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Our Tests Gut Health Assessment

Stool Tests:

Description/Background Information

Calprotectin is a small calcium- and zinc-binding protein that derives mainly from neutrophils, constituting 60% of the cytosolic protein.1 Active inflammation in the gut that induces neutrophil influx into the mucosa will eventually disrupt the mucosal architecture, allowing neutrophils (with their cytosolic calprotectin) to leak into the intestinal lumen and be excreted with the feces.2 Fecal calprotectin (fCal) has been shown to correlate with the severity of intestinal inflammation, and is a sensitive biomarker of inflammatory bowel disease (IBD).3,4

Although endoscopy remains the gold standard for assessing IBD activity and mucosal healing, it is an invasive procedure that carries risks and burdens (e.g., patient discomfort and complications), and is time-consuming and expensive.2,5 Measurement of fCal represents a reliable, accurate, and noninvasive method of detecting mucosal inflammation in the GI tract, and may reduce the need for endoscopic procedures.6 It allows for sample collection at home and has demonstrated utility for regular monitoring of IBD patients, not only for differential diagnosis of IBD from non-IBD, but for assessing disease activity, relapse prediction, and response to therapy.

Clinical Utility & Indications

Abdominal pain or discomfort is one of the most common reasons for going to see a doctor. Irritable bowel syndrome (IBS) or related symptoms account for 10–20% of primary care physician visits and up to 20% of gastrointestinal outpatient clinic time.7,8 In turn, ~1.6 million Americans (1 in 200) currently have IBD (Crohn’s disease or ulcerative colitis), and ~70,000 new cases are diagnosed in the United States each year.9

Both IBS and IBD are thought to be triggered by intestinal dysbiosis or infection, toxic luminal substances (e.g., gut-damaging medications, foods, or allergens), and stress, with genetic susceptibility playing a greater role in IBD.10,11 Typical features common to IBS and IBD may include diarrhea, abdominal pain, and chronic relapsing course, although the inflammation in IBS never reaches the extent of that in IBD. Because the cumulative tissue damage in IBD carries risk of colorectal cancer and colectomy if untreated, accurate detection and diagnosis is critical. The clinical challenge lies in selecting patients for endoscopy—more than 50% of patients with symptoms suggesting IBD will have negative endoscopy and be diagnosed with IBS.2 fCal measurement can help the physician:

  • Determine severity of mucosal inflammation: fCal correlates well with the severity of gut inflammation as measured by endoscopy in IBD or mucosal lesions of the stomach.4,6 The Salveo Diagnostics monoclonal testing of fCal is superior to both polyclonal calprotectin testing and fecal lactoferrin, a less-specific marker of inflammation, in identifying organic intestinal disease in symptomatic patients.12
  • Distinguish organic GI diseases (e.g., IBD, diverticulitis, gastric or colorectal cancers, peptic ulcers, or infectious diarrhea) from those that are functional (e.g., IBS)6,10: fCal levels are normal in IBS.13 A mean sensitivity and specificity of 83% and 84%, respectively, has been reported for fCal in distinguishing organic from functional disorders.14 In a recent meta-analysis, pooled sensitivity and specificity were 93% and 96% for separating IBD from non-IBD.15 fCal may clarify the need for endoscopy or colonoscopy in patients with abdominal discomfort.
  • Assess IBD disease activity and predict clinical relapse: Chronic IBD is characterized by refractory periods punctuated with symptom flare-ups that can be severely disabling. Detection of subclinical intestinal inflammation in IBD patients who are in remission via a rise in fCal can predict disease relapse, allowing prompt treatment adjustment and avoidance of unnecessary endoscopies and hospitalizations.1,6,16
  • Evaluate response to treatment: Treatment of IBD requires active management. Beyond controlling symptoms, the goal is deep remission and mucosal healing, which improves prognosis and can be assessed by normalization of fCal.1,2,17 As the course of IBD is unpredictable, periodic assessment of activity is necessary in order to modify therapy on an ongoing basis.
  • Predict postoperative IBD recurrence: fCal levels that remain high postsurgery indicate risk of recurrence.1,18

Calprotectin Cut Points & Interpretation

Optimal Mildly Elevated High
≤ 79 μg/g 80 – 159 μg/g ≥ 160 μg/g

The Salveo Diagnostics cut points for fCal have been established on the basis of organic disease prevalence, following assay manufacturer’s recommendations, to provide 82% sensitivity (71–82% positive predictive value), and 97–99% specificity (98% negative predictive value) for organic disease.

