Autoimmune Hepatitis: Shifts in Gut Microbiota and Metabolic Pathways among Egyptian Patients

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Abstract

Autoimmune hepatitis (AIH) is a chronic inflammatory disorder with complex immunopathogenesis. Dysbiosis has been linked to many autoimmune diseases, but its detailed role in autoimmune hepatitis (AIH) still needs rigorous evaluation, especially in Egypt. We aimed to identify the shift in the gut microbiota profile and resultant metabolic pathways in AIH Egyptian patients compared to healthy individuals. Stool samples were collected from 15 AIH-naive patients and from 10 healthy individuals. The V3-V4 hyper-variable regions in16S rRNA gene was amplified and sequenced using Illumina MiSeq platform. Significantly lower bacterial diversity in AIH patients was found compared to the controls. A phylum-level analysis showed the overrepresentation of Firmicutes, Bacteroides, and Proteobacteria. At the genus level, AIH-associated enrichment of Faecalibacterium, Blautia, Streptococcus, Haemophilus, Bacteroides, Veillonella, Eubacterium, Lachnospiraceae and Butyricicoccus was reported in contrast to Prevotella, Parabacteroides and Dilaster, which were significantly retracted in such patients. Overall, the predicted metabolic pathways associated with dysbiosis in AIH patients could orchestrate the potential pathogenic roles of gut microbiota in autoimmune disease, though not in a disease-specific manner, calling for future large-scale studies.

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Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine.

Aiden Haghikia, Stefanie Jörg, Alexander Duscha … (2015)

Growing empirical evidence suggests that nutrition and bacterial metabolites might impact the systemic immune response in the context of disease and autoimmunity. We report that long-chain fatty acids (LCFAs) enhanced differentiation and proliferation of T helper 1 (Th1) and/or Th17 cells and impaired their intestinal sequestration via p38-MAPK pathway. Alternatively, dietary short-chain FAs (SCFAs) expanded gut T regulatory (Treg) cells by suppression of the JNK1 and p38 pathway. We used experimental autoimmune encephalomyelitis (EAE) as a model of T cell-mediated autoimmunity to show that LCFAs consistently decreased SCFAs in the gut and exacerbated disease by expanding pathogenic Th1 and/or Th17 cell populations in the small intestine. Treatment with SCFAs ameliorated EAE and reduced axonal damage via long-lasting imprinting on lamina-propria-derived Treg cells. These data demonstrate a direct dietary impact on intestinal-specific, and subsequently central nervous system-specific, Th cell responses in autoimmunity, and thus might have therapeutic implications for autoimmune diseases such as multiple sclerosis.

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An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis

Jun Chen, Kerry Wright, John M Davis … (2016)

Background The adaptive immune response in rheumatoid arthritis (RA) is influenced by an interaction between host genetics and environment, particularly the host microbiome. Association of the gut microbiota with various diseases has been reported, though the specific components of the microbiota that affect the host response leading to disease remain unknown. However, there is limited information on the role of gut microbiota in RA. In this study we aimed to define a microbial and metabolite profile that could predict disease status. In addition, we aimed to generate a humanized model of arthritis to confirm the RA-associated microbe. Methods To identify an RA biomarker profile, the 16S ribosomal DNA of fecal samples from RA patients, first-degree relatives (to rule out environment/background as confounding factors), and random healthy non-RA controls were sequenced. Analysis of metabolites and their association with specific taxa was performed to investigate a potential mechanistic link. The role of an RA-associated microbe was confirmed using a human epithelial cell line and a humanized mouse model of arthritis. Results Patients with RA exhibited decreased gut microbial diversity compared with controls, which correlated with disease duration and autoantibody levels. A taxon-level analysis suggested an expansion of rare taxa, Actinobacteria, with a decrease in abundant taxa in patients with RA compared with controls. Prediction models based on the random forests algorithm suggested that three genera, Collinsella, Eggerthella, and Faecalibacterium, segregated with RA. The abundance of Collinsella correlated strongly with high levels of alpha-aminoadipic acid and asparagine as well as production of the proinflammatory cytokine IL-17A. A role for Collinsella in altering gut permeability and disease severity was confirmed in experimental arthritis. Conclusions These observations suggest dysbiosis in RA patients resulting from the abundance of certain rare bacterial lineages. A correlation between the intestinal microbiota and metabolic signatures could determine a predictive profile for disease causation and progression. Electronic supplementary material The online version of this article (doi:10.1186/s13073-016-0299-7) contains supplementary material, which is available to authorized users.

