Top Intestinal Inflammatory Biomarkers Commonly Used In Functional Medicine

Inflammatory bowel disease encompasses inflammatory processes that affect the gastrointestinal tract, causing severe symptoms, chronic inflammation, and health complications if not treated appropriately. Inflammatory bowel disease symptoms can be easily confused with irritable bowel syndrome or other non-inflammatory gastrointestinal diseases. Therefore, diagnostic evaluation of digestive symptoms includes differentiating between inflammatory and non-inflammatory digestive disorders. Intestinal inflammatory biomarkers are important in diagnosing and managing inflammatory bowel disease because they give a non-invasive objective measurement of disease activity, severity, and response to treatment.

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What is Inflammatory Bowel Disease (IBD)?

IBD is a chronic gastrointestinal disease characterized by recurrent episodes of inflammation that can lead to permanent intestinal damage, complications, and increased risk of chronic disease over time (1). IBD affects 3 million American adults, and the prevalence of this disease continues to rise.

Crohn's disease (CD) and ulcerative colitis (UC) are the two most common subtypes of IBD. These subtypes differ by the location of inflammation and the depth of involvement of the bowel wall. CD is defined by full-thickness inflammation that presents as patchy skip lesions in any portion of the digestive tract. In contrast, inflammation is limited to the innermost layer of the colonic wall and ascends continuously from the rectum in UC. (1)

IBD Symptoms

IBD symptoms occur in a remitting-relapsing pattern, meaning that patients experience symptom flares between asymptomatic remission periods. The most common IBD symptoms during symptom flares include abdominal pain, changes in bowel movements, and bloody diarrhea. High levels of inflammation during flares can also cause symptoms outside of the gastrointestinal tract, including fever, eye pain and inflammation, joint pain, and skin lesions. (2)

Intestinal malabsorption is common in patients with CD affecting the small intestine. Signs that you are not absorbing nutrients include unintentional weight loss, anemia, and nutrient deficiencies.

Poorly controlled IBD can lead to increased risk of other health complications over time, including (1):

• Anal fistulas
• Arthritis
• Blood clots
• Colon cancer
• Gallstones
• Hemorrhage
• Intestinal strictures, perforation, and obstruction
• Liver disease
• Osteoporosis
• Toxic megacolon

Possible Causes of Inflammatory Bowel Disease

The exact cause of IBD is unknown, but it can occur in genetically susceptible people after exposure to environmental triggers causes a hyperstimulated and inappropriate immune response, resulting in inflammation in the intestinal wall. (3)

Approximately 10% of patients with IBD have a first-degree relative with the disease. Over 150 genetic markers have also been identified to increase susceptibility to IBD. However, having genetic susceptibility alone does not guarantee that an individual will develop IBD during their lifetime. Exposure to environmental factors is an important aspect of the onset and presentation of clinical manifestations.

The most commonly studied environmental factors in IBD development and relapse include sleep disturbance, chronic stress, inflammatory dietary patterns, pharmacologic agents, dysbiosis and infection, environmental pollution and toxins, and allergies.

What Do Intestinal Inflammatory Biomarkers Tell You?

Colonoscopy is an invasive, and often undesirable, diagnostic procedure required to diagnose IBD. Because many patients with irritable bowel syndrome (IBS) present with gastrointestinal symptoms similar to IBD, ordering inflammatory biomarkers can help narrow the differential diagnosis to decide if a colonoscopy is necessary during the diagnostic evaluation. Inflammatory bowel markers are nonspecific markers of inflammation; they are likely to be elevated in more severe diseases like IBD and colon cancer, but unlikely to be elevated in functional gastrointestinal conditions like IBS. (4)

Traditionally, monitoring the severity of IBD and treatment response has been based on symptom presentation, activity scores, and repeat endoscopic imaging. These have significant limitations, including the cost and invasiveness of colonoscopy and the subjective nature of patient-reported symptom severity. For these reasons, serum and fecal inflammatory biomarkers are routinely utilized in the clinical setting as non-invasive and cost-effective alternatives to monitoring IBD. (5, 6)

No ideal biomarker exists for diagnosing disease, aiding treatment decision-making, monitoring treatment response, and surveying disease activity. A combination of serum and fecal biomarkers are often measured as objective markers of intestinal inflammation. (7)

Top Functional Medicine Inflammatory Markers to Measure for Patients with IBD

Functional medicine labs help practitioners diagnose diseases and personalize treatment options for their patients. Below are some of the most common intestinal inflammatory markers ordered for patients suffering from gastrointestinal disorders.