  • fCal values ≤ 79 μg/g indicate that mucosal inflammation is not likely to be the cause of symptoms.
  • fCal values between 80 and 159 μg/g may represent mild organic disease with low-grade inflammation stemming from, for example, bacterial pathogens, esophagitis, parasites, food sensitivities, mild diverticulitis, colorectal polyps, chronic gastritis or stomach/duodenal ulcer, some neoplasms, chronic use of gut-damaging medications, and IBD in remission phase.6,21  Consider treatment and re-evaluation in 4–6 weeks.
  • fCal values ≥ 160 μg/g are markedly elevated, consistent with active organic disease with inflammation in the GI tract (e.g., IBD, diverticulitis, some bacterial infections, and GI cancers).6,20 Depending on clinical correlation, consider endoscopic or radiographic follow-up.

Recommended cut-points for using fCal as a surrogate marker of mucosal healing18,19

IBD subtype Cut point Sensitivity Specificity
Ulcerative colitis 250 µg/g 74% 90%
Crohn’s disease 274 µg/g 76% 97%


  1. Increases in fCal have been linked to use of non-steroidal anti-inflammatory medications for just 14 days.21
  2. Newborn infants have higher fCal concentrations that decline to adult levels by the age of 5 years.22

1. Walsham NE, Sherwood RA. Clin Exp Gastroenterol 2016;9:21–29.
2. Lehmann FS, et al. Ther Adv Gastroenterol 2015;8(1):23–36.
3. Roseth AG, et al. Scand J Gastroenterol 1999;34:50–54.
4. Schoepfer AM, et al. Inflamm Bowel Dis 2013;19:332–341.
5. D’Inca, Caccaro. Clin Exp Gastroenterol 2014;7:151–161.
6. Manz M, et al. BMC Gastroenterol 2012;12:5.
7. Canavan C, et al. Clin Epidemiol 2014;6:71–80.
8. Talley NJ. Neurogastroenterol Motil 2008;121–129.
9. Crohn’s and Colitis Foundation of America. IBD factbook. Nov 2014. May 24, 2016.
10. Quigley EMM. Ther Adv Gastroenterol 2016;9(2):199–212.
11. Barbara G, et al. Curr Opin Gastroenterol 2014;30(4):352–358.
12. Burri E, et al. Clin Chim Acta 2013;416:41–47.
13. Keohane J, et al. Am J Gastroenterol 2010;105:1789–1794.
14. Gisbert JP, et al. Dig Liv Dis 2009;41:56–66.
15. van Rheenan PF, et al. BMJ 2010;341:c3349.
16. Molander P, et al. J Crohns Colitis 2015;9(1):33–40.
17. Roseth AG, et al. Scand J Gastroenterol 2004;39:1017–1020.
18. Lobatón T, et al. J Crohns Colitis 2013;7:e641–e651.
19. Lobatón T, et al. Inflamm Bowel Dis 2013;19:1034–1042.
20. Wang S, et al. J Intern Med Res 2013;41(4):1357–1361.
21. Maiden L, et al. Gastroenterology 2005;128(5):1172–1178.
22. Rugtveit J, et al. J Pediatr Gastroenterol Nutr 2002;34:323–325.

Eosinophil-Derived Neurotoxin

Description/Background Information

Measurement of eosinophil-derived neurotoxin (EDN; also called eosinophil protein X or EPX) is the preferred method for sensitive, noninvasive assessment of intestinal eosinophilic activity, commonly associated with intestinal parasites and food allergies—both IgE-mediated (e.g., food anaphylaxis or protein-induced enteropathy) and non-IgE dependent (e.g., celiac disease).1

Eosinophils, which make up about 1–6% of the white blood cells, are readily distinguished form other leukocytes by their bi-lobed nuclei and large eosin-staining granules. These cells, important in both innate and adaptive immunity, are well-known for their pro-inflammatory and destructive response to allergic inflammation or parasitic infection, and more recently recognized as participants in tissue repair/remodeling in response to mucosal damage.2-4 Eosinophils directly identify pathogens (parasites, viruses, certain fungi, and bacteria) through a host of cell surface receptors which, when activated, stimulate the release of cytotoxic granule proteins—the most prominent of which is EDN—along with cytokines, chemokines, and growth factors.2 Eosinophil degranulation is also triggered by mucosal injury. As a ribonuclease, EDN has antiviral properties and also promotes the activation, maturation, and migration of dendritic cells, thus acting as an endogenous “alarmin” that alerts the adaptive immune system and enhances antigen-specific responses.2,5-7

