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González Rosas Z, Martínez-Jiménez HS, Arroyo-Landín M, Fragoso G, Chávez-Canales M, Hernández M, Rosetti MF, López-Alvarenga JC, Sciutto E, Cárdenas G. Long-Term Neuropsychiatric Sequelae of COVID-19 in an Open Population: A Prospective Pilot Study. J Neuropsychiatry Clin Neurosci 2025:appineuropsych20240040. [PMID: 40384037 DOI: 10.1176/appi.neuropsych.20240040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/20/2025]
Abstract
OBJECTIVE COVID-19 has been associated with a wide range of systemic and neurological complications, known as long COVID or postacute sequelae of COVID-19 (PASC). Such sequelae can be observed among all infected individuals, even among those with a mild disease course. Dysbiosis, a common condition associated with low-grade inflammation, has been proposed as a potential mechanism of PASC by altering levels of circulating lipopolysaccharide (LPS) and the tryptophan pathway metabolites kynurenine and quinolinic acid, known to affect neurocognitive function. The authors evaluated the evolution of neurological, neurocognitive, and neuropsychiatric COVID-19 sequelae and their relationship with circulating LPS and kynurenine and quinolinic acid levels. METHODS A prospective, longitudinal, and analytical study was conducted. Neurological, neurocognitive, and neuropsychiatric assessments of participants who had recovered from COVID-19 and did not require hospitalization during the acute stages of the infection were performed. Peripheral levels of LPS and tryptophan metabolites were measured 1, 3, 6, and 12 months after infection. RESULTS Of 95 participants recruited, 67 COVID-19-convalescent individuals and 20 COVID-19-free individuals were included. Significantly higher occurrences of asthenia, olfaction and taste alterations, headache, memory dysfunction, and systemic symptoms such as dyspnea, cough, and periodontal diseases were found among participants in the COVID-19-convalescent group compared with participants in the comparison group. A significant decrease in kynurenine levels, which correlated with cognitive impairment, was observed among PASC convalescents. CONCLUSIONS Significant neurocognitive and neuropsychiatric impairments were observed among COVID-19-convalescent individuals, along with decreased kynurenine levels, which recovered during a 12-month follow-up period.
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Affiliation(s)
- Zeltzin González Rosas
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (González Rosas, Fragoso, Hernández, Sciutto); Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Mexico City (González Rosas, Martínez-Jiménez, Arroyo-Landín, Cárdenas); Department of Neurology, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Chávez-Canales); Department of Cellular Biology and Physiology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, and Psychopathology and Development Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Rosetti); School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas (López-Alvarenga)
| | - Hanna Samara Martínez-Jiménez
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (González Rosas, Fragoso, Hernández, Sciutto); Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Mexico City (González Rosas, Martínez-Jiménez, Arroyo-Landín, Cárdenas); Department of Neurology, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Chávez-Canales); Department of Cellular Biology and Physiology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, and Psychopathology and Development Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Rosetti); School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas (López-Alvarenga)
| | - Manuel Arroyo-Landín
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (González Rosas, Fragoso, Hernández, Sciutto); Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Mexico City (González Rosas, Martínez-Jiménez, Arroyo-Landín, Cárdenas); Department of Neurology, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Chávez-Canales); Department of Cellular Biology and Physiology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, and Psychopathology and Development Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Rosetti); School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas (López-Alvarenga)
| | - Gladis Fragoso
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (González Rosas, Fragoso, Hernández, Sciutto); Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Mexico City (González Rosas, Martínez-Jiménez, Arroyo-Landín, Cárdenas); Department of Neurology, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Chávez-Canales); Department of Cellular Biology and Physiology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, and Psychopathology and Development Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Rosetti); School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas (López-Alvarenga)
| | - María Chávez-Canales
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (González Rosas, Fragoso, Hernández, Sciutto); Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Mexico City (González Rosas, Martínez-Jiménez, Arroyo-Landín, Cárdenas); Department of Neurology, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Chávez-Canales); Department of Cellular Biology and Physiology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, and Psychopathology and Development Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Rosetti); School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas (López-Alvarenga)
| | - Marisela Hernández
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (González Rosas, Fragoso, Hernández, Sciutto); Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Mexico City (González Rosas, Martínez-Jiménez, Arroyo-Landín, Cárdenas); Department of Neurology, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Chávez-Canales); Department of Cellular Biology and Physiology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, and Psychopathology and Development Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Rosetti); School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas (López-Alvarenga)
