Physicians Gastrointestinal Imbalance & Chronic Disease
Dysbiosis is an undesirable shift in the composition of the microbiota that can lead to a plethora of chronic diseases if left unchecked.4,5 However, potentially harmful microbes may coexist peacefully with beneficial ones if the overall balance of the microbiome is healthy. A high-fat, high-sugar (standard Western) diet may induce dysbiosis in the gut through the actions of bile which can affect the growth of some microbes. Chronic dysbiosis can alter the environment (e.g., pH) in the gut and thus invite pathogenic bacteria, fungi, or parasites to flourish. This can result in lower levels of beneficial bacteria, promoting intestinal hyperpermeability (“leaky gut”) and inflammation.
Firmicutes/Bacteroidetes Ratio Provides an estimate of the predominance of major phyla of gut bacteria; associated with dysbiosis and metabolic disorders.6
Short Chain Fatty Acids Markers of dietary fiber fermentation in the gut; important for health of intestinal mucosa and protection against dysbiosis.7
(n-butyrate, propionate, acetate)
Maldigestion of food can cause GI symptoms such as bloating, abdominal pain, gas, constipation, or diarrhea, and can stem from issues such as low stomach acid, abnormal gut motility (either rapid or slow transit times), lack of bile acids, and exocrine pancreatic insufficiency (reduced secretion of digestive enzymes from the pancreas).8 Chronic maldigestion can promote bacterial/fungal overgrowth, which can compromise the intestinal barrier, allowing toxins, bacteria, and undigested food particles to enter the circulation and increase risk for food allergies, autoimmune disorders, and an overburdened liver.9
Malabsorption of nutrients can be a consequence of maldigestion and can also occur when infection or inflammation damages the intestinal mucosa or increases transit times.8 The resulting nutrient deficiencies can lead to other health complications such as anemia, skin and cognitive/mood disorders, impaired vision, and osteoporosis.10
Pancreatic Elastase A pancreas-specific protease that passes unchanged through the intestine; an excellent marker of exocrine pancreatic insufficiency.11
Lipase Pancreatic enzyme for the digestion of dietary fat; marker of pancreatitis.12
Amylase Pancreatic enzyme for the digestion of dietary starch; marker of pancreatitis.12
Prealbumin A prealbumin (transthyretin) test is often ordered to assess nutritional status and metabolic stress, and to help diagnose protein malnutrition or
underlying disease severity in patients with chronic illness.13
Vitamin D Vitamin D deficiency is associated with gut inflammation, autoimmunity, and increased susceptibility to GI disorders (e.g., colorectal cancer, IBD, diverticulitis, and IBS).14,15 Low serum vitamin D is linked to higher risk and severity of intestinal malabsorption syndromes (e.g., IBD and celiac disease).14
Dysregulation of the normal homeostatic relationships between the gut microbiota and host immune system can lead to intestinal inflammation, and evidence suggests that luminal flora may be a central factor in the development of inflammatory bowel disease (IBD).16 Crohn’s disease and ulcerative colitis are immune-mediated conditions characterized by chronic inflammation of the small and large intestine. The pathogenesis of these conditions is multifactorial, but they are generally thought to result from “an exaggerated immune response towards the gut microbiome/toxic luminal substances in a genetically susceptible individual.”17
Possible triggers may include:
Candida (yeast) overgrowth — intestinal dysbiosis (imbalance) favoring yeast overgrowth disrupts the intestinal epithelium, causing hyperpermeability
Certain medications — chronic use of drugs such as antibiotics, aspirin, acid-reducing drugs, or nonsteroidal anti-inflammatory drugs (NSAIDs)
Food additives and inflammatory foods — gluten, emulsifiers, excess sugar/alcohol consumption, and dairy
Stress and age
Calprotectin A neutrophil-derived calcium-binding protein, calprotectin is a highly sensitive and specific marker for intestinal neutrophil activity and
gastrointestinal inflammation; can be used for distinguishing IBD from IBS.18