Clinical Utility & Indications

Eosinophils are produced in the bone marrow and migrate via the circulation to the thymus and gastrointestinal (GI) tract, where they regulate immune homeostasis.2 They are also recruited to other tissues in response to inflammatory stimuli. Eosinophil infiltration is a common feature of allergic diseases such as asthma, rhinosinusitis, and atopic dermatitis, and GI disorders such as inflammatory bowel disease (IBD), gastroesophageal reflux disease (GERD), and eosinophilic GI disorders.1,2,8 Fecal EDN is considered the best of the cytotoxic granule proteins for assessment of gut inflammation, as it most accurately reflects clinical, endoscopic, and histologic scores of disease activity and mucosal damage.9,10

Elevated levels of fecal EDN are linked to multiple inflammatory conditions:

Food Allergy/Sensitivity: Hypersensitivity reactions to food are typically associated with GI infiltration of inflammatory cells such as eosinophils and mast cells.

  • Fecal EDN concentrations are elevated in both IgE-mediated food allergies as well as non-IgE allergies and sensitivities, and have been shown to correlate with severity of symptoms (e.g., abdominal pain and distension)11,12,13 and decline after elimination of the offending food.14 
  • Fecal EDN assessment is considered superior to other allergen testing methods such as IgE and IgG serum testing, skin prick and atopy patch testing, and other fecal biomarkers of inflammation, for the diagnosis of cow’s milk allergy in infants.15
  • The association of celiac disease with eosinophils in the small intestinal and esophageal mucosa is increasingly recognized and requires individualized assessment and treatment.8,16

Pathogenic Infection: Long known for their role in fighting off parasites, eosinophils also exhibit broad antiviral activity and selectively release EDN upon contact with bacterial pathogens (e.g., C. difficile and H. pylori) but not probiotic strains (e.g., Bifidobacteria).5,2 In one study, fecal EDN levels were significantly elevated in patients infected with Schistosoma mansoni parasite, and also weakly correlated with ova count. Treatment with praziquantel (two doses, 5 weeks apart) significantly reduced fecal EDN.17

Inflammatory Bowel Diseases: A main feature of IBD is increased mucosal levels of neutrophils, eosinophils, and mast cells, along with altered cytokine patterns. EDN in the stool (but not serum) is often increased in ulcerative colitis, Crohn’s disease, and collagenous colitis.8-10,13,18-20

Eosinophilic Gastrointestinal Disorders: These conditions (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, and eosinophilic colitis) are relatively rare (< 1:1000) but their prevalence is increasing.1  Patients may present with various symptoms, including failure to thrive, abdominal pain, gastric dysmotility, vomiting, diarrhea, and dysphagia.8 These disorders are characterized by eosinophil-rich mucosal inflammation in the absence of known cause.1,21  Eosinophils also accumulate in the esophageal mucosa in patients with GERD, the presence of which does not exclude the diagnosis of these disorders or food allergy.1

Malignancies: Eosinophils are part of an early inflammatory reaction at the site of tumorigenesis and accumulate in tumors via signals released from areas of necrosis.22

Additional tests: Other Salveo Gut Health Assessment biomarkers (e.g., calprotectin, iFOBT, zonulin, celiac disease antibodies) may provide further information, in addition to food sensitivity/allergy testing and imaging approaches (e.g., transabdominal or endoscopic ultrasound, CT, or MRI).

Eosinophil-Derived Neurotoxin Cut Points & Interpretation

Optimal Mildly Elevated Elevated Highly Elevated
≤ 0.99 µg/g 1.00 – 3.24 µg/g  3.25-10.10 µg/g ≥ 10.11 µg/g

EDN values 1.00 – 3.24 µg/g are mildly elevated, suggesting an eosinophil-mediated immune response. The most common causes of this kind of elevation include IgE-mediated food allergies, intestinal parasitic infections, and IBD. On the basis of clinical correlation, further testing may be warranted (e.g., for food allergies or parasites).

EDN values 3.25 – 10.10 µg/g are elevated, suggesting an eosinophil-mediated immune response. The most common causes of this kind of elevation include IgE-mediated food allergies, intestinal parasitic infections, and IBD. On the basis of clinical correlation, further testing may be warranted (e.g., for food allergies or parasites).

EDN values ≥ 10.11 µg/g are highly elevated, suggesting an acute eosinophil-mediated immune response (e.g., triggered by IgE-mediated food allergy, IBD, allergic colitis, gastroesphageal reflux, collagenous colitis, excessive alcohol intake, and some GI cancers). If clinical correlation supports a disease process like IBD or a GI cancer, consider endoscopic evaluation, particularly with concurrent increases in calprotectin or a positive iFOBT.