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Alterations of gut microbiome in autoimmune hepatitis

Yiran Wei, Yanmei Li, Li Yan … (2019)

The significance of the liver-microbiome axis has been increasingly recognised as a major modulator of autoimmunity. The aim of this study was to take advantage of a large well-defined corticosteroids treatment-naïve group of patients with autoimmune hepatitis (AIH) to rigorously characterise gut dysbiosis compared with healthy controls. We performed a cross-sectional study of individuals with AIH (n=91) and matched healthy controls (n=98) by 16S rRNA gene sequencing. An independent cohort of 28 patients and 34 controls was analysed to validate the results. All the patients were collected before corticosteroids therapy. The gut microbiome of steroid treatment-naïve AIH was characterised with lower alpha-diversity (Shannon and observed operational taxonomic units, both p<0.01) and distinct overall microbial composition compared with healthy controls (p=0.002). Depletion of obligate anaerobes and expansion of potential pathobionts including Veillonella were associated with disease status. Of note, Veillonella dispar , the most strongly disease-associated taxa (p=8.85E–8), positively correlated with serum level of aspartate aminotransferase and liver inflammation. Furthermore, the combination of four patients with AIH-associated genera distinguished AIH from controls with an area under curves of approximately 0.8 in both exploration and validation cohorts. In addition, multiple predicted functional modules were altered in the AIH gut microbiome, including lipopolysaccharide biosynthesis as well as metabolism of amino acids that can be processed by bacteria to produce immunomodulatory metabolites. Our study establishes compositional and functional alterations of gut microbiome in AIH and suggests the potential for using gut microbiota as non-invasive biomarkers to assess disease activity.

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Journal

Journal ID (nlm-ta): Microorganisms

Journal ID (iso-abbrev): Microorganisms

Journal ID (publisher-id): microorganisms

Title: Microorganisms

Publisher: MDPI

ISSN (Electronic): 2076-2607

Publication date (Electronic): 06 July 2020

Publication date Collection: July 2020

Volume: 8

Issue: 7

Electronic Location Identifier: 1011

Affiliations

[1 ]Medical Microbiology and Immunology Department, Faculty of Medicine, Assiut University, Assiut 71515, Egypt

[2 ]Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt; mohamedhussien@ 123456azhar.edu.eg (M.R.); elkady4work@ 123456azhar.edu.eg (M.E.A.)

[3 ]Gastroenterology and Tropical Medicine Department, Faculty of Medicine, Assiut University, Assiut 71515, Egypt; mam_elham75@ 123456yahoo.com (E.A.H.); sharafabeer@ 123456yahoo.com (A.S.A.E.-R.)

[4 ]Internal Medicine Department, Gastroenterology and Hepatology Unit, Faculty of Medicine, Assiut University, Assiut 71515, Egypt; Drwaelabbas@ 123456yahoo.com (W.A.A.); mabozaid1980@ 123456aun.edu.eg (M.A.A.A.)

[5 ]Clinical Pathology, Ministry of Health, Assiut 71511, Egypt; roofy2006@ 123456yahoo.com

[6 ]Internal Medicine Department, College of Medicine, University of Cincinnati, Cincinnati, OH 45267-0595, USA

Author notes

[* ]Correspondence: nahlaelsherbiny@ 123456aun.edu.eg (N.M.E.); helal.hetta@ 123456uc.edu (H.F.H.)

Author information

Elham A. Hassan https://orcid.org/0000-0003-2575-758X

Abeer S. Abd El-Rehim https://orcid.org/0000-0002-7549-3394

Helal F. Hetta https://orcid.org/0000-0001-8541-7304

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Publisher ID: microorganisms-08-01011

DOI: 10.3390/microorganisms8071011

PMC ID: 7409351

PubMed ID: 32640728

SO-VID: 17a68acf-d14a-4d3c-825c-1c7941f7a97a

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Autoimmune Hepatitis: Shifts in Gut Microbiota and Metabolic Pathways among Egyptian Patients

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Most cited references 32

Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine.

An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis

Alterations of gut microbiome in autoimmune hepatitis

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