Increased Serum Zonulin Levels as an Intestinal Permeability Marker in Autistic Subjects

Esnafoğlu, Erman; Cırrık, Selma; Ayyıldız, Sema Nur; Erdil, Abdullah; Ertürk, Emine Yurdakul; Dağlı, Abdullah; Noyan, Tevfik

doi:10.1016/j.jpeds.2017.04.004

Cited by 102 publications

(73 citation statements)

References 39 publications

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“…Both these changes are reminiscent of findings reported in limited subgroups of individuals with ASD. [51][52][53][54] The altered microbial environment and leaky gut induced by MIA resulted in altered serum metabolites. The most significant increase was in 4-ethylphenylsulfate (4EPS), a predicted metabolite of gut microbes, which was increased 46-fold.…”

Section: Bb Warnermentioning

confidence: 99%

The contribution of the gut microbiome to neurodevelopment and neuropsychiatric disorders

2018

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Bidirectional communication between the gut and brain is well recognized, with data now accruing for a specific role of the gut microbiota in that link, referred to as the microbiome-gut-brain axis. This review will discuss the emerging role of the gut microbiota in brain development and behavior. Animal studies have clearly demonstrated effects of the gut microbiota on gene expression and neurochemical metabolism impacting behavior and performance. Based on these changes, a modulating role of the gut microbiota has been demonstrated for a variety of neuropsychiatric disorders, including depression, anxiety, and movement including Parkinson's, and importantly for the pediatric population autism. Critical developmental windows that influence early behavioral outcomes have been identified that include both the prenatal environment and early postnatal colonization periods. The clearest data regarding the role of the gut microbiota on neurodevelopment and psychiatric disorders is from animal studies; however, human data have begun to emerge, including an association between early colonization patterns and cognition. The importance of understanding the contribution of the gut microbiota to the development and functioning of the nervous system lies in the potential to intervene using novel microbial-based approaches to treating neurologic conditions. While pathways of communication between the gut and brain are well established, the gut microbiome is a new component of this axis. The way in which organisms that live in the gut influence the central nervous system (CNS) and host behavior is likely to be multifactorial in origin. This includes immunologic, endocrine, and metabolic mechanisms, all of which are pathways used for other microbial-host interactions. Germ-free (GF) mice are an important model system for understanding the impact of gut microbes on development and function of the nervous system. Alternative animal model systems have further clarified the role of the gut microbiota, including antibiotic treatment, fecal transplantation, and selective gut colonization with specific microbial organisms. Recently, researchers have started to examine the human host as well. This review will examine the components of the CNS potentially influenced by the gut microbiota, and the mechanisms mediating these effects. Links between gut microbial colonization patterns and host behavior relevant to a pediatric population will be examined, highlighting important developmental windows in utero or early in development.

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Section: Bb Warnermentioning

confidence: 99%

The contribution of the gut microbiome to neurodevelopment and neuropsychiatric disorders

2018

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“…The "leaky gut theory" postulates that an exceptionally increased permeability of the intestinal mucosa barrier represents a fundamental mechanism underlying autistic pathology (de Magistris et al, 2010;D'Eufemia et al, 1996;Horvath & Perman, 2002;Panksepp, 1979;Wakefield et al, 1998). Studies on subgroups of ASD subjects have revealed that this deficiency is partly contributed by (a) alterations in microbial composition, with an overrepresentation of bacterium Akkermansia muciniphila, known to degrade the mucus lining (Wang et al, 2011), (b) prevalence of Clostridia and reduced abundance of Bifidobacteria, increasing pro-inflammatory cytokines production, which aggravates mucosa permeability (Heberling, Dhurjati, & Sasser, 2013), (c) elevated plasma levels of zonulin, a protein that regulates permeability (Esnafoglu et al, 2017), (d) decreased amounts of tight junction proteins at the intestinal barrier (Fiorentino et al, 2016), potentially due to increased toxins from Clostridia (Hecht, Pothoulakis, LaMont, & Madara, 1988), (e) infection by Escherichia coli, which leads to transformation of actin and tight junction structures (Long, Nisa, Donnenberg, & Hassel, 2014), (f) abundance of Candida fungi, which expresses root-like formations that invade the intestinal wall (de Magistris et al, 2010), and (g) increased levels of claudin, a molecule that contributes to pores formation (Fiorentino et al, 2016). Individuals with both autistic and gastrointestinal disorders exhibit a distinct cytokine (Ashwood & Wakefield, 2006;Torrente et al, 2002) and regulatory (Ashwood, Anthony, Torrente, & Wakefield, 2004) profile.…”