1. Rothenberg ME. J Allergy Clin Immunol 2004;113:11–28.
2. Long H, et al. Transfus Med Hemother 2016;43:96–108.
3. Rosenberg HF, et al. Nat Rev Immunol 2013;13:9–22.
4. Travers J, Rothenberg ME. Mucosl Immunol 2015;8:464–475.
5. Rosenberg HF. Int J Mol Sci 2015;16:15442–15455.
6. Lofti R, Lotze MT. J Leokocyte Biol 2008;83:456–460.
7. Yang, D et al. J Exp Med 2008;205:79–90.
8. Mehta P, Furuta GT. Immunol Allergy Clin N Am 2015;35:413–437.
9. Peterson CGB, et al. Am J Gastroenterol 2002;97:1755–1762.
10. Peterson CGB, et al. Scand J Clin Lab Invest 2007;67:810–820.
11. Magnusson J, et al. Clin Exp Allergy 2003;33:1052–1059.
12. Van Odjik J, et al. Int Arch Allergy Immunol 2006;140:334–341.
13. Bischoff SC, et al. Dig Dis Sci 1997;42:394–403.
14. Majamaa H, et al. Clin Exp Allergy 1999;29:1502–1506.
15. Kalach N, et al. Clin Chem Lab Med 2013;51:351–361.
16. Brown IS, et al. Am J Clin Pathol 2012;138(1):42–49.
17. Reimert CM, et al. Acta Tropica 2008;105:253–259.
18. Saitoh O, et al. Am J Gastroenterol 1999;94:3513–3520.
19. Dainese R, et al. Eur J Gastroenterol Hepatol 2012;24:393–397.
20. Wagner M, et al. World J Gastroenterol 2008;14:5584–5589.
21. Spergel JM, et al. J Pediatr Gastroentrol Nutr 2011;52:300–306.
22. Cormier SA, et al. J Leukoc Biol 2006;79(6):1131–1139.

Secretory IgA

Description/Background Information

Secretory IgA (sIgA) is the primary antibody in mucous membranes in humans, which are the entry point for most foreign antigens (e.g., in the nose, lungs, and gut lining). It therefore plays a critical role in mucosal immunity—the protection and homeostatic regulation of mucosal epithelia.1,2  Upon exposure to microbial or other antigens, sIgA is synthesized in B-lymphocyte-derived plasma cells and transported across the mucosa by the polymeric immunoglobulin receptor (pIgR) into external secretions (e.g., tears, saliva, and mucus lining the gut).1-3

In the gastrointestinal (GI) tract, sIgA is the first line of defense in shielding the intestinal epithelium against ingested toxins, pathogens, and other proteins.1,4 In discriminating between symbiotic, harmless (“commensal”) bacteria and potentially life-threatening microorganisms, sIgA helps the immune system to continuously monitor the gut contents, maintaining a balance between tolerance to the microbiota or other antigens encountered in a normal diet, and rapid defense against microbial pathogens.2,3,5 sIgA induction in the gut is exquisitely sensitive to the presence of microbes. By coating them, sIgA facilitates “sampling” of the microbiota by the gut-associated lymphoid tissue (GALT), acting as an immunological “buffer.”5,6

sIgA is integral to mucosal homeostasis1-3,5:

  • influencing composition of the intestinal microbiota
  • preventing overstimulation of the immune system to resident (“commensal”) microbes
  • keeping inflammatory processes under control (e.g., quenching proinflammatory cytokines that would normally be associated with uptake of pathogens or allergens)
  • strengthening epithelial cell tight junctions to reinforce gut barrier integrity

sIgA promotes the clearance of antigens and pathogens from the intestinal lumen3-5,7:

  • blocking their access and attachment to epithelial receptors by serving as “decoys”
  • anchoring them in the mucus layer to keep them away from the epithelial surface (“immune exclusion”)
  • disrupting the activation or expression of virulence factors involved in bacterial entry
  • facilitating their removal by enhancing peristalsis

In early life, breast milk-derived maternal sIgA performs these functions until the intestinal immune system of the offspring can take over.2 sIgA does allow some translocation of sIgA-antigen complexes into the mucosa, controlling the dialog between immune system and symbionts to ensure tolerance to innocuous proteins.1,3 When pathogens/toxins threaten to invade the gut barrier, sIgA supports the immune system in eliminating them.1,4,5

Clinical Utility & Indications

Inflammation is both beneficial and necessary, but interference with the homoeostatic mechanisms that regulate it may result in chronic inflammatory or autoimmune diseases.7,8 Disruption of the balance between microbiota, intestinal epithelial cells, and mucosal immune system can lead to pathologies with altered sIgA production:

