What causes elevated fecal Matrix Metalloproteinase-9 (MMP-9) levels?

Elevated Fecal MMP-9 Levels: Causes and Clinical Significance

Elevated fecal MMP-9 levels are most strongly associated with active ulcerative colitis and pouchitis, where they correlate directly with endoscopic and histologic disease severity, while remaining undetectable or negligible in healthy individuals and functional bowel disorders. 1, 2

Primary Causes of Elevated Fecal MMP-9

Ulcerative Colitis (Most Common)

• Fecal MMP-9 shows strong correlation with clinical, endoscopic, and histologic activity in UC, with levels significantly elevated during active disease and undetectable (≤0.22 ng/mL) in healthy controls 2
• MMP-9 levels correlate with the overall Mayo score (P < 0.001), endoscopic score (P < 0.001), and serum C-reactive protein levels (P = 0.002) in UC patients 2
• The elevation reflects active mucosal inflammation and tissue injury, as MMP-9 is activated and localized to the apical surface of the colonic epithelium during inflammatory episodes 3
• Fecal MMP-9 demonstrates high sensitivity for detecting endoscopically active UC, making it a useful noninvasive marker for disease activity assessment 1

Pouchitis

• Strong associations exist between fecal MMP-9 and clinical, endoscopic, and histologic activities of pouchitis in patients with ileal pouch-anal anastomosis 1
• MMP-9 performs similarly well in pouchitis as in UC for detecting active inflammation 1

Crohn's Disease (Less Reliable)

• Fecal MMP-9 does not correlate with any activity indices in Crohn's disease, making it a poor marker for CD-specific inflammation 1
• This lack of correlation distinguishes UC from CD when interpreting elevated MMP-9 levels 1

Pathophysiologic Mechanisms

Intestinal Barrier Disruption

• MMP-9 directly increases intestinal epithelial tight junction permeability through activation of the p38 kinase signaling pathway, which upregulates myosin light-chain kinase (MLCK) gene activity 4
• This mechanism causes time- and dose-dependent increases in intestinal permeability both in vitro and in vivo 4
• The barrier dysfunction perpetuates intestinal inflammation and contributes to disease chronicity 4

Microbiome Dysregulation

• MMP-9 expression causes alterations in the fecal microbiome composition and impacts bacterial colonization patterns 3
• MMP-9 deficiency protects against reductions in fecal microbial diversity during bacterial enteric infections 3

Tissue Injury Mediation

• MMP-9-mediated tissue injury overrides any protective effects of MMP-2 during colitis, with MMP-9 playing an overriding pathogenic role 5
• MMP-9 is markedly elevated in intestinal tissue of IBD patients and contributes to the defective intestinal barrier function characteristic of these conditions 4

Clinical Interpretation Algorithm

When MMP-9 is Elevated (>0.22 ng/mL):

1. Strongly suspect active ulcerative colitis or pouchitis as the primary diagnosis 2
2. Exclude Crohn's disease as the sole explanation, as MMP-9 does not correlate with CD activity 1
3. Rule out IBS-D and functional disorders, where MMP-9 remains undetectable 2
4. Correlate with fecal calprotectin (>150 μg/g), which shows significant correlation with MMP-9 in UC (P = 0.014) 2, 6
5. Proceed with endoscopic assessment to confirm active mucosal inflammation, as elevated MMP-9 reliably predicts endoscopic disease activity 1, 2

When MMP-9 is Undetectable or Very Low (≤0.22 ng/mL):

• This effectively rules out active UC or pouchitis as the cause of symptoms 2
• Consider functional disorders, IBS-D, or non-inflammatory causes of symptoms 2
• Normal MMP-9 levels are found in all healthy controls and IBS-D patients 2

Comparison with Other Biomarkers

Fecal MMP-9 offers distinct advantages over calprotectin for UC-specific diagnosis, as it remains undetectable in functional disorders while calprotectin may show mild elevations in various conditions 2, 6

• MMP-9 provides 100% specificity for distinguishing UC from IBS-D and healthy controls 2
• Calprotectin has broader sensitivity but lower specificity, with elevations possible in infections, NSAID use, and other non-IBD inflammatory conditions 6
• Both markers should be used together: elevated MMP-9 confirms UC-specific inflammation, while calprotectin provides quantitative assessment of overall inflammatory burden 2

Critical Clinical Caveats

• Do not use fecal MMP-9 as a screening tool for Crohn's disease, as it lacks correlation with CD activity indices and will miss active CD 1
• MMP-9 elevation specifically indicates mucosal inflammation requiring endoscopic confirmation before initiating or escalating immunosuppressive therapy 6, 7
• Serial MMP-9 monitoring can assess treatment response and mucosal healing in UC, similar to calprotectin monitoring strategies 2, 6
• Very high MMP-9 levels (significantly above detection threshold) indicate severe active disease requiring urgent evaluation and treatment intensification 2