**1. Introduction**

Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract (GIT) that occurs due to the dysregulation of the immune system. Although the explicit etiology and underlying remain uncertain, both environmental and genetic factors

**Citation:** Bilal, M.; Nunes, L.V.; Duarte, M.T.S.; Ferreira, L.F.R.; Soriano, R.N.; Iqbal, H.M.N. Exploitation of Marine-Derived Robust Biological Molecules to Manage Inflammatory Bowel Disease. *Mar. Drugs* **2021**, *19*, 196. https:// doi.org/10.3390/md19040196

Academic Editors: Donatella Degl'Innocenti and Marzia Vasarri

Received: 6 March 2021 Accepted: 26 March 2021 Published: 30 March 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

are involved in immune dysregulation. Historically, IBD has been categorized into Crohn's disease (CD) and ulcerative colitis (UC). Both diseases show heterogeneous pathological and clinical features and can be distinguished by their location, nature and characteristics of inflammation. More specifically, the laboatory analysis and careful stool evaluation are considered initial measures to diagnose the patient who is suspected to have IBD (Figure 1) [1]. Crohn's disease is a deeper transmural inflammation affecting any segment of the GI tract from the mouth to anus, whereas ulcerative colitis is a chronic inflammatory disease that attacks the colonic mucosa [1]. Approximately, 25% of UC patients require hospitalization for acute severe ulcerative colitis (ASUC) at any phase during this complication, leading to colectomy in 40% of patients [2,3].

**Figure 1.** Initial workup of a patient suspected of having inflammatory bowel disease (IBD). The initial workup is ideally started by the referring physician, with the subspecialist performing anything missing plus endoscopies and small bowel assessment(s) [1]. License Number: 5022881429496. Abbreviations: CBC (Complete Blood Count), CRP (C-reactive protein), ESR (Erythrocyte Sedimentation Rate), MRI (Magnetic resonance imaging), and CT (computed tomography).

The origin and disease progression of UC and CD are significantly different from each other. The changes in microbial diversity of lumen, impaired barrier functions of mucus and epithelial layer through interrupting tight junctions are strongly associated with the UC pathogenesis. Figure 2 portrays a graphical representation of the pathophysiology of UC [4]. Though individuals with UC show a great percentage of Enterobacteriaceae Gammaproteobacteria [5], and sulfite-reducing bacteria [6], and minimum Firmicutes diversity, such changes are intestinal inflammation-mediated or vice versa remains debatable. In the case of CD, inflammation of the small bowel results in an increased concentration of proinflammatory cytokines, like IL-17A, and IFN-γ [7]. Furthermore, Th17 cell-derived IL-17 in turn favors the Th-1 response [8]. IL-6, IL-23, and TGF-β secreted by antigen-presenting and innate immune cells influence the IL-17 pathway (Figure 3) [4].

**Figure 2.** Pathophysiology of Ulcerative Colitis. Impairment of tight junctions and the mucous layer leads to increased permeability of the intestinal epithelium, resulting in more uptake of luminal antigens. Antigen presenting cells (APC) become activated upon recognizing non-pathogenic bacteria (commensal microbiota) through Toll-like receptors (TLRs). Activated APC initiate differentiation of naïve CD4+ T-cells into Th-2 effector cells (which produce pro-inflammatory cytokines such as TNF-α, IL-5, IL-6, and IL-13). TNF-α and IL-1 activate nuclear factor κB (NF-κB) pathway, which facilitate expression of pro-inflammatory and cell survival genes. Binding of integrin-α4β7 bearing T cells to the mucosal adhesion molecule MAdCAM-1 facilitate entry of more T cells into the lamina propria. Recruitment of circulating leucocytes due to the upregulation of inflammatory chemokines (chemokine ligands: CXCL1, CXCL3, CXCL8 and CXCL10) perpetuates the inflammatory cycle. MAdCAM-1, mucosal addressin cell adhesion molecule-1; IL, interleukin; TNF-α, tumor necrosis factor-alpha; TGF-β, transforming growth factor-beta; NKT, natural killer T; DC, dendritic cell; Th, T helper; GATA3, GATA binding protein 3; IRF4, interferon regulatory factor 4; PU.1, purine-rich PU-box binding protein; FOXP3, Forkhead box protein 3. Reprinted from Ref. [4] with permission under the Creative Commons Attribution (CC BY) license. Copyright © 2020 the authors. Licensee MDPI, Basel, Switzerland.