C-Reactive Protein (CRP)

CRP is an acute phase reactant, an inflammatory marker that elevates significantly in the presence of inflammation. It is a nonspecific inflammatory marker, meaning that elevations can be attributed to diseases besides IBD, such as cancer or infection. (11)

CRP has a high sensitivity for differentiating between IBD and IBS; according to one meta-analysis, patients with a normal CRP have less than a 1% likelihood of having IBD. Elevated CRP correlates with disease severity and activity and has been shown to predict clinical relapse and therapy failure. CRP tends to be a more reliable marker in CD, and even still, there are reports of false-negative results. As such, it is recommended that CRP be ordered in conjunction with other biomarkers. (10)

Calprotectin

Fecal calprotectin is a fundamental biomarker used to diagnose and monitor IBD. Calprotectin is a calcium-binding protein present predominantly in neutrophilic white blood cells. Fecal calprotectin levels increase in patients with active IBD due to neutrophil activation within the intestinal mucosa during inflammatory responses. (12)

Calprotectin can be measured to differentiate between IBS and intestinal inflammatory conditions. Patients with IBS symptoms and a fecal calprotectin level less than 40 μg/g have a 1% or less chance of having IBD. (10)

Similarly to CRP, calprotectin can increase in other intestinal conditions, including celiac disease and colon cancer. Therefore, elevated calprotectin indicates the need for colonoscopy for a definitive diagnosis of pathology and disease. Calprotectin levels can be used to rate IBD severity and activity and predict clinical relapse and patient response to treatment. (10)

Lactoferrin

Fecal lactoferrin is a similar marker to calprotectin. Lactoferrin is an iron-binding protein stored in neutrophilic granules. It is released from neutrophils and secreted by intestinal mucosal membranes in response to inflammation, making it a sensitive and specific marker in measuring the activity of IBD. Elevated fecal lactoferrin can help rule out IBS and other non-inflammatory intestinal diseases in clinical practice, along with quantifying the activity of IBD. (13)

Secretory IgA (sIgA)

sIgA is the most abundant class of antibody in the intestinal lumen and a first-line defense in protecting the body from pathogens and toxins passing through the digestive tract. Fecal sIgA is a nonspecific marker, but elevations indicate immune activation within the intestines. Causes of elevated sIgA include intestinal infections, increased intestinal permeability, celiac disease, colon cancer, IBS, and IBD. sIgA cannot be used as a reliable marker in patients with immunoglobulin deficiencies. (14)

Eosinophil Protein X (EPX)

EPX is expressed by eosinophilic white blood cells when the intestinal lamina propria, a connective tissue layer under the intestinal mucosa, is damaged during ongoing inflammation and tissue destruction. Elevations in EPX are most commonly associated with allergies and parasitic infections, but can also occur during active celiac disease, IBD, or other types of colitis. EPX is measured in a stool sample, such as Genova's GI Effects Comprehensive Profile. (14)

Lysozyme

Lysozyme is an enzyme that induces the breakdown of bonds that make up bacterial cell walls. Elevated fecal levels have been identified in colonic IBD. Levels tend to be slightly higher in those with CD than those with UC. (15)

Interleukins

Interleukins (IL) are a class of cytokines, or proteins, made by immune cells in response to pathogens and other triggers to regulate and mediate inflammatory and immune responses. IL-6, IL-8, and IL-17A are implicated in active IBD, responsible for stimulating immune cell and acute phase reactant differentiation and activation. Therefore, they can be used to predict and monitor IBD disease activity. Interleukins are also therapeutic targets for several pharmacologic agents that induce and maintain disease remission. (8, 9)

Tumor Necrosis Factor Alpha (TNF-α)

Like interleukins, TNF-α is another type of cytokine involved in pro-inflammatory immune responses, partly responsible for the intestinal and extraintestinal pathological complications of IBD. TNF-α can predict and monitor disease activity and is targeted by pharmacologic agents to treat disease. (8, 9)

Serum Amyloid A (SAA)

SAA proteins are synthesized in response to cytokines released by activated white blood cells during inflammatory processes. It is as sensitive as CRP in measuring IBD-induced inflammation to quantify disease severity. (8, 16)

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Summary

Effective management of IBD requires efficient diagnosis and close monitoring of patient symptoms and disease activity. While colonoscopy is the gold standard for disease monitoring, it is invasive and expensive. Therefore, serum and fecal inflammatory biomarkers are preferred in differentiating non-inflammatory and inflammatory bowel conditions and monitoring disease severity and patient response to therapeutic interventions. Combining multiple intestinal inflammatory biomarkers ensures accurate results, guides treatment recommendations, and provides an understanding of underlying contributors to disease pathology and activity.