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NLRP3 Inflammasome and Gut Dysbiosis Linking Diabetes Mellitus and Inflammatory Bowel Disease - PubMed

NLRP3 Inflammasome and Gut Dysbiosis Linking Diabetes Mellitus and Inflammatory Bowel Disease

Ugljesa Malicevic et al. Arch Intern Med Res. 2024.

Abstract

Diabetes mellitus and inflammatory bowel disease are chronic conditions with significant overlap in their pathophysiology, primarily driven by chronic inflammation. Both diseases are characterized by an aberrant immune response and disrupted homeostasis in various tissues. However, it remains unclear which disease develops first, and which one contributes to the other. Diabetes mellitus increases the risk of inflammatory bowel disease and inflammatory bowel disease may increase the risk of developing diabetes. This review focuses on comprehensively discussing the factors commonly contributing to the pathogenesis of diabetes mellitus and inflammatory bowel disease to draw a relationship between them and the possibility of targeting common factors to attenuate the incidence of one if the other is present. A key player in the intersection of diabetes mellitus and inflammatory bowel disease is the NLRP3 inflammasome, which regulates the production of pro-inflammatory cytokines leading to prolonged inflammation and tissue damage. Additionally, toll-like receptors via sensing microbial components contribute to diabetes mellitus and inflammatory bowel disease by initiating inflammatory responses. Gut dysbiosis, a common link in both diseases, further intensifies inflammation and metabolic dysfunction. Alterations in gut microbiota composition affect intestinal permeability and immune modulation, perpetuating a vicious cycle of inflammation and disease progression by changing protein expression. The overlap in the underlying inflammatory mechanisms has led to the potential of targeting mediators of chronic inflammation using anti-inflammatory drugs and biologics that benefit both conditions or attenuate the incidence of one in the presence of the other.

Keywords: Bile acids; Chronic inflammation; Crohn’s disease; Diabetes mellitus; Gut dysbiosis; Inflammatory bowel disease; NLRP3; Therapeutic targets; Toll-like Receptor; Ulcerative colitis.

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Conflict of interest statement

Competing interests: All authors have read the manuscript and declare no conflict of interest. No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1:
Figure 1:

Risk factors for diabetes. T1DM and T2DM are the two primary forms of diabetes mellitus. The risk factors for T1DM include a family history, genetic predisposition, a specific ethnic background, and age. For T2DM, there are two categories of risk factors: modifiable and non-modifiable. Non-modifiable factors include family history/genetics, race or ethnic background, age, and gestational diabetes. Modifiable factors encompass dietary choices, alcohol and tobacco consumption, physical inactivity, obesity, cardiovascular diseases, polycystic ovary syndrome, depression, and others.

Figure 2:
Figure 2:

Risk factors for Inflammatory Bowel Disease. Risk factors for IBD include genetic predisposition, age, and lifestyle factors such as chronic stress, lack of sleep, and physical inactivity. Unhealthy habits like a high-fat, low-fiber diet, and smoking significantly elevate risk, particularly for Crohn’s disease. Other important contributors to IBD are dysbiosis, vitamin D deficiency, appendectomy, and the use of various medications. These factors, combined with genetics, drive the onset and progression of IBD.

Figure 3:
Figure 3:

The illustration above highlights the role of TLRs and the process of their activation in DM and its subsequent correlation with IBD. Diabetes, especially T2DM, and obesity are characterized by persistent low-grade inflammation, which plays a crucial role in the etiology and development of these conditions. Hyperglycemia, high FFA levels, oxidative stress, and other conditions trigger mostly TLR2 and TLR4 activation, which in turn promotes the creation of several transcriptional factors that lead to the generation of pro-inflammatory cytokines and inflammation. Inflammation and the subsequent production of cytokines in the gut result in dysbiosis, which leads to increased permeability of the intestines, sometimes referred to as “leaky gut” by impairing epithelial tight junctions and facilitating the translocation of microbial products like lipopolysaccharide (LPS) into the bloodstream, which in turn causes systemic inflammation. Increased concentrations of circulating LPS are linked to the development of insulin resistance. Dysbiosis can initiate abnormal immunological reactions, resulting in an excessive release of pro-inflammatory cytokines that can contribute to the development of IBD; therefore, implying a connection between diabetes, obesity, and IBD.

Figure 4:
Figure 4:

Groups of medicines used in the treatment of diabetes mellitus and inflammatory bowel disease, as well as groups of medicines that could potentially be used to treat individuals with both diabetes mellitus and inflammatory bowel disease. These drugs are shown with question mark (?).

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