  • Elevated fecal sIgA levels may indicate an upregulated immune response to an antigen in the gut (e.g., bacteria, parasites, viruses, yeasts, or other allergenic proteins).3,4,9 Testing for pathogens may reveal the source of the inflammation, in which case sIgA should normalize with eradication of the culprit(s).
  • Elevated fecal sIgA in the absence of pathogen may reflect a normal or heightened response as seen in atopic conditions (e.g., food sensitivity, skin disorder).10,11
  • Chronically low fecal sIgA indicates compromised mucosal immunity (loss of normal tolerance to the commensal microbiota) and is often found in people who have chronic digestive conditions and intestinal dysbiosis [e.g., inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS)].12,13Such individuals may be more susceptible to infections as a consequence.13-15
  • Chronic low levels of fecal sIgA may promote intestinal permeability and the development of food allergies/sensitivities.3,16
  • Reduced sIgA levels are often associated with inadequate or poor nutrition, dietary restrictions, and excessive alcohol intake.17,18 Whenever the immune response in the gut evokes chronic inflammation, there will be risk of malnutrition and further impairment of host defense.
  • sIgA production is influenced by the duration (acute or chronic) and intensity of mental or physical stress, negative mood, and anxiety. Chronic stress tends to lower both fecal sIgA and gut lymphocytes via a direct effect of corticosteroids, increasing susceptibility to infection and intestinal inflammation.19

Secretory IgA Cut Points & Interpretation

Low Mildly Decreased Optimal Mildly Elevated High
≤ 0.3 μg/g 0.4-0.7 μg/g 0.8– 3.8 μg/g 3.8 – 8.9 μg/g ≥ 9.0 μg/g

1. Corthésy B. Front Immunol 2013;4:185.
2. Kaetzel CS, et al. Immunol Lett 2014:162:10–21.
3. Mantis NJ, et al. Mucosal Immunol 2011;4(6):603–611.
4. Mantis NJ, Forbes SJ. Immunol Invest 2010;39(0):383–406.
5. Hooper LV, et al. Science 2012;336:1268–1273.
6. Mathias A, et al. Gut Microbes 2014;5(6):688–695.
7. Mestecky J, et al. Gut 1999;44:2–5.
8. Janssen WJ, Henson PM. Toxicol Pathol 2012;40:166–173.
9. Mahmoud MSE, Saleh WA. J Egypt Soc Parasitol 2003;33(1):13–30.
10. Faria AM, et al. Front Immunol 2013;4:102.
11. Viljanen M, et al. Pediatr Allergy Immunol 2005;16:65–71.
12. Henderson P, et al. Inflamm Bowel Dis 2011;17:382–395.
13. Fava F, Danese S. World J Gastroenterol 2011;17(5):557–566.
14. Scher JU, et al. Arthritis Rheumatol 2015;67(1):128–139.
15. Van de Ven, et al. J Clin Immunol 2014;34:962–970.
16. Chahine BG, Bahna SL. Curr Opin Allergy Clin Immunol 2010;10:220–225.
17. Cunningham-Rundles S, Lin DH. Nutrition 1998;14:573–579.
18. Szabo G, Mandrekar P. Alcohol Clin Exp Res 2009;33(2):220–232.
19. Campos-Rodríguez R, et al. Front Integr Neurosci 2013;7:86.

Serum Tests:

Vitamin D

Description/Background Information

Vitamin D is a fat-soluble vitamin produced in the skin upon exposure to sunlight. It is essential for strong bones and muscles as it regulates intestinal and renal absorption of calcium and phosphate, and ensures that serum levels of these minerals remain optimal.1,2 Vitamin D3 occurs naturally in a few foods (e.g., oily fish, egg yolks, butter, and beef liver) and in fortified dairy and grain products. Vitamin D2 is derived from ergosterol, a sterol present in fungi, and is not normally present in the human body.3

To become biologically active, vitamin D is modified to 25-hydroxyvitamin D [25(OH)D] and then 1,25-dihydroxyvitamin D [1,25(OH)2D].2,4 1,25[OH]2D (calcitriol) is a steroid hormone which regulates the expression of hundreds of genes and triggers signaling cascades in many tissues and organs.1,5 Serum 25(OH)D (calcidiol) is the most stable circulating form of vitamin D and reflects both UV-stimulated synthesis and dietary intake.5,6

Besides its well-known role in the musculoskeletal system, vitamin D has other important functions:

  • Protects against inflammation and infection by regulating immune cell trafficking and function4,7
  • Enhances the protective function of mucosal barriers throughout the body5,8
  • Modulates cellular proliferation and apoptosis7,9
  • Enhances neuromuscular function, with cognitive, antidepressant, and anticonvulsant benefits10-12
  • Enhances secretion and action of insulin13
  • Important for iron metabolism: promotes red blood cell production14

