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Cited by 27Liver Disease Diagnosis and TreatmentGut microbiota and healthAlcohol Consumption and Health Effects

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Demonstration of Gut-Barrier Dysfunction in Early Stages of Non-alcoholic Fatty Liver Disease: A Proof-Of-Concept Study

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Kaushal, Kanav, Agarwal, Samagra, Sharma, Sanchit, Goswami, Pooja, Singh, Namrata, Sachdev, Vikas, Poudel, Shekhar, Das, Prasenjit, Yadav, Rajni, Kumar, Dinesh, Pandey, Gaurav, Gunjan, Deepak, Saraya, Anoop·2022·Journal of Clinical and Experimental Hepatology
DOI 10.1016/j.jceh.2022.01.006PMC PMC9257921
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Abstract

Background/aims Gut-barrier dysfunction is well recognized in pathogenesis of both non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). However, comparison of components of this dysfunction between the two etiologies remains unexplored especially in early stages of NAFLD. Methods Components of gut-barrier dysfunction like alterations in intestinal permeability (IP) by lactulose mannitol ratio (LMR) in urine, systemic endotoxemia (IgG and IgM anti-endotoxin antibodies), systemic inflammation (serum tumor necrosis factor alpha [TNF-α] and interleukin-1 [IL-1] levels), tight junction (TJ) proteins expression in duodenal biopsy and stool microbiota composition using Oxford Nanopore MinION device were prospectively evaluated in patients with NAFLD (n = 34) with no cirrhosis, ALD (n = 28) and were compared with disease free controls (n = 20). Results Patients with ALD had more advanced disease than those with NAFLD (median liver stiffness -NAFLD:7.1 kPa [5.9-8.9] vs. ALD:14.3 kPa [9.6-24], P < 0.001]. Median LMR was significantly higher in NAFLD and ALD group when compared to controls (NAFLD 0.054 [0.037-0.17] vs. controls 0.027 [0.021-0.045] (P = 0.001)) and ALD 0.043 [0.03-0.068] vs. controls 0.027 [0.021-0.045] (P = 0.019)]. Anti-endotoxin antibody titer (IgM) (MMU/mL) was lowest in NAFLD 72.9 [3.2-1089.5] compared to ALD 120.6 [20.1-728]) (P = 0.042) and controls 155.3 [23.8-442.9]) (P = 0.021). Median TNF-α (pg/mL) levels were elevated in patients with NAFLD (53.3 [24.5-115]) compared to controls (16.1 [10.8-33.3]) (P < 0.001) and ALD (12.3 [10.1-42.7]) (P < 0.001). Expression of zonulin-1 and claudin-3 in duodenal mucosa was lowest in NAFLD. On principal co-ordinate analysis (PCoA), the global bacterial composition was significantly different across the three groups (PERMANOVA test, P < 0.001). Conclusion While remaining activated in both etiologies, gut-barrier dysfunction abnormalities were more pronounced in NAFLD at early stages compared to ALD despite more advanced disease in the latter.

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  • The multiple hits theory is supported by rodent models of MASH characterised by excess calorie intake, weight gain and onset of insulin resistance in which increased hepatic lipid accumulation is observed, but additional insults are required to initiate inflammation and fibrosis.

    “The 'multiple hits' theory is supported by rodent models of MASH characterised by excess calorie intake, weight gain and the onset of IR in which increased hepatic lipid accumulation is observed, but additional insults are required to initiate inflammation and fibrosis.”

    From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [223]

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  • Additional insults in MASH include altered gut flora and increased intestinal permeability, circadian rhythm misalignment, epigenetic modifications, and changes to the composition of liver myeloid cell populations.

    “These include altered gut flora and an increase in intestinal permeability(222, 223), circadian rhythm misalignment(224), epigenetic modifications(210, 225) and changes to the composition of liver myeloid cell populations(210, 211, 226).”

    From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [223]

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Metadata

Authors
Kaushal, K., Agarwal, S., Sharma, S., Goswami, P., Singh, N., Sachdev, V., Poudel, S., Das, P., Yadav, R., Kumar, D., Pandey, G., Gunjan, D., & Saraya, A.
Affiliations
  • All India Institute of Medical Sciences (IN)
  • Sanjay Gandhi Post Graduate Institute of Medical Sciences (IN)
Corresponding author
Saraya, Anoop
ORCID
Venue
Journal of Clinical and Experimental Hepatology
Publisher
Elsevier BV
Published
2022-07
Volume
12
Issue
4
Pages
1102-1113
ISSN
0973-6883 (ISSN-L)
DOI
10.1016/j.jceh.2022.01.006
PMC
PMC9257921
OpenAlex
W4206927902
Cited by
27
References
3
Citations by year
2026: 5 · 2025: 7 · 2024: 9 · 2023: 4 · 2022: 2
FWCI
3.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Clinical and Experimental Hepatology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
Keywords
non-alcoholic fatty liver disease, alcoholic liver disease, intestinal barrier dysfunction, intestinal permeability, lactulose/mannitol ratio, endotoxemia, anti-endotoxin antibodies, systemic inflammation, TNF-α, interleukin-1, tight junction proteins, duodenal biopsy, gut microbiota, liver stiffness, Oxford Nanopore MinION

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