CD14 (sCD14)
Soluble CD14 (sCD14) is a protein that mediates the interaction between LPS and our immune cells 2 . When LPS enters the circulation, it binds to sCD14, which then presents it to immune cells, signaling the presence of gram-negative bacteria and triggering the release of pro-inflammatory cytokines 5 .
In conditions featuring impaired barrier function—such as sepsis, HIV, and inflammatory bowel disease—elevated levels of sCD14 serve as a reliable marker of excessive bacterial translocation 5 . Researchers hypothesized that if HS patients truly have a "leaky gut," they should show increased sCD14 levels in their blood compared to healthy individuals.
This theory was particularly plausible given that HS patients display dysregulation of their gut and skin microbiomes and have overrepresentation of myeloid cells (like monocytes and macrophages) that produce sCD14 5 .
A Preliminary Investigation: Testing the Theory
The Research Question and Hypothesis
In 2022, a research team from Trinity College Dublin and University College Dublin set out to investigate whether HS patients have elevated levels of sCD14 in their blood, which would support the "leaky gut" theory 5 . Their study, published in HRB Open Research, asked a deceptively simple question: Do patients with hidradenitis suppurativa have increased soluble CD14 levels compared to healthy individuals?
The hypothesis was straightforward: If HS involves a compromised gut barrier allowing bacterial products like LPS to enter circulation, then HS patients should have higher sCD14 levels than healthy controls.
Methodology: Examining the Blood
The research team adopted a case-control design, comparing sCD14 levels between 17 HS patients and 12 healthy controls 5 . The participant recruitment and laboratory analysis followed a meticulous process:
- Participant Recruitment: HS patients were recruited during routine clinical visits to St. Vincent's University Hospital in Dublin. Healthy controls were identified as individuals without inflammatory or infectious diseases.
- Blood Collection: Researchers collected 5 ml of blood from each participant using serum collection tubes.
- Sample Storage: The separated serum was immediately aliquoted and frozen at -80°C.
- sCD14 Measurement: The team used commercial Quantikine sCD14 ELISA kits to measure soluble CD14 concentrations.
- Statistical Analysis: The researchers used an unpaired Student's t-test to determine statistical significance.
Participant Demographic Characteristics
| Characteristic | HS Patients (n=17) | Healthy Controls (n=12) |
|---|---|---|
| Smoking Status | 30% current, 35% ex-smokers, 35% non-smokers | 11% current, 11% ex-smokers, 77% non-smokers |
| Treatments | 41% no treatment, 24% anti-TNF biologics, 6% anti-IL-17, 18% antibiotics, 12% other | Not applicable |
Summary of Key Experimental Results
| Measurement | HS Patients | Healthy Controls | Statistical Significance |
|---|---|---|---|
| Mean sCD14 Level | 5.021 ng/ml ± 2.223 | 3.680 μg/ml ± 1.691 | P = 0.09 (not significant) |
| Correlation with BMI | No significant correlation | No significant correlation | Not applicable |
| Correlation with CRP | No significant correlation | Not measured | Not applicable |
Results: An Unexpected Outcome
Contrary to the researchers' hypothesis, the study found no statistically significant difference in sCD14 levels between HS patients and healthy controls 5 . The mean serum level of sCD14 in HS patients was 5.021 ng/ml (± 2.223), compared to 3.680 μg/ml (± 1.691) in healthy controls, with a p-value of 0.09—above the threshold for statistical significance 5 .
The researchers also examined whether sCD14 levels correlated with other factors that might influence inflammation: Body Mass Index (BMI), Age, and C-reactive protein (CRP), but found no significant correlations with any of these factors.
The Scientist's Toolkit: Essential Research Reagents
Conducting a study like this requires specialized materials and reagents. Here are some of the key tools that enable sCD14 research:
| Reagent/Kit | Function | Manufacturer/Source |
|---|---|---|
| Human CD14 Quantikine ELISA Kit | Measures soluble CD14 in serum, plasma, or cell culture supernatants | R&D Systems 2 |
| CD14 ELISA Kits | Alternative kits for quantifying CD14 in various sample types | Thermo Fisher Scientific 6 |
| EasySep Human CD14 Positive Selection Kit II | Isolates CD14+ cells for further study | STEMCELL Technologies 7 |
| Serum Collection Tubes | Collects and preserves blood samples for serum separation | BD Vacutainer system 5 |
| Cell Culture Reagents | Grows and maintains human cells for experimental work | Various manufacturers 2 |
ELISA Technology
The Enzyme-Linked Immunosorbent Assay (ELISA) is a plate-based technique for detecting and quantifying substances such as proteins, antibodies, and hormones. In this study, ELISA kits were used to precisely measure sCD14 concentrations in serum samples.