Clinical Utility & Indications

Vitamin D deficiency is present in almost half the US population.15 If severe, it can lead to rickets (children) or osteomalacia (adults). Vitamin D insufficiency (serum 25(OH)D < 30 ng/mL) may be linked to hyperparathyroidism, osteoporosis, and muscle weakness/pain.2,16 Prolonged vitamin D insufficiency drives inflammation and increased risk for multiple chronic conditions, including anemia, cardiometabolic and autoimmune diseases, depression, neurodegenerative/cognitive and sleep disorders, and some cancers.6,12,14,17-22Less obvious symptoms include chronic low back pain and headaches.2,12 Low serum vitamin D may stem from several factors:5,19,23

  • Limited exposure to sunlight
  • Insufficient dietary intake of vitamin D
  • Liver or renal malfunction (e.g., primary biliary cirrhosis, kidney disease)
  • Conditions that cause malabsorption and/or intestinal inflammation (e.g., Crohn’s disease, ulcerative colitis, pancreatic insufficiency, cystic fibrosis, celiac disease
  • Use of vitamin D-depleting drugs (e.g., anticonvulsants, bile acid sequestrants, glucocorticoids, some immunosuppressants)

Vitamin D and Autoimmune Diseases

Vitamin D modulates both innate and adaptive immune responses, and its deficiency has been linked to several chronic autoimmune conditions, including type 1 diabetes, systemic lupus erythematosus, celiac disease, multiple sclerosis, asthma, inflammatory bowel diseases (IBD), food allergies, and rheumatoid arthritis.6,7,21,24,25

Vitamin D and Gut Health

Vitamin D deficiency increases susceptibility to various gastrointestinal (GI) disorders, including colorectal cancer (CRC), IBD, diverticulitis, and irritable bowel syndrome (IBS).26,27 The importance of vitamin D to gut health stems primarily from its immune-modulating function in the intestinal mucosa:4,5

  • It inhibits secretion of pro-inflammatory cytokines and promotes proliferation of regulatory T cells that dampen inflammation5,8
    • In one study of patients with Crohn’s disease, fecal calprotectin (measure of gut inflammation) was several-fold higher in those with vitamin D insufficiency28
  • It induces the secretion of antimicrobial peptides, helping to defend against pathogens4,17,18
  • It enhances gut barrier function and integrity by increasing the expression of tight junction proteins5,8,17
  • It favorably modulates the composition of the gut microbiota5,26
    • Vitamin D deficiency-fueled intestinal dysbiosis can lead to B-vitamin deficiencies and inflammation24


  • Colorectal cancer is the third most common malignancy worldwide29
  • Patients with IBD have a higher incidence of CRC than the general population5,17
  • Lower vitamin D levels are causally linked to worse CRC prognosis and increased mortality30
  • Higher serum vitamin D protects against cancer development and progression by promoting cellular apoptosis while inhibiting proliferation and angiogenesis5,20


  • Low vitamin D levels occur in ~30% of IBD patients and are linked to higher morbidity and disease severity31
  • Prevalence of osteopenia and osteoporosis is higher in patients with IBD than in the general population5
  • Low IBD incidence in subjects with high serum 25(OH)D suggests a protective, anti-inflammatory role for vitamin D32
  • Serum vitamin D ≤ 35ng/mL during remission increases risk of clinical relapse in patients with ulcerative colitis33
  • Anti-TNFα therapy is less effective in vitamin D-deficient IBD patients34

Vitamin D Cut Points & Interpretation

Low Mildly Decreased Optimal High
≤ 14 ng/dL 15-31 ng/dL 32-119 ng/dL ≥ 120 ng/dL

Optimal 25(OH)D levels may vary with specific disease and clinical outcome goal. The Endocrine Society clinical practice guidelines for vitamin D state that serum 25(OH)D > 30 ng/ml maximizes its effect on calcium, bone, and muscle metabolism.16 Serum 25(OH)D > 120 ng/mL is considered potentially toxic. Vitamin D toxicity can cause anorexia, weight loss, polyuria, and heart arrhythmias. More seriously, it can raise blood calcium levels, leading to vascular and tissue calcification with damage to the heart, blood vessels, and kidneys.35

