Current Pharmaceutical Design - Volume 22, Issue 40, 2016

Background: In steady state conditions intestinal immune homeostasis is maintained by a sophisticated bidirectional dialogue between the microbiota and the intestinal immune system. This “cross talk“ is enabled by the presence of highly adapted secretory cells, sampling cells and pattern recognition receptors in the gastric epithelium. Methods: Herein we discuss the mechanisms involved in the breakdown of intestinal homeostasis and the development of systemic immune activation and neuroinflammation with a view to discussing the importance of these processes, in tandem with genetic and environmental factors, in the pathophysiology of (auto)immune diseases.Data is presented explaining how immune tolerance is maintained and how it may breakdown. Conclusion: The breakdown of immune homeostasis following the development of gut inflammation, caused for example by gut dysbiosis, and the consequent increased intestinal permeability, is increasingly considered to be the ultimate source of the systemic immune activation and T helper 17/T regulatory cell imbalances, and maybe neurological disturbances, seen in autoimmune diseases such as Type 1 diabetes and inflammatory bowel disease. Increased intestinal permeability and translocation of commensal antigens into the systemic circulation is also a likely cause of the severe fatigue and an almost bewildering range of neurocognitive, neuroimaging and overall symptom presentations seen in patients with a diagnosis of Chronic Fatigue Syndrome.

Background: Autoimmune phenotypes are prevalent in major psychiatric disorders. Disequilibria of cellular processes occurring in the gastrointestinal (GI) tract likely contribute to immune dysfunction in psychiatric disorders. As the venue of a complex community of resident microbes, the gut in a homeostatic state equates with a functional digestive system, cellular barrier stability and properly regulated recognition of self and non-self antigens. When gut processes become disrupted as a result of environmental or genetic factors, autoimmunity may ensue. Methods: Here, we review the issues pertinent to autoimmunity and the microbiome in psychiatric disorders and show that many of the reported immune risk factors for the development of these brain disorders are in fact related and consistent with dysfunctions occurring in the gut. We review the few human microbiome studies that have been done in people with psychiatric disorders and supplement this information with mechanistic data gleaned from experimental rodent studies. Results: These investigations demonstrate changes in behavior and brain biochemistry directly attributable to alterations in the gut microbiome. We present a model by which autoantigens are produced by extrinsicallyderived food and microbial factors bound to intrinsic components of the gut including receptors present in the enteric nervous system. Conclusion: This new focus on examining activities outside of the CNS for relevance to the etiology and pathophysiology of psychiatric disorders may require new modalities or a re-evaluation of pharmaceutical targets found in peripheral systems.

The comorbid prevalence of major depressive disorder (MDD) with obesity and type II diabetes mellitus reflects the existence of a subset of individuals with a complex common pathophysiology and overlapping risk factors. Such comorbid disease presentations imply a number of difficulties, including: decreased treatment responsivity and adherence; altered glycemic control and increased risk of wider medical complications. A number of factors link MDD to metabolic-associated disorders, including: higher rates of shared risk factors such as poor diet and physical inactivity and biological elements including increased inflammation; insulin resistance; oxidative and nitrosative stress; and mitochondrial dysfunction. All of these biological factors have been extensively investigated in the pathophysiology of obesity and type 2 diabetes mellitus as well as MDD. In this review, we aim to: (1) overview the epidemiological links between MDD, obesity and type 2 diabetes mellitus; (2) discuss the role of synergistic neurotoxic effects in MDD comorbid with obesity, and type 2 diabetes mellitus; (3) review evidence of intestinal dysbiosis, leaky gut and increased bacterial translocation, in the pathophysiology of MDD, obesity and type 2 diabetes mellitus; and (4) propose a model in which the gut-brain axis could play a pivotal role in the comorbidity of these disorders.

