Currently, there is no standardized diagnostic test tool for IBD [36,37]. The standard state-of-the-art diagnosis of IBD relies on amassing of clinical, radiologic, endoscopic, and histopathologic clarification [38,39]. This inexact compilation technique is not always accurate, and about 15% of colonic IBD patients cannot be delineated as UC or CC and are labeled as having ‘‘indeterminate colitis’’ (IC). This is because the clarification criteria for UC and CC are indefinite [40,41]. In addition, another 15% of the colonic IBD cases that undergo pouch surgery, i.e., restorative proctocolectomy with ileal pouch-anal anastomosis (RPC-IPAA) for their definitive UC diagnosis based on the pathologist’s final designation of endoscopic biopsies, will have their initial UC diagnosis reciprocated to ileal Crohn’s disease (CD) based on the postoperative follow-up when clinical and histopathology changes indicate the evolution of CD in the ileal reservoir and/or because authentic CC was not evident prior to colectomy [42,43]. Half of these patients with pouch ileal CD will require reservoir/pouch excision or diversion [44,45].

Ulcerative colitis’ (UC) peak onset is mostly in early adulthood [46]. A consequence of untreated UC is chronic inflammation and ulcerations in the mucosal and to a lesser degree submucosal linings confined to the large intestine (colon and rectum) [39,46]. Approximately 15% of patients may encounter hostile development, and these patients may require hospital admission for fulminant disease [46,47]. To establish the diagnosis and disease state of a patient sample, gastrointestinal pathologists depend most on nanoscopic visual examination and the elucidation of marked and/or colored tissue sections [48,49]. These procedures are endowed with a significant degree of discourse [50], and are surfeited with expostulations [50,51]. Careful professional tutoring in pathology subspecialties has helped to achieve the benchmark of care and abolish exorbitant oversights [52,53]. Notwithstanding these eminently thorough benchmarks, ineludible scenes arise in which impartiality cannot be formally assured and where significant variance of opinion occurs amongst consultant specialists [54]. Further to the fundamental guidelines and associated specialized reviews, moderate to severe UC is circumscribed based on the Truelove and Witts criteria and Mayo Clinic score [55,56,57] [55-57]. Mayo Clinic scores of 6–12 with an endoscopic subscore of 2 or 3 are viewed as moderate to severe disease. These guidelines are explicated as hospital-admitted patients with the following Truelove and Witts criteria: six or more hematochezia (bloody diarrhea) movements/day with at least one marker of inseparable toxicity, including heartbeat/rate > 90 beats/min, body temperature > 37.8 °C, blood hemoglobin < 10.5 g/dL, and/or an erythrocyte sedimentation rate (ESR) of −30 mm/h [56].

Predominantly colonic Crohn’s disease, or Crohn’s colitis, is an IBD diagnosed in at least four patients per 100,000 live births in the United States and Canada, and the incidence and prevalence are rising internationally [58,59,60] [58-59], specifically in developing nations [26,58]. Clinically, CC differs from UC in that it may result in inflammation deeper within the entire colonic walls (mucosa, submucosa, muscularis and serosa, (transmural) (colon, and rectum) [39]. Furthermore, CC may also affect other systemic organs outside the colon tract through fistulation [3,4,61]. The conciliate features for diagnosing CC comprise an inexact combination of classification systems discussed above in Section 3 for IBD clinical diagnosis, and histopathological findings demonstrating focal, asymmetric, transmural, or granulomatous features [62,63]. Abdominal computed tomography (CT) colonography is the most widely recommended and preferred first-line radiologic study used in the evaluation/assessment of CC. The diagnostic accuracy of magnetic resonance colonography is equivalent to that of CT scans and prevents liability exposure to ionizing radiation. Endoscopic score metrics are the gold standard tool used to estimate the activity of CC, and they are used more often in clinical trials to compute proof of the efficacy and safety of various drugs inducing and maintaining remission and mucosal healing. There are several multipronged scoring systems, but the most used to measure clinical disease severity include the CC Activity Index (CDAI), the Harvey–Bradshaw index (HBI), the short IBD questionnaire (SIBDQ) and the Lehmann score [62,63].

In colonic IBD, delineation between CC from UC is often inconclusive [11,40,41,64], thereby confounding effective and appropriate surgeries [39]. Approximately 30% of patients with colonic IBD are indistinguishable, especially during the prodromal stage, and are therefore labeled as ‘‘indeterminate colitis’’ (IC) due to the non-definitive establishment of criteria for CC and UC [40,65,66]. Therefore, understanding the biomolecules and different cellular mechanisms driving IBD heterogeneity is vital to the development of future drug inhibitors to improve patient care [67,68,69,70] [67-70]. The distinction between UC and CC in otherwise IC is of utmost importance when determining a patient’s candidacy for RPC-IPAA, the standard curative surgical procedure in the treatment for UC. The success of RPC-IPAA surgery and convalescence largely depend on correct diagnosis. To address the IBD diagnosis dilemma in clinical settings, there are published data that have shown robust evidence supporting the presence of human alpha defensin 5 (DEFA5, alias HD5) in the colon crypt mucosa with aberrant expression of Paneth cell-like cells (PCLCs) and/or apparent crypt-cell-like cells (CCLCs) in areas identified with an ectopic colonic ileal metaplasia that is consistent with the diagnosis of CC [11,71]. This conceptual innovation relies on the expression of DEFA5 and the CCLCs in the colonic mucosal crypt of CC patients and its definitive discriminatory use as a biomarker to facilitate the unambiguous diagnosis of CC with a positive predictive value (PPV) of 96 percent [11,71].