| | - Marcos Francisco Rosetti
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (González Rosas, Fragoso, Hernández, Sciutto); Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Mexico City (González Rosas, Martínez-Jiménez, Arroyo-Landín, Cárdenas); Department of Neurology, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Chávez-Canales); Department of Cellular Biology and Physiology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, and Psychopathology and Development Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Rosetti); School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas (López-Alvarenga)
| | - Juan Carlos López-Alvarenga
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (González Rosas, Fragoso, Hernández, Sciutto); Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Mexico City (González Rosas, Martínez-Jiménez, Arroyo-Landín, Cárdenas); Department of Neurology, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Chávez-Canales); Department of Cellular Biology and Physiology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, and Psychopathology and Development Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Rosetti); School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas (López-Alvarenga)
| | - Edda Sciutto
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (González Rosas, Fragoso, Hernández, Sciutto); Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Mexico City (González Rosas, Martínez-Jiménez, Arroyo-Landín, Cárdenas); Department of Neurology, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Chávez-Canales); Department of Cellular Biology and Physiology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, and Psychopathology and Development Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Rosetti); School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas (López-Alvarenga)
| | - Graciela Cárdenas
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (González Rosas, Fragoso, Hernández, Sciutto); Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Mexico City (González Rosas, Martínez-Jiménez, Arroyo-Landín, Cárdenas); Department of Neurology, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Chávez-Canales); Department of Cellular Biology and Physiology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, and Psychopathology and Development Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Rosetti); School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas (López-Alvarenga)
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Dutta S, Chatterjee N, Gallina NLF, Kar S, Koley H, Nanda PK, Biswas O, Das AK, Biswas S, Bhunia AK, Dhar P. Diet, microbiome, and probiotics establish a crucial link in vaccine efficacy. Crit Rev Microbiol 2025:1-26. [PMID: 40110742 DOI: 10.1080/1040841x.2025.2480230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 12/12/2024] [Accepted: 03/10/2025] [Indexed: 03/22/2025]
Abstract
Vaccination plays a critical role in public health by reducing the incidence and prevalence of infectious diseases. The efficacy of a vaccine has numerous determinants, which include age, sex, genetics, environment, geographic location, nutritional status, maternal antibodies, and prior exposure to pathogens. However, little is known about the role of gut microbiome in vaccine efficacy and how it can be targeted through dietary interventions to improve immunological responses. Unveiling this link is imperative, particularly in the post-pandemic world, considering impaired COVID-19 vaccine response observed in dysbiotic individuals. Therefore, this article aims to comprehensively review how diet and probiotics can modulate gut microbiome composition, which is linked to vaccine efficacy. Dietary fiber and polyphenolic compounds derived from plant-based foods improve gut microbial diversity and vaccine efficacy by promoting the growth of short-chain fatty acids-producing microbes. On the other hand, animal-based foods have mixed effects - whey protein and fish oil promote gut eubiosis and vaccine efficacy. In contrast, lard and red meat have adverse effects. Studies further indicate that probiotic supplements exert varied effects, mostly strain and dosage-specific. Interlinking diet, microbiome, probiotics, and vaccines will reveal opportunities for newer research on diet-induced microbiome-manipulated precision vaccination strategies against infectious diseases.
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Affiliation(s)
- Soumam Dutta
- Laboratory of Food Science and Technology, Food and Nutrition Division, University of Calcutta, Kolkata, India
- Division of Bacteriology, ICMR-National Institute for Research in Bacterial Infections, Beliaghata, Kolkata, India
| | - Niloy Chatterjee
- Laboratory of Food Science and Technology, Food and Nutrition Division, University of Calcutta, Kolkata, India
- Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, Salt Lake City, Kolkata, India
| | - Nicholas L F Gallina
- Molecular Food Microbiology Laboratory, Department of Food Science, Purdue University, West Lafayette, IN, USA
- Purdue Institute of Inflammation, Immunology and Infectious Diseases, Purdue University, West Lafayette, IN, USA
| | - Sanjukta Kar
- Division of Bacteriology, ICMR-National Institute for Research in Bacterial Infections, Beliaghata, Kolkata, India
| | - Hemanta Koley
- Division of Bacteriology, ICMR-National Institute for Research in Bacterial Infections, Beliaghata, Kolkata, India
| | - Pramod Kumar Nanda
- Eastern Regional Station, ICAR-Indian Veterinary Research Institute, Kolkata, India
| | - Olipriya Biswas
- Department of Fishery Engineering, West Bengal University of Animal and Fishery Sciences, Kolkata, India
| | - Arun K Das
- Eastern Regional Station, ICAR-Indian Veterinary Research Institute, Kolkata, India
| | - Subhasish Biswas
- Department of Livestock Products Technology, West Bengal University of Animal and Fishery Sciences, Kolkata, India
| | - Arun K Bhunia
- Molecular Food Microbiology Laboratory, Department of Food Science, Purdue University, West Lafayette, IN, USA
- Purdue Institute of Inflammation, Immunology and Infectious Diseases, Purdue University, West Lafayette, IN, USA
