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Ailioaie, L.M.; Ailioaie, C.; Litscher, G. Gut Microbiota and Mitochondria during Long COVID. Encyclopedia. Available online: (accessed on 17 June 2024).
Ailioaie LM, Ailioaie C, Litscher G. Gut Microbiota and Mitochondria during Long COVID. Encyclopedia. Available at: Accessed June 17, 2024.
Ailioaie, Laura Marinela, Constantin Ailioaie, Gerhard Litscher. "Gut Microbiota and Mitochondria during Long COVID" Encyclopedia, (accessed June 17, 2024).
Ailioaie, L.M., Ailioaie, C., & Litscher, G. (2023, December 11). Gut Microbiota and Mitochondria during Long COVID. In Encyclopedia.
Ailioaie, Laura Marinela, et al. "Gut Microbiota and Mitochondria during Long COVID." Encyclopedia. Web. 11 December, 2023.
Gut Microbiota and Mitochondria during Long COVID

The gut microbiota has been shown to contribute to the regulation of angiotensin-converting enzyme 2 (ACE2) expression in the renin-angiotensin complex through systemic and local pathways. ACE2 is already known to be the cornerstone of SARS-CoV-2 infection in the COVID-19 disease due to the specific coupling of the spike protein of the SARS-CoV-2 virus. As SARS-CoV-2 penetrates the cell membrane, it also affects the mitochondria of infected cells, thereby triggering altered metabolism, mitophagy, and atypical levels of mitochondrial proteins in extracellular vesicles.

immunomodulation long COVID microbiome

1. Molecular and Cellular Pathophysiological Mechanisms at Gut Level in Long COVID

The pathophysiology of LC is a hot, unresolved, current topic that raises the opinions of many experts who have proposed various scenarios, but which generally have roughly the same guidelines. Although the intestine and the lung apparently function separately, these two organs share the same embryonic origin and similar morphological components. In the fetal period, starting at about the 4th week, the lung bud develops as a protrusion of endodermal tissue from the foregut and then forms the laryngotracheal bud. After the 16th week and throughout infancy, the lung continues to develop and mature [1].
Comparing the structures of the lung with those of the intestine, it can be noticed that both are covered with mucous membranes that produce a nitrogenous glycoprotein called mucin, which has a local protective role and a common immunological ability to defend through the mucosa. There is evidence to show that when changes occur in the gut microbiota, signals are also transmitted to the lungs. Thus, gut microbiota and microbial metabolites actively participate in monitoring and regulating lung microbiota composition in cases of inflammation or infection and may even reject lung transplantation [2][3].
The entry of the SARS-CoV-2 virus into the human body will change the microbiota and the balance of microbial metabolites, which will lead to important systemic disorders with organ damage and the appearance of a variety of clinical symptoms. The gut microbiota has been shown to contribute to the regulation of angiotensin-converting enzyme 2 (ACE2) expression in the renin-angiotensin complex through systemic and local pathways. ACE2 is already known to be the cornerstone of SARS-CoV-2 infection in the COVID-19 disease due to the specific coupling of the spike protein of the SARS-CoV-2 virus. While in the intestine, particularly at the “brush” border of proximal and distal enterocytes in the small intestine, ACE2 expression is more than fourfold higher than in other tissues and is reduced in the lung [4], which makes it plausible to consider the intestine as the entry point of the virus into the human body.
The variety of presentations of LC is illustrated in Figure 1. This has delayed scientific progress in unraveling all its pathophysiological mechanisms, and therefore the approach must be multidisciplinary.
Figure 1. A representation of the complex picture of the clinical manifestations of LC, classified into four syndromes, in correlation with the pathophysiological elements. 
Because of research gaps and especially the fluctuation of current hypotheses in the literature, numerous studies are needed to better understand the relationships between the gastrointestinal tract and its involvement in LC, to better manage the disease, and to discover innovative treatments or means of preventive intervention at the digestive tract level [5].
The pathophysiological processes leading to the appearance of the more than 200 symptoms of LC are believed to have a multifactorial etiology that includes host conditions (age, sex, ethnicity, genetic factors, metabolic or endocrine diseases, chronic inflammation, immunological imbalances, and autoimmune diseases), viral agents (occult persistence of SARS-CoV-2 or its viral components and reactivation of latent viruses), and downstream effects (grade of lesions from primary acute SARS-CoV-2 infection, vascular endothelial abnormalities, microclots, thrombosis, neurological signaling dysfunction, reduction in tissue oxygen, and disruption of the gut microbiome) [6][7][8][9][10] (Table 1).
Table 1. The multifactorial etiology of the pathophysiology of LC.


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