In 2017, about 6.8 million cases of IBD were documented worldwide [9]. Over 1.6 million, 85,000, 250,000 and 260,000 people are affected by IBD in Australia, the USA, the UK and China, respectively [10–12]. IBD remains dominant in western countries in the last few decades because of the higher prevalence and incidence rates than in the developing world. Nevertheless, the incidence of IBD has now intensified dramatically in several Asian countries [12] with a consistently increasing trend, mainly in China, Japan, Hong Kong, and Korea [13]. Due to lacking national registries in many African, Asian, and Latin American nations, there is very scarce information regarding the occurrence and prevalence of IBD.

IBD has been reported to occur at any age, however, the peak incidence appears in early adulthood and adolescence [14–16]. Symptoms associated with IBD can be unpredicted and highly variable. Children may exhibit inimitable physical examination findings along with several upper or lower GI manifestations. There might be only a few symptoms in some cases, with inexplicable weight loss and growth retardation. It is imperative to distinguish that IBD is not irritable bowel syndrome (IBS). Though both diseases may present identical symptoms, only IBD results in stunted height, growth retardation, ostomies, surgeries, and many other undesirable outcomes or risks. Besides the systemic symptoms, like fatigue, fever, mouth sores, uveitis, arthralgia, and nail clubbing, IBD is also related to a variety

of extra-intestinal symptoms. These manifestations appear in approximately 25–35% of individuals with IBD particularly at a young age [17,18].

**Figure 3.** Pathophysiology in Crohn's disease. The uptake of luminal microflora stimulates APCs (e.g., dendritic cells and macrophages) which in turn produce proinflammatory cytokines such as TNF-α, IL-6, and IL-23. Activated APCs facilitate subsequent differentiation of naïve CD4<sup>+</sup> T-cells into Th1 and Th17 via expression of master transcription factors. Inside the high endothelial venule, binding of α4β7-bearing lymphocytes to MAdCAM-1 causes entry of more T cells into the lamina propria. IFN-γ, interferon-gamma; FOXP3, Forkhead box protein 3; RORγt, retinoic acid receptor-related orphan nuclear receptor gamma. Reprinted from Ref. [4] with permission under the Creative Commons Attribution (CC BY) license. Copyright © 2020 the authors. Licensee MDPI, Basel, Switzerland.

> The treatment protocols being practiced for the IBD involve either medication therapy or surgery [19]. The preferred choice of medication therapy in the case of IBD is the treatment with the use of anti-inflammatory drugs, such as aminosalicylates and corticosteroids. The second line medication for IBD encompasses using immunosuppressants to halt the immune response, responsible for un-regulated inflammation. In addition to immunosuppressants, tumor necrosis factor-α (TNF-α) inhibitors, or biologics works by neutralizing immune system protein. In Crohn's disease, where the infection is a concern, antibiotics can be used to reduce the chances of infection. On the other hand, surgery may be an option in severe cases when all these therapeutic options do not work. However, treatment protocols are also being practiced culminating devastating colorectal cancer, but no treatment is required for benevolent stage cancer. In the case of metastatic invasion, surgery can be opted to eradicate malignant tumors and lymph nodes [20].

> The marine environment has been demonstrated as a prolific source of bio-active compounds with unique chemical, structural and functional features. Furthermore, the molecular modeling and synthesis of new drugs based on marine-derived therapeutic and biological cues might present greater efficacy and specificity for the therapeutics (Table 1). A vast number of compounds have been derived and identified from marine sources that exhibit a noteworthy role to circumvent the reactive oxygen species (ROS) generation, show anti-inflammatory effects, and hinder various metabolic pathways. The current review is focused on marine-derived bioactive compounds to treat and manage

IBD. Furthermore, a detailed overview of clinical applications and future perspectives are also given in this review.


**Table 1.** Marine-derived compounds and biological activities with therapeutic potential.