Background: Many lines of scientific research suggest that Autism Spectrum Disorders (ASDs) may be associated with alterations in the enteric ecosystem, including alterations of the enteric macrobiome (i.e. helminthes and fauna) and changes in predominant microbiome species, particularly a reduction in microbiome species diversity. Methods: We performed a comprehensive review of the literature and summarized the major findings. Results: Alterations in the enteric ecosystem are believed to be due to a variety of factors including changes in the post-industrial society related to decreased exposure to symbiotic organisms, increased human migration, overuse of antibiotics and changes in dietary habits. Changes in the enteric ecosystem are believed to alter metabolic and immune system function and epigenetic regulation. If these changes occur during critical developmental windows, the trajectory of brain development, as well as brain function, can be altered. This paper reviews theoretical models that explain how these perturbations may in isolation or in combination be causative for ASDs as well as the preclinical and clinical studies that support these models. We discuss how these alterations may converge to trigger or exacerbate the formation of an ASD phenotype. We focus on possible preconception, prenatal, perinatal and postnatal factors that may alter the enteric ecosystem leading to physiological disruptions, potentially through triggering events. Conclusion: If these theoretical models prove to be valid, they may lead to the development of practical interventions which could decrease ASD prevalence and/or morbidity.

Background: The underlying pathophysiology of schizophrenia still remains elusive. Thus, there is a pressing need to identify novel targets for the development of new interventions and elucidate related biomarkers for the identification and monitoring of potentially responsive patients. In this sense, several hypotheses involving immune/inflammatory changes and the consequent oxidative/nitrosative stress, as well as a dysregulation in the immuno-inflammatory response have come into sight. Methods: Considering the great amount of genes encoded by the microbiome and the evidences pointing to the potential role of the gut microbiota on several neurologic and psychiatric diseases, the aim of this review is to evaluate the possible role of these organisms in the immunopathogenesis of schizophrenia. To that end, we will focus not only on gut microbiota dysbiosis but also on bacterial translocation as an inductor of neuroinflammation. Results: Studies have shown that the gut microbiota may play a key role in the immunopathogenesis of schizophrenia and that essential pathways implicated in the etiopathophysiology of schizophrenia are also regulated by the microbiota-gut-brain (MGB) axis. Moreover, studies also indicate a possible role of the innate immunity through the Toll-like receptors (TLRs) and their activation by bacterial translocation, as a consequence of intestinal dysfunction, in the pathophysiology of psychotic disorders. Conclusion: This is a promising area of investigation with huge potential to offer advances in the realm of personalized medicine and accordingly, future research should examine several microbiota-targeted therapies in order to improve symptoms and to decrease the immune dysregulation seen in patients with schizophrenia.

Background: Alterations in gut microbiota, coupled to increased gut permeability are now widely recognized as having a role in the etiology, course and treatment of many medical conditions, including autoimmune and neurodegenerative disorders. Methods: In this review, the role that such gut changes play over the course of multiple sclerosis (MS) is detailed. Results: Given the wide array of biological factors and processes that have been shown to be altered in MS, including changes in the gut, this allows for a better integration of the diverse array of pathophysiological processes linked to MS. Such pathophysiological processes include increases in oxidative and nitrosative stress, pro-inflammatory immune responses, especially T helper (Th)17 cell proliferation and activation, tryptophan catabolites, pain, fatigue and increased levels of depression. By raising levels of immune activation, increased gut permeability and alterations in gut microbiota impact on all of these MS-associated processes. Alterations in the regulation of local melatonergic pathway activation is proposed to be an important hub for such pathophysiological processes in MS, allowing for the increased frequency of depression that may be prodromal in MS, both in the first episode as well as in relapses, to become more intimately associated with the etiology and course of MS. We propose this occurs by decreasing serotonin availability as a precursor for the melatoninergic pathways. Conclusion: Changes in the gut are evident in the early stages of MS, including in paediatric MS, and may interact with pro-inflammatory genetic susceptibility genes to drive the biological underpinnings of MS. Such a conceptualization of the biological underpinnings of MS also has treatment implications.