Sample Preservation
Proper sample handling is critical in biomarker research. Freezing serum at -80°C prevents degradation of sensitive proteins like sCD14 and ensures accurate measurement when samples are later analyzed.
Interpreting the Null Results: What Does It Mean?
The finding of no significant difference in sCD14 levels between HS patients and controls raises important questions about the "leaky gut" theory in HS. The researchers drew two primary conclusions from their results:
1. sCD14 as a Clinical Marker
sCD14 is not a useful inflammatory marker for HS patients in clinical settings 5 .
2. Gut Barrier Integrity
HS patients may not have a grossly compromised gut epithelial barrier—at least not to the extent that would cause significant bacterial translocation and elevated sCD14 5 .
These conclusions challenge the simple narrative that a "leaky gut" is a major driver of HS inflammation. However, there are several important limitations and alternative explanations to consider:
Study Limitations
Small Sample Size
The Dublin study was preliminary in nature, with a relatively small sample size of only 17 HS patients and 12 controls 5 . With limited participants, the study may have been underpowered to detect subtle differences in sCD14 levels that might exist between groups.
Treatment Heterogeneity
Additionally, the HS patient group was heterogeneous in their treatments—some were using anti-TNF biologics, others antibiotics, and 41% were untreated 5 . These varied treatments could have influenced sCD14 levels, potentially masking differences between HS patients and healthy controls.
Alternative Explanations
Different Mechanisms
While sCD14 may not be elevated in HS, this doesn't entirely rule out gut involvement in the disease. The inflammatory process in HS might be driven by mechanisms other than LPS translocation, or perhaps the gut inflammation in HS is not severe enough to elevate sCD14 to the levels seen in conditions like Crohn's disease or sepsis.
Other Biomarkers
It's also possible that other biomarkers might better reflect gut barrier integrity in HS patients. The researchers measured only sCD14, but other markers like zonulin (a protein that regulates gut permeability) or intestinal fatty-acid binding protein (I-FABP, a marker of intestinal cell damage) might tell a different story 1 .
The Future of HS and Gut-Skin Research
Despite the null findings of this particular study, research into the gut-skin connection in hidradenitis suppurativa continues. The search for reliable biomarkers—measurable indicators of disease processes—remains a priority in HS research 4 .
A 2022 systematic review published in JAMA Dermatology identified only four biomarkers that achieved a "high" GRADE rating for HS, underscoring the need for more validated tools to understand and monitor this complex disease 4 . While this review didn't include sCD14 as a validated biomarker, it highlighted the importance of continuing the search for reliable indicators of disease activity and underlying mechanisms.
4
biomarkers with "high" GRADE rating for HS
Future Research Directions
Larger Studies
Larger replication studies with greater statistical power
Other Biomarkers
Examination of other gut barrier biomarkers beyond sCD14
Intervention Studies
Intervention studies examining how gut-targeted treatments affect HS symptoms
Microbiome Analysis
More sophisticated microbiome analyses to identify specific bacterial populations
Conclusion: A Step Forward in Scientific Understanding
The Dublin sCD14 study represents an important contribution to our understanding of hidradenitis suppurativa, even—and perhaps especially—through its null findings. In science, negative results are not failures but rather crucial pieces of the puzzle that help narrow down possible explanations and redirect research efforts toward more promising avenues.
While the "leaky gut" theory as measured by sCD14 wasn't supported in this preliminary investigation, the study exemplifies the rigorous process of scientific inquiry: forming a hypothesis based on clinical observations, testing it with appropriate methods, and drawing conclusions based on the evidence regardless of initial expectations.
For the millions living with hidradenitis suppurativa, each study—whether confirming or refuting a theory—brings us incrementally closer to understanding this complex condition and developing more effective treatments. The gut-skin connection may not be explained by sCD14 and bacterial translocation, but researchers will continue to explore other potential mechanisms linking our digestive health to skin inflammation.
As research continues, studies like this preliminary investigation of soluble CD14 serve as important waypoints in the journey toward unraveling the mysteries of hidradenitis suppurativa and providing relief to those who live with its challenging symptoms every day.
Scientific Progress
Each study brings us closer to understanding HS and developing better treatments