1. Haussler MR, et al. Calcif Tissue Int 2013;92:77–98
2. Wintermeyer E, et al. Nutrients 2016;8:319.
3. Norman AW. Am J Clin Nutr 2008;88(2):491S–499S.
4. Baeke F, et al. Curr Opin Pharmacol 2010;10:482–496.
5. Meeker S, et al. World J Gastroenterol 2016;22(3):933–948.
6. Thacher TD, Clarke BL. Mayo Clin Proc 2011;86(1):50–60.
7. Yin K, Agrawal DK. J Inflamm Res 2014:7 69–87.
8. Zhang Y, et al. Tissue Barriers 2015;1(1):e23118.
9. Samuel S, Sitrin MD. Nutr Rev 2008; 66(10 Suppl 2):S116-24.
10. Littlejohns TJ, et al. Neurology 2014;83(10):920–928.
11. Teagarden DL, et al. Epilepsy Res 2014;108(8):1352–1356.
12. Vasquez A. Altern Ther 2004;10(5):28–36.
13. Chiu KC, et al. Am J Clin Nutr 2004;79:820–825.
14. Smith EM, Tangpricha V. Curr Opin Endocrinol Diabetes Obes 2015;22(6):432–438.
15. Forrest KYZ, Stuhldreher WL. Nutr Res 31;48–54.
16. Holick MF, et al. J Clin Endocrinol Metab 2011;96:1911–1930.
17. Cai GH, et al. Curr Pharmaceut Des 2015;21:2917–2923.
18. Ghaly S, Lawrance I. Expert Rev Gastroenterol Hepatol 2014;8(8):909–923.
19. Zittermann A. Anticancer Res 2014;34:4641–4648.
20. Feldman D, et al. Nat Rev Cancer 2014;14:342–357.
21. Suaini NHA, et al. Nutrients 2015;7:6088–6108.
22. Gominak SC. Med Hypo 2016;94:103–107.
23. Margulies AL, et al. J Dig Dis 2015;16:617–633.
24. Agmon-Levin N, et al. Clinic Rev Allerg Immunol 2013;45:256-266.
25. Ritterhouse LL, et al. Ann Rheum Dis 2011;70:1569–1574.
26. Ferguson LR, et al. Mol Nutr Food Res 2016;60:119–133.
27. Abbasnezhad A, et al. Neurogastroenterol Motil 2016; May 7. doi:10.1111/nmo.12851. 
28. Raftery T, et al. Dig Dis Sci 2015;60(8):2427-35.
29. Torre LA, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87–108.
30. Zgaga L, et al. J Clin Oncol 2014;32:2430–2439.
31. Kabbani TA, et al. Am J Gastroenterol 2016;111:712–719.
32. Ananthakrishnan AN, et al. Gastroenterology 2012;142:482–489.
33. Gubatan J, et al. Clin Gastroenterol Hepatol 2016; Jun 4. doi:
10.1016/j.cgh.2016.05.035. [Epub ahead of print]
34. Santos-Antunes J, et al. Inflamm Bowel Dis 2016;22(5):1101–1106.
35. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press, 2010.



Description/Background Information

C-reactive protein (CRP) has long been recognized as the blood-based biomarker of choice for evaluating inflammatory conditions or suspected infections.1,2Synthesized in the liver in response to pro-inflammatory cytokines, CRP is an acute-phase reactant whose level in human serum can increase 1000-fold within 48 hours after the onset of inflammation, infection, or tissue injury.1 It is also a modulator of innate immunity and plays an important role in host defense against invading pathogens.1

Baseline serum CRP levels tend to be stable and characteristic for any one individual, apart from occasional spikes related to minor or subclinical infections, inflammation, or trauma. CRP is a more sensitive indicator of acute inflammation than most other acute-phase reactants; its rapid response and short half-life (19 hours) mean that CRP levels rise and fall rapidly when the inducing stimulus evokes inflammation or subsides.1,3,4

High-sensitivity CRP (hs-CRP) immunoassay systems are the most precise when measuring baseline serum CRP and are sufficiently sensitive to detect low-grade inflammatory processes. This nonspecific biomarker of inflammation can increase in response to tissue injury or inflammation from any source in the body. Consideration should thus be given to other laboratory assessments, if needed, based on the patient’s symptoms and clinical presentation.

Clinical Utility & Indications

CRP measurement is useful for the detection and evaluation of infection, tissue injury, and inflammatory disorders, and for monitoring response to treatment. Increased serum CRP levels are associated with obesity, insulin resistance, and hyperlipidemia, and are a strong predictor of cardiometabolic disease and atherothrombotic events.5,6 Hs-CRP has been endorsed as a biomarker of atherosclerotic cardiovascular disease (CVD) risk by several guidelines.7-9

In addition to detecting the markedly elevated levels that signal acute inflammation, serum CRP assessment is useful in monitoring chronic inflammation or remission associated with autoimmune disorders and malignancy (see Table 1).1,10 Chronic autoimmune diseases, where serum CRP may be persistently elevated, are linked to premature CVD.11