Background: Increased gut permeability (leaky gut) and alterations in gut microbiota are now widely accepted as relevant to the etiology, course and treatment of many neuropsychiatric disorders, including Parkinson disease (PD). Although a wide array of data on the biological underpinnings of PD has not yet been linked to such gut-associated changes, increased gut permeability and dysregulated microbiota alter many pathways germane to PD. Methods: In this article we review and integrate these wider biological changes in PD, including increased oxidative and nitrosative stress, immune-inflammatory processes, tryptophan catabolites and alterations in serotoninergic and melatoninergic pathways. Results: These wider biological changes in PD are compatible with alterations in gut permeability and changes in gut microbiota. By driving tryptophan down the kynurenine pathway, pro-inflammatory cytokines and chronic stress-driven activation of the hypothalamic-pituitary-adrenal axis decrease the availability of serotonin as a precursor for activation of the melatonergic pathways. Conclusion: Decreased local melatonin synthesis in glia, gut, neuronal and immune cells is likely to be important to the etiology, course and management of PD.

Alzheimer’s disease (AD), the most common form of dementia, is a progressive disorder manifested by gradual memory loss and subsequent impairment in mental and behavioral functions. Though the primary risk factor for AD is advancing age, other factors such as diabetes mellitus, hyperlipidemia, obesity, vascular factors and depression play a role in its pathogenesis. The human gastrointestinal tract has a diverse commensal microbial population, which has bidirectional interactions with the human host that are symbiotic in health, and in addition to nutrition, digestion, plays major roles in inflammation and immunity. The most prevalent hypothesis for AD is the amyloid hypothesis, which states that changes in the proteolytic processing of the amyloid precursor protein leads to the accumulation of the amyloid beta (Aβ) peptide. Aβ then triggers an immune response that drives neuroinflammation and neurodegeneration in AD. The specific role of gut microbiota in modulating neuro-immune functions well beyond the gastrointestinal tract may constitute an important influence on the process of neurodegeneration. We first review the main mechanisms involved in AD physiopathology. Then, we review the alterations in gut microbiota and gut-brain axis that might be relevant to mediate or otherwise affect AD pathogenesis, especially those associated with aging. We finally summarize possible mechanisms that could mediate the involvement of gut-brain axis in AD physiopathology, and propose an integrative model.

Over the last few decades proteins and peptide therapeutics have occupied an enormous fraction of pharmaceutical industry. Despite their high potential as therapeutics, the big challenge often encountered is the effective administration and bioavailability of protein therapeutics in vivo system. Peptide molecules are well known for their in vivo short half-lives. In addition, due to high molecular weight and susceptibility to enzymatic degradation, often it is not easy to administer peptides and proteins orally or through any other noninvasive routes. Conventional drug management system often demands for frequent and regular interval intravenous/subcutaneous administration, which decreases overall patient compliance and increases chances of side-effects related to dose-fluctuation in systemic circulation. A controlled mode of delivery system could address all these short-comings at a time. Therefore, long-acting sustained release formulations for both invasive and noninvasive routes are under rigorous study currently. Long-acting formulations through invasive routes can address patient compliance and dose-fluctuation issues by less frequent administration. Also, any new route of administration other than invasive routes will address cost-effectiveness of the therapeutic by lessening the need to deal with health professional and health care facility. Although a vast number of studies are dealing with novel drug delivery systems, till now only a handful of controlled release formulations for proteins and peptides have been approved by FDA. This study therefore focuses on current and perspective controlled release formulations of existing and novel protein/peptide therapeutics via conventional invasive routes as well as potential novel non-invasive routes of administration, e.g., oral, buccal, sublingual, nasal, ocular, rectal, vaginal and pulmonary.

Nanotechnology has emerged as a promising strategy toward inflammatory bowel disease (IBD) treatment. Nano-sized drug delivery systems exhibit an increased accumulation in inflamed tissues due to their nanometer size and present the ability to overcome the challenging inflamed colonic barriers (i.e. thick mucus layer, disrupted epithelium, altered colonic transit time). Moreover, nanocarriers are able to increase the amount of drug present at the colonic site decreasing their associated systemic side effects and increasing their efficacy. This review aims to analyze the nanoparticulate systems that have been evaluated for IBD treatment based on (i) the strategy followed towards an increased colonic accumulation and/or permeation, (ii) the small or biopharmaceutical antiinflammatory drug encapsulated within the nanocarriers and (iii) the polymer(s) used for their preparation, highlighting the profits and the drawbacks of each of the candidates based on reported results.