Current Understanding of Dysbiosis in Disease in Human and Animal Models

Abstract

Inflammatory bowel disease (IBD) is an intestinal inflammatory condition that affects more than 2 million people in the United States. Although the etiology and pathogenesis of IBD are still largely unknown, dysregulated host/enteric microbial interactions are requisite for the development of IBD. So far, many researchers have tried to identify a precise relationship between IBD and an imbalance of the intestinal microbiota, termed "dysbiosis." Despite extensive efforts, it is still largely unknown about the interplay among microbes, their hosts, and their environments, and whether dysbiosis is a causal factor or an effect of IBD. Recently, deep-sequencing analyses of the microbiota in patients with IBD patients have been instrumental in characterizing the strong association between dysbiosis and IBD development, although it is still unable to identify specific-associated species level changes in most cases. Based on many recent reports, dysbiosis of the commensal microbiota is implicated in the pathogenesis of several diseases, including IBD, obesity, and allergic disorders, in both human and animal models. In this review article, the authors have focused on explaining the multiple types of dysbiosis, as well as dysbiosis-related diseases and potential treatments to apply this knowledge to understand a possible cause and potentially find therapeutic strategies for IBD as well as the other dysbiosis-related diseases.

Figure 1. Normal and dysbiotic intestinal microbiota

A. The healthy intestines of normal individuals are colonized by a wide range of bacteria of over 1000 species. In healthy individuals, these bacteria are in a homeostatic balance between commensal and potentially pathogenic bacteria, and the intestinal tract does not display overgrowth of pathogenic bacteria. The microflora provide the host with protection from foreign microbes, acting as a central line of resistance to colonization by these exogenous bacteria. This protection is known as the “barrier effect”, or colonization resistance [1]. Through the mucosal surface of the intestine, the microbiota interacts with the host immune system, providing the host with immune regulatory functions, like priming the mucosal immune system [1,2]. The microbiota also possesses various metabolic functions, like breaking down complex carbohydrates and generating short-chain fatty acids, which the host benefits from [1, 3]. Surprisingly, the gut microbiota is also capable of interacting with distant organs, such as the brain, which has led to studies of the influence of the gut microbiota on mental disorders, like autism, and diseases such as Alzheimer’s [2]. B. When the intestinal bacterial homeostasis is disrupted, dysbiosis occurs. Dysbiosis is defined by an imbalance in bacterial composition, changes in bacterial metabolic activities, or changes in bacterial distribution within the gut. The three types of dysbiosis are: 1) Loss of beneficial bacteria, 2) Overgrowth of potentially pathogenic bacteria, and 3) Loss of overall bacterial diversity. In most cases, these types of dysbioses occur at the same time. Green colors representing pathogenic bacteria and each different color bacteria representing a different commensal species to show diversity or lack thereof in each case. Dysbiosis has been associated with diseases such as Inflammatory Bowel Disease (IBD), Obesity, Type 1 and Type 2 Diabetes, Autism, and certain gastrointestinal cancers.

Figure 2. Normal and mutated NOD2 functions

A. Normal functions of NOD2. The normal NOD2 variant is activated by muramyl dipeptide, which is a component of bacterial cell walls. Activated NOD2 recruits receptor-interacting protein 2 (PIP2), which then activates the mitogen activated protein kinase (MAPK) and nuclear factor kappa B (NFκB) cascades. This results in the release of proinflammatory molecules to help kill pathogenic bacteria (Left). Activated NOD2 also guides autophagy-related 16-like 1 (ATG16L1) protein from the cytoplasm to the plasma membrane to initiate autophagosome formation (Right). B. Mutated variants of NOD2 cause impairments in sensing and recognizing MDP. Without this activation, RIP2 and the resulting cytokine release does not occur (Left). Without active NOD2, ATG16L1 is not guided to the plasma membrane and remains in the cytosol, which impairs autophagosome formation and results in impaired killing of invading bacteria (Right). NOD2 variants and their impaired cellular functions may lead to dysbiosis within the intestinal epithelium, and are associated with earlier onset of ileal Crohn’s disease.

Figure 3. Advantages and disadvantages of different symbiotic interventions of gut microbial flora

Exogenous bacteria can influence the dysbiotic gut to achieve restoration of a healthy flora. These exogenous bacteria can be introduced in the form of probiotics or fecal microbiota transplantation that has their own advantages and disadvantages. Microbes present in the environment can also alter the endogenous gut microbiome composition and confer disease susceptibility or protection.