Eosinophil-Derived Neurotoxin A glycoprotein that is released from eosinophil granulocytes, commonly in allergic response to certain foods or intestinal parasites. Increased fecal levels may reflect infection, inflammation, and/or severity of tissue damage.19,20
Secretory IgA The major antibody produced in tears, saliva, and the intestinal mucosa in response to harmful or antigenic substances. Elevated fecal levels
may indicate an upregulated immune response in the intestinal mucosa. Low sIgA can signal chronic stress in the GI tract and can be a factor in the development of food allergy or intolerance. 21
Vitamin D Vitamin D deficiency is associated with gut inflammation, autoimmunity, and increased susceptibility to GI disorders (e.g., colorectal cancer,
IBD, diverticulitis, and IBS).14,15 Low serum vitamin D is also linked to higher risk and severity of intestinal malabsorption syndromes (e.g., IBD and celiac disease).15
C-reactive protein (hs-CRP) A nonspecific acute-phase protein whose serum levels can be elevated in response to inflammation, infection, or tissue injury.22
The permeability of the intestinal epithelium is finely regulated by the presence of tight junctions—molecular complexes that seal the spaces between the epithelial cells, guiding passage of select molecules (e.g., nutrients) through the transcellular spaces. The epithelial cells produce mucus and antimicrobial molecules to further protect against toxins or infectious agents. Breakdown of this barrier can cause a disruption of normal mucosal immune homeostasis and uncontrolled inflammation, allowing increased passage of undigested food particles, microorganisms, and their immune-stimulating antigenic products (e.g., lipopolysaccharide) into the circulation.23 The integrity of the epithelial cells themselves can also affect intestinal barrier function; if disrupted, tight-junction components and regulatory proteins will appear in the stool.
Zonulin A protein that modulates the permeability of tight junctions between cells of the wall of the digestive tract and can be elevated due to
microbial overgrowth or food triggers (e.g., gluten). Because elevated zonulin signifies impaired gut barrier function, healing the gut lining is key to preventing systemic entry of antigens, inflammation, and autoimmunity.24
The immunochemical fecal occult blood test (iFOBT) detects the presence of hidden blood in the stool, which may indicate a benign or cancerous growth, IBD, or other damage to the gut lining.25,26
Immunochemical Fecal Occult Blood Test (iFOBT) Hidden blood in the stool could indicate benign or malignant polyps, ulcers, or inflammatory bowel diseases.
Intestinal parasites, pathogenic bacteria, and viruses can be a significant source of GI illness.27 If the immune system does not manage to clear them or keep them in check, they may start to cause patient symptoms. We perform immunoassays for H. pylori Antigen and Blastocystis spp. Antigens, and molecular diagnostic tests for the following common pathogenic causes of infectious gastroenteritis.28
Parasites Cryptosporidium spp., Cyclospora cayetanensus, Giardia lamblia, Entamoeba histolytica
Bacteria and Bacterial Toxins Campylobacter spp., C. difficile (toxin A/B), Plesiomonas shigelloides, E. coli O157, Enteroaggregative E. coli (EAEC), Enteropathogenic E. coli (EPEC), Enterotoxigenic E. coli (ETEC), Shiga-toxin-producing E. coli (STEC), Salmonella, Shigella/Enteroinvasive E. coli (EIEC), Vibrio spp., Vibrio cholerae cholera toxin gene (ctx), Yersinia enterocolitica
Viruses Adenovirus F40/41, Astrovirus, Norovirus GI/GII, Rotovirus A, Sapovirus (I, II, IV, and V)
Autoimmune disorders are often triggered or made worse in genetically susceptible individuals by intestinal dysbiosis and a dysregulated gut inflammatory response (often with increased intestinal permeability) to stress, toxins, infections, nutrient insufficiencies, and various foods.29,30
Antinuclear Antibodies by IFA Antinuclear antibodies (ANA) are a key feature of systemic or other autoimmune conditions.31,32 This test has high negative predictive value
for ruling out suspected connective tissue disorders.33 The presence of ANA in asymptomatic patients may indicate subclinical
autoimmunity and/or increased risk for future autoimmune disease.34
While the human microbiota is made up mostly of bacterial species, everybody carries some fungal species too — a much smaller component of the microbiota, separately referred to as the “mycobiota.”35,36 In healthy individuals, these fungi cause no problem. However, when the gut microbiota is upset by antibiotics, chemotherapy, or immunosuppressive drugs, or the immune system is compromised, certain fungi can become opportunistic and pathogenic. Diseases caused by overgrowth of indigenous yeast species, such as Candida albicans (C. albicans), are a significant cause of illness and death in critical care settings, and also play a significant role in a growing number of chronic diseases affecting the general population.36
Yeast Culture Semi-quantitative, accurate, and rapid identification of yeast in the stool (Candida albicans and other Candida species versus non- Candida species) using microbiological and colorimetric enzymatic methods.37,38
Anti-Candida Antibodies High titers may indicate opportunistic Candida overgrowth, intestinal dysbiosis, and damage to the gut lining, often exacerbated by immune system depletion, certain medications, metabolic disease, or sugar-rich diet.37,
Celiac Disease Antibodies
Celiac disease or gluten-sensitive enteropathy is an autoimmune disorder characterized by chronic inflammation of the small-intestinal mucosa in response to ingested gluten (the storage protein of wheat, rye, and barley) in genetically predisposed individuals.39 In this condition, undigested gliadin peptides—the toxic component of gluten—leak through the intestinal barrier, where they are deamidated by tissue transglutaminase (tTG) to form deamidated gliadin peptides (DGP), triggering an inflammatory immune reaction in the process.
Anti-tTG (IgA and IgG) Tissue transglutaminase antibodies are highly sensitive and specific for the diagnosis of celiac disease.40
Anti-DGP (IgA and IgG) Combined testing for anti-tTG and anti-DGP (deamidated gliadin peptides) provides the best diagnostic accuracy for celiac disease.40
- Habba SF. Diarrhea predominant irritable bowel syndrome (IBS-D): Fact of fiction. Medical Hypotheses 2011;76:97–99.
- Ayling RM. New faecal tests in gastroenterology. Ann Clin Biochem 2012;49:44–54.
- Alibrahim B, et al. Fecal calprotectin use in inflammatory bowel disease and beyond: A mini-review. Can J Gastroenterol Hepatol 2015;29(3):157–163.
- Sekirov I, et al. Gut microbiota in health and disease. Physiol Rev 2010;90:859–904.
- Carding S, et al. Dysbiosis of the gut microbiota in disease. Microb Ecol Health Dis 2015;26:26191.
- Remely M, et al. Gut microbiota composition correlates with changes in body fat content due to weight loss. Benef Microbes 2015;6(4):431–439.
- Rios-Covian D, et al. Intestinal short chain fatty acids and their link with diet and health. Front Microbiol 2016;7:185.
- Keller J, Layer P. The pathophysiology of malabsorption. Viszeralmedizin 2014;30:150–154.
- Sachdev AH, Pimentel M. Gastrointestinal bacterial overgrowth: pathogenesis and clinical significance. Ther Adv Chronic Dis 2013;4(5):223–231.
- Ward E. Addressing nutritional gaps with multivitamin and mineral supplements. Nutr J 2014;13:72.
- Loser C, et al. Faecal elastase 1: a novel, highly sensitive, and specific tubeless pancreatic function test. Gut 1996;39(4):580–586.
- Goldberg DM, Durie PR. Biochemical tests in the diagnosis of chronic pancreatitis and in the evaluation of pancreatic insufficiency. Clin Biochem 1993;26(4):253–275.
- Johnson AM, et al. Clinical indications for plasma protein assays: transthyretin (prealbumin) in inflammation and malnutrition. Clin Chem Lab Med 2007;45(3):419–426.
- Ferguson LR, et al. The role of vitamin D in reducing gastrointestinal disease risk and assessment of individual dietary intake needs: Focus on genetic and genomic technologies. Mol Nutr Food Res 2016;60:119–133.
- Santos-Antunes J, et al. The relevance of vitamin D and antinuclear antibodies in patients with inflammatory bowel disease under anti-TNF treatment: a prospective study. Inflamm Bowel Dis 2016;22(5):1101–1106.
- Bellaguarda E, Chang EB. IBD and the gut microbiota—from bench to personalized medicine. Curr Gastroenterol Rep 2015;17:15.
- Michielan A, D’Inca R. Intestinal permeability in inflammatory bowel disease: Pathogenesis, clinical evaluation, and therapy of leaky gut. Mediators Inflamm 2015; 2015:628157.
- Burri E, Beglinger C. The use of fecal calprotectin as a biomarker in gastrointestinal disease. Expert Rev Gastroenterol Hepatol 2014;8(2):197–210.
- Peterson CG, et al. Fecal levels of leukocyte markers reflect disease activity in patients with ulcerative colitis. Scand J Clin Lab Invest 2007;67(8):810–820.
- Van Odijk J, et al. Measurements of eosinophil activation before and after food challenges in adults with food hypersensitivity. Int Arch Allergy Immunol 2006;140:334–341.
- Corthesy B. Multi-faceted functions of secretory IgA at mucosal surfaces. Front Immunol 2013;4:1–11.
- Sands BE. Biomarkers of inflammation in inflammatory bowel disease. Gastroenterology 2015;149:1275-1285.
- Bischoff S, et al. Intestinal permeability – a new target for disease prevention and therapy. BMC Gastroenterology 2014;14:189.
- Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev 2011;91:151–175.
- Shah R, et al. Biomarkers for early detection of colorectal cancer and polyps. Cancer Epidemiol Biomarkers Prev 2014;23(9):1712–1728.
- Allison JE, et al. Population screening for colorectal cancer means getting FIT: the past, present, and future of colorectal cancer screening using the immunochemical test for hemoglobin (FIT). Gut Liver 2014;8(2):117–130.
- Boyce TG. Overview of gastroenteritis. Merck Manual [database online]. Kenilworth, NJ; Merck Sharp & Dohme Corp 2016. Accessed June 16, 2016.
- Huang RSP, et al. Performance of the Verigene® enteric pathogens test, Biofire FilmArray™gastrointestinal panel and Luminex xTAG® gastrointestinal pathogen panel for detection of common enteric pathogens. Diagn Microbiol Infect Dis 2016;86(4):336–339.
- Campbell AW. Autoimmunity and the gut. Autoimmune Dis 2014; 2014: 152428.
- Lerner A, Matthias T. Changes in intestinal tight junction permeability associated with industrial food additives explain the rising incidence of autoimmune disease. Autoimmune Rev 2015;14(6):479–489.
- Satoh M, et al. Clinical interpretation of antinuclear antibody tests in systemic rheumatic diseases. Mod Rheumatol 2009;19(3):219–228.
- Granito A, et al. Antinuclear antibodies as ancillary markers in primary biliary cirrhosis. Expert Rev Mol Diagn 2012;12(1):65–74.
- Lee AYS, et al. Evaluation of antinuclear antibody (ANA) in ANA-associated connective tissue diseases. J Clin Pathol 2015;68(10):853–854.
- Selmi C, et al. Serum antinuclear and extractable nuclear antigen antibody prevalence and associated morbidity and mortality in the general population. Autoimmunity Rev 2016;15(2):162–166.
- Huffnagle GB, Noverr MC. The emerging world of the fungal microbiome. Trends Microbiol 2013;21(7):334-341.
- Suhr MJ, Hallen-Adams HE. The human gut mycobiome: pitfalls and potentials—a mycologist’s perspective. Mycologia 2015;107(6):1057-1073.
- Neville BA, et al. Candida albicans commensalism in the gastrointestinal tract. FEMS Yeast Res 2015;15(7):fov081.
- Romani L. Immunity to fungal infections. Nat Rev Immunol 2011;11:275–288.
- Rubio-Tapia A, et al. ACG Clinical Guidelines: Diagnosis and Management of Celiac Disease. Am J Gastroenterol 2013;108:656–676.
- World Gastroenterology Organisation (WGO) Global Guidelines. Celiac Disease (March 2016). http://www.worldgastroenterology.org/guidelines/global-guidelines/celiac-disease.