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      The Prevention of Inflammation and the Maintenance of Iron and Hepcidin Homeostasis in the Gut, Liver, and Brain Pathologies

      review-article
      , , , *
      Journal of Alzheimer's Disease
      IOS Press
      Brain, dysbiosis, hepcidin, high fat-high sugar diet, intestines, mBDNF, TMAO, vagus nerve, Western diet

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          Abstract

          The human gut microbiome consists of a variety of microorganisms that inhabit the intestinal tract. This flora has recently been shown to play an important role in human disease. The crosstalk between the gut and brain axis has been investigated through hepcidin, derived from both hepatocytes and dendritic cells. Hepcidin could potentially play an anti-inflammatory role in the process of gut dysbiosis through a means of either a localized approach of nutritional immunity, or a systemic approach. Like hepcidin, mBDNF and IL-6 are part of the gut-brain axis: gut microbiota affects their levels of expression, and this relationship is thought to play a role in cognitive function and decline, which could ultimately lead to a number of neurodegenerative diseases such as Alzheimer’s disease. This review will focus on the interplay between gut dysbiosis and the crosstalk between the gut, liver, and brain and how this is mediated by hepcidin through different mechanisms including the vagus nerve and several different biomolecules. This overview will also focus on the gut microbiota-induced dysbiotic state on a systemic level, and how gut dysbiosis can contribute to beginnings and the progression of Alzheimer’s disease and neuroinflammation.

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          Most cited references67

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          Influence of diet on the gut microbiome and implications for human health

          Recent studies have suggested that the intestinal microbiome plays an important role in modulating risk of several chronic diseases, including inflammatory bowel disease, obesity, type 2 diabetes, cardiovascular disease, and cancer. At the same time, it is now understood that diet plays a significant role in shaping the microbiome, with experiments showing that dietary alterations can induce large, temporary microbial shifts within 24 h. Given this association, there may be significant therapeutic utility in altering microbial composition through diet. This review systematically evaluates current data regarding the effects of several common dietary components on intestinal microbiota. We show that consumption of particular types of food produces predictable shifts in existing host bacterial genera. Furthermore, the identity of these bacteria affects host immune and metabolic parameters, with broad implications for human health. Familiarity with these associations will be of tremendous use to the practitioner as well as the patient.
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            Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice.

            Indigenous microbiota have several beneficial effects on host physiological functions; however, little is known about whether or not postnatal microbial colonization can affect the development of brain plasticity and a subsequent physiological system response. To test the idea that such microbes may affect the development of neural systems that govern the endocrine response to stress, we investigated hypothalamic-pituitary-adrenal (HPA) reaction to stress by comparing germfree (GF), specific pathogen free (SPF) and gnotobiotic mice. Plasma ACTH and corticosterone elevation in response to restraint stress was substantially higher in GF mice than in SPF mice, but not in response to stimulation with ether. Moreover, GF mice also exhibited reduced brain-derived neurotrophic factor expression levels in the cortex and hippocampus relative to SPF mice. The exaggerated HPA stress response by GF mice was reversed by reconstitution with Bifidobacterium infantis. In contrast, monoassociation with enteropathogenic Escherichia coli, but not with its mutant strain devoid of the translocated intimin receptor gene, enhanced the response to stress. Importantly, the enhanced HPA response of GF mice was partly corrected by reconstitution with SPF faeces at an early stage, but not by any reconstitution exerted at a later stage, which therefore indicates that exposure to microbes at an early developmental stage is required for the HPA system to become fully susceptible to inhibitory neural regulation. These results suggest that commensal microbiota can affect the postnatal development of the HPA stress response in mice.
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              The role of iron in brain ageing and neurodegenerative disorders.

              In the CNS, iron in several proteins is involved in many important processes such as oxygen transportation, oxidative phosphorylation, myelin production, and the synthesis and metabolism of neurotransmitters. Abnormal iron homoeostasis can induce cellular damage through hydroxyl radical production, which can cause the oxidation and modification of lipids, proteins, carbohydrates, and DNA. During ageing, different iron complexes accumulate in brain regions associated with motor and cognitive impairment. In various neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, changes in iron homoeostasis result in altered cellular iron distribution and accumulation. MRI can often identify these changes, thus providing a potential diagnostic biomarker of neurodegenerative diseases. An important avenue to reduce iron accumulation is the use of iron chelators that are able to cross the blood-brain barrier, penetrate cells, and reduce excessive iron accumulation, thereby affording neuroprotection.
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                Author and article information

                Journal
                J Alzheimers Dis
                J Alzheimers Dis
                JAD
                Journal of Alzheimer's Disease
                IOS Press (Nieuwe Hemweg 6B, 1013 BG Amsterdam, The Netherlands )
                1387-2877
                1875-8908
                18 February 2023
                04 April 2023
                2023
                : 92
                : 3
                : 769-789
                Affiliations
                [1] Department of Anatomy and Neurobiology, Boston University Aram V. Chobanian & Edward Avedisian School of Medicine , Boston, MA, USA
                Author notes
                [* ]Correspondence to: Jonathan J. Wisco, PhD, Associate Professor, Boston University Aram V. Chobanian & Edward Avedisian School of Medicine, Department of Anatomy and Neurobiology, Laboratory for Translational Anatomy of Degenerative Diseases and Developmental Disorders (TAD4), 72 E Concord St, L-1004, Boston, MA 02118, USA. Tel.: +1 617 358 2002; E-mail: jjwisco@ 123456bu.edu .
                Article
                JAD220224
                10.3233/JAD-220224
                10116142
                36846996
                5f553d24-2dba-406f-a593-9340fb062078
                © 2023 – The authors. Published by IOS Press

                This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 January 2023
                Categories
                Review

                brain,dysbiosis,hepcidin,high fat-high sugar diet,intestines,mbdnf,tmao,vagus nerve,western diet

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