Table 1. Routine clinical uses of CRP measurement

  • Detection of acute systemic inflammation
  • Assessment of disease activity (severity) in inflammatory conditions
    e.g., rheumatoid arthritis, ankylosing spondylitis, psoriatic arthropathy,
    vasculitides, inflammatory bowel disease (IBD; Crohn’s disease or
    ulcerative colitis), CVD, rheumatic fever, familial fevers (including familial
    Mediterranean fever), acute pancreatitis, neurocognitive disorders,
    depression, diabetes mellitus
  • Diagnosis and management of infection
    Treatment response to antibiotics
  • Differential diagnosis/classification of inflammatory disease
    e.g., systemic lupus erythematosus (mean CRP ~10-20 mg/L) vs.
    rheumatoid arthritis (~60 mg/L)12
  • Assessment of chronic disease progression
    Elevations in serum CRP can indicate disease progression or a “preclinical”
    phase of immune-mediated disease, and are thus linked to onset of many
    chronic conditions, as well as multimorbidity and functional limitations13,14

Serum CRP is (along with fecal calprotectin) among the best-studied noninvasive biomarkers of inflammation in IBD, where it has multiple clinical uses:5,15-18

  • Differentiating IBD from irritable bowel syndrome (IBS) (CRP ≤ 5 mg/L predicts a ≤ 1% likelihood of IBD)
  • Assessing endoscopic disease extent and activity
  • Predicting risk of clinical relapse and hospitalization (CRP levels may rise 4 to 6 months prior) so that therapy may be optimized and a clinical flare
  • Evaluating response to therapy
  • Identifying recurrent inflammation after medically- or surgically-induced remission

Serum CRP levels may rise significantly during active IBD and are also higher in patients with IBS (especially diarrhea-predominant IBS) than in healthy controls.19However, CRP can be falsely low despite active mucosal inflammation due to DNA variants in the CRP gene and is more often elevated in transmural inflammation (as in Crohn’s disease) than in mild-to-moderate mucosal inflammation more often associated with ulcerative colitis.17 A persistently elevated CRP in either form of IBD should prompt further blood/stool tests for infection, and endoscopic evaluation for active disease. Rapid normalization of CRP levels helps sustain long-term response to medical therapy.17

hs-CRP Cut Points & Interpretation

Optimal Mildly Elevated High Very High
<1.0 mg/L  1.0-2.9 mg/L 3.0-9.9 mg/dL ≥10.0 mg/L

As the CRP response is nonspecific, it is recommended that the patient wait for two weeks after any acute event has resolved before assessing basal levels. If the initial CRP result is elevated, two or more serial samples taken at intervals of two weeks should be retested until a stable baseline value is seen.

A CRP value persistently above 10 mg/L indicates the presence of a significant acute-phase response. CRP values between 10 and 100 mg/L are suggestive of moderate acute inflammation, although do not distinguish between bacterial and viral infections. However, as values increase above 40 to 50 mg/L, the likelihood of a bacterial infection becomes greater. CRP values above 200 mg/L are generally seen in patients with serious bacterial infections, burns, severe arthritis, or vasculitis, while a persistent elevation following antibiotics is consistent with treatment failure, a non-treated coinfection, or some other cause.

1. Pepys MB, Hirschfield GM. J Clin Invest 2003;111(12):1805–1812.
2. Wu Y, et al. Biol Chem 2015;396(11):1181–1197.
3. Sands BE. Gastroenterology 2015;149:1275–1285.
4. Mendoza JL, Abreu MT. Gastroenterol Clin Biol 2009;33(Suppl 3):S158–S173.
5. Ridker PM. J Am Coll Cardiol 2016;67(6):712–723.
6. Li W, et al. Exp Ther Med 2013;6:1271–1276.
7. Saboori S, et al. Eur J Clin Nutr 2015;69:867–873.
8. Menees SB, et al. Am J Gastroenterol 2015;110:444–454.
9. Henriksen M, et al. Gut 2008;57:1518–1523.
10. Laveti D, et al. Inflamm Allergy 2013;12:349-361.
11. Chang S, et al. World J Gastroenterol 2015;21(40):11246–11259.
12. Click B, et al. Inflamm Bowel Dis 2015;21(10):2254–2261.
13. Dregan A, et al. Circulation 2014;130:837–844.
14. Nielson FH. Curr Opin Clin Nutr Metab Care 2014;17:525–530.
15. Friedman EM, et al. J Aging Health 2015;27(5):843–863.
16. Lochhead P, et al. Clin Gastroenterol Hepatol 2016;14:818–824.
17. Hod K, et al. Neurogastroenterol Motil 2011;23:1105–e541.