Section: Gastrointestinal Mucosa Permeabilitymentioning

confidence: 99%

A systematic review of gut‐immune‐brain mechanisms in Autism Spectrum Disorder

Azhari

Azizan

Esposito

2018

Developmental Psychobiology

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Despite decades of research, the etiological origins of Autism Spectrum Disorder (ASD) remain elusive. Recently, the mechanisms of ASD have encompassed emerging theories involving the gastrointestinal, immune, and nervous systems. While each of these perspectives presents its own set of supporting evidence, the field requires an integration of these modular concepts and an overarching view of how these subsystems intersect. In this systematic review, we have synthesized relevant evidences from the existing literature, evaluating them in an interdependent manner and in doing so, outlining their possible connections. Specifically, we first discussed gastrointestinal and immuno‐inflammation pathways in‐depth, exploring the relationships between microbial composition, bacterial metabolites, gut mucosa, and immune system constituents. Accounting for temporal differences in the mechanisms involved in neurodevelopment, prenatal and postnatal phases were further elucidated, where the former focused on maternal immune activation (MIA) and fetal development, while the latter addressed the role of immune dysregulation in contributing to atypical neurodevelopment. As autism remains, foremost, a neurodevelopmental disorder, this review presents an integration of disparate modules into a “Gut‐Immune‐Brain” paradigm. Existing gaps in the literature have been highlighted, and possible avenues for future research with an integrated physiological perspective underlying ASD have also been suggested.

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“…Increased levels of lipopolysaccharides have been found in the blood of ASD patients, corresponding to increased peripheral levels of IL‐6 (a neuromodulating cytokine). Similarly, increased intestinal permeability has been reported in subjects with autism and their first‐degree relatives, suggesting that these changes may be involved in the pathogenesis of the disease rather than a consequence of autistic behavior (Esnafoglu et al, ). To date, numerous studies have suggested microbial dysbiosis in ASD, summarized in Table .…”

Section: The Microbiome In Clinical Populationsmentioning

confidence: 82%

The gut microbiome in psychiatry: A primer for clinicians

et al. 2019

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Research in the past decade has shown that variations in the gut microbiome may influence behavior, and vice versa. As such, interest in the role of the gut microbiome in psychiatric conditions has drawn immense interest. This is evidenced by the recent surge in published studies examining microbial dysbiosis in clinical psychiatric populations, particularly autism spectrum disorder and depression. However, critical examination of these studies reveals methodological flaws in design and execution, suggesting that they may not be held to the same standards as other bodies of clinical research. Given the complex nature of the gut microbiome, this narrative review attempts to clarify concepts critical to effectively examine its potential role in psychopathology to appropriately inform mental health researchers. More specifically, the numerous variables known to affect the gut microbiome are discussed, including inflammation, diet, weight, and medications. A comprehensive review of the extant microbiome literature in clinical psychiatric populations is also provided, in addition to clinical implications and suggestions for future directions of research. Although there is a clear need for additional studies to elucidate the gut microbiome's role in psychiatric disorders, there is an even greater need for well-designed, appropriately controlled studies to truly impact the field.

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Increased Serum Zonulin Levels as an Intestinal Permeability Marker in Autistic Subjects

Cited by 102 publications

References 39 publications

The contribution of the gut microbiome to neurodevelopment and neuropsychiatric disorders

The contribution of the gut microbiome to neurodevelopment and neuropsychiatric disorders

A systematic review of gut‐immune‐brain mechanisms in Autism Spectrum Disorder

The gut microbiome in psychiatry: A primer for clinicians

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