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA
| | - Pubali Dhar
- Laboratory of Food Science and Technology, Food and Nutrition Division, University of Calcutta, Kolkata, India
- Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, Salt Lake City, Kolkata, India
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Iqbal NT, Khan H, Khalid A, Mahmood SF, Nasir N, Khanum I, de Siqueira I, Van Voorhis W. Chronic inflammation in post-acute sequelae of COVID-19 modulates gut microbiome: a review of literature on COVID-19 sequelae and gut dysbiosis. Mol Med 2025; 31:22. [PMID: 39849406 PMCID: PMC11756069 DOI: 10.1186/s10020-024-00986-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 11/01/2024] [Indexed: 01/25/2025] Open
Abstract
BACKGROUND Long COVID or Post-acute sequelae of COVID-19 is an emerging syndrome, recognized in COVID-19 patients who suffer from mild to severe illness and do not recover completely. Most studies define Long COVID, through symptoms like fatigue, brain fog, joint pain, and headache prevailing four or more weeks post-initial infection. Global variations in Long COVID presentation and symptoms make it challenging to standardize features of Long COVID. Long COVID appears to be accompanied by an auto-immune multi-faceted syndrome where the virus or viral antigen persistence causes continuous stimulation of the immune response, resulting in multi-organ immune dysregulation. MAIN TEXT This review is focused on understanding the risk factors of Long COVID with a special emphasis on the dysregulation of the gut-brain axis. Two proposed mechanisms are discussed here. The first mechanism is related to the dysfunction of angiotensin-converting enzyme 2 receptor due to Severe Acute Respiratory Syndrome Corona Virus 2 infection, leading to impaired mTOR pathway activation, reduced AMP secretion, and causing dysbiotic changes in the gut. Secondly, gut-brain axis dysregulation accompanied by decreased production of short-chain fatty acids, impaired enteroendocrine cell function, and increased leakiness of the gut, which favors translocation of pathogens or lipopolysaccharide in circulation causing the release of pro-inflammatory cytokines. The altered Hypothalamic-Pituitary-Adrenal axis is accompanied by the reduced level of neurotransmitter, and decreased stimulation of the vagus nerve, which may cause neuroinflammation and dysregulation of serum cortisol levels. The dysbiotic microbiome in Long COVID patients is characterized by a decrease in beneficial short chain fatty acid-producing bacteria (Faecalibacterium, Ruminococcus, Dorea, and Bifidobacterium) and an increase in opportunistic bacteria (Corynebacterium, Streptococcus, Enterococcus). This dysbiosis is transient and may be impacted by interventions including probiotics, and dietary supplements. CONCLUSIONS Further studies are required to understand the geographic variation, racial and ethnic differences in phenotypes of Long COVID, the influence of viral strains on existing and emerging phenotypes, to explore long-term effects of gut dysbiosis, and gut-brain axis dysregulation, as well as the potential role of diet and probiotics in alleviating those symptoms.
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Affiliation(s)
- Najeeha Talat Iqbal
- Department of Biological and Biomedical Sciences, Department of Pediatrics and Child Health, Aga Khan University, Stadium Road, P. O Box 3500, Karachi, 74800, Pakistan.
- Department of Pediatrics & Child Health, Aga Khan University, Karachi, Pakistan.
| | - Hana Khan
- Undergraduate Medical Education (UGME), Year II, Aga Khan University, Karachi, Pakistan
| | - Aqsa Khalid
- Department of Pediatrics & Child Health, Aga Khan University, Karachi, Pakistan
| | | | - Nosheen Nasir
- Department of Medicine, Aga Khan University, Karachi, Pakistan
| | - Iffat Khanum
- Department of Medicine, Aga Khan University, Karachi, Pakistan
| | | | - Wes Van Voorhis
- Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, USA
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Li NN, Kang K, Zhou Y, Liu YQ, Zhang QQ, Luo PY, Wang L, Man MY, Lv JF, Wang XB, Peng YH, Luan FY, Li Y, Zhang JN, Chong Y, Wang YQ, Wang CS, Zhao MY, Yu KJ. Throat microbiota drives alterations in pulmonary alveolar microbiota in patients with septic ARDS. Virulence 2024; 15:2350775. [PMID: 38736041 PMCID: PMC11093027 DOI: 10.1080/21505594.2024.2350775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 04/27/2024] [Indexed: 05/14/2024] Open
Abstract
OBJECTIVES The translocation of intestinal flora has been linked to the colonization of diverse and heavy lower respiratory flora in patients with septic ARDS, and is considered a critical prognostic factor for patients. METHODS On the first and third days of ICU admission, BALF, throat swab, and anal swab were collected, resulting in a total of 288 samples. These samples were analyzed using 16S rRNA analysis and the traceability analysis of new generation technology. RESULTS On the first day, among the top five microbiota species in abundance, four species were found to be identical in BALF and throat samples. Similarly, on the third day, three microbiota species were found to be identical in abundance in both BALF and throat samples. On the first day, 85.16% of microorganisms originated from the throat, 5.79% from the intestines, and 9.05% were unknown. On the third day, 83.52% of microorganisms came from the throat, 4.67% from the intestines, and 11.81% were unknown. Additionally, when regrouping the 46 patients, the results revealed a significant predominance of throat microorganisms in BALF on both the first and third day. Furthermore, as the disease progressed, the proportion of intestinal flora in BALF increased in patients with enterogenic ARDS. CONCLUSIONS In patients with septic ARDS, the main source of lung microbiota is primarily from the throat. Furthermore, the dynamic trend of the microbiota on the first and third day is essentially consistent.It is important to note that the origin of the intestinal flora does not exclude the possibility of its origin from the throat.
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Affiliation(s)
- Na-Na Li
- Departments of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
| | - Kai Kang
- Departments of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
| | - Yang Zhou
- Departments of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
| | - Yan-Qi Liu
- Departments of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
| | - Qian-Qian Zhang
- Departments of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
| | - Pei-Yao Luo
- Departments of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
| | - Lei Wang
- Departments of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
| | - Ming-Yin Man
- Departments of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
- Departments of Critical Care Medicine, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China
| | - Jia-Feng Lv
- Departments of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
| | - Xi-Bo Wang
- Departments of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
| | - Ya-Hui Peng
- Departments of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
| | - Fei-Yu Luan
- Departments of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
| | - Yue Li
- Departments of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
- Departments of Critical Care Medicine, the Second Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
| | - Jian-Nan Zhang
- Departments of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
| | - Yang Chong
- Departments of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
| | - Yi-Qi Wang
- Departments of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
| | - Chang-song Wang
- Departments of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
| | - Ming-yan Zhao
- Departments of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
| | - Kai-jiang Yu
- Departments of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
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Yu LCH. Gastrointestinal pathophysiology in long COVID: Exploring roles of microbiota dysbiosis and serotonin dysregulation in post-infectious bowel symptoms. Life Sci 2024; 358:123153. [PMID: 39454992 DOI: 10.1016/j.lfs.2024.123153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 10/01/2024] [Accepted: 10/14/2024] [Indexed: 10/28/2024]
Abstract
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered an unprecedented public health crisis known as the coronavirus disease 2019 (COVID-19) pandemic. Gastrointestinal (GI) symptoms develop in patients during acute infection and persist after recovery from airway distress in a chronic form of the disease (long COVID). A high incidence of irritable bowel syndrome (IBS) manifested by severe abdominal pain and defecation pattern changes is reported in COVID patients. Although COVID is primarily considered a respiratory disease, fecal shedding of SARS-CoV-2 antigens positively correlates with bowel symptoms. Active viral infection in the GI tract was identified by human intestinal organoid studies showing SARS-CoV-2 replication in gut epithelial cells. In this review, we highlight the key findings in post-COVID bowel symptoms and explore possible mechanisms underlying the pathophysiology of the illness. These mechanisms include mucosal inflammation, gut barrier dysfunction, and microbiota dysbiosis during viral infection. Viral shedding through the GI route may be the primary factor causing the alteration of the microbiome ecosystem, particularly the virome. Recent evidence in experimental models suggested that microbiome dysbiosis could be further aggravated by epithelial barrier damage and immune activation. Moreover, altered microbiota composition has been associated with dysregulated serotonin pathways, resulting in intestinal nerve hypersensitivity. These mechanisms may explain the development of post-infectious IBS-like symptoms in long COVID. Understanding how coronavirus infection affects gut pathophysiology, including microbiome changes, would benefit the therapeutic advancement for managing post-infectious bowel symptoms.
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Affiliation(s)
- Linda Chia-Hui Yu
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
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Fallah A, Sedighian H, Kachuei R, Fooladi AAI. Human microbiome in post-acute COVID-19 syndrome (PACS). CURRENT RESEARCH IN MICROBIAL SCIENCES 2024; 8:100324. [PMID: 39717208 PMCID: PMC11665312 DOI: 10.1016/j.crmicr.2024.100324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2024] Open
Abstract
The global COVID-19 pandemic, which began in 2019, is still ongoing. SARS-CoV