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From the late 1990s, research publications began identifying specific biochemical changes present in tissue biopsies and serum samples from IBS patients that suggested symptoms had an organic rather than psychosomatic cause.

These studies identified cytokines and secretory products in tissues taken from IBS patients. The cytokines identified in IBS patients produce inflammation and are associated with the body's immune response.

• A study showed that intestinal biopsies from patients with constipation predominant IBS secreted higher levels of serotonin in-vitro.[36] Serotonin plays a role in regulating gastrointestinal motility and water content, and can be altered by some diseases and infections.[37][38][39]
• A study of rectal biopsy tissue from IBS patients showed increased levels of cellular structures involved in the production of the cytokine Interleukin 1 Beta.[40]
• A study of blood samples from IBS patients identified elevated levels of cytokines Tumor necrosis factor-alpha, Interleukin 1, and Interleukin 6 in patients with IBS.[41]
• A study of intestinal biopsies from IBS patients showed increased levels of protease enzymes used by the body to digest proteins, and by infectious agents to combat the host's immune system.[42]
• A study of blood samples from IBS patients found elevated levels of antibodies to the protozoan Blastocystis.[43]

Specific forms of immune response that have been implicated in IBS symptoms include Coeliac disease and other Food allergy conditions.[44] Coeliac disease (also spelled "celiac") is an immunoglobulin type A-(IgA) mediated allergic response to the Gliadin protein in gluten grains, which exhibits wide variety of symptoms and can present as IBS.

"Some patients with diarrhea-predominant irritable bowel syndrome (IBS-D) may have undiagnosed celiac sprue (CS). Because the symptoms of CS respond to a gluten-free diet, testing for CS in IBS may prevent years of morbidity and attendant expense."[45] "Coeliac disease is a common finding among patients labelled as irritable bowel syndrome. In this sub-group, a gluten free diet may lead to a significant improvement in symptoms. Routine testing for coeliac disease may be indicated in all patients being evaluated for irritable bowel syndrome."[46] Food allergies, particularly those mediated by IgE and IgG-type antibodies have been implicated in IBS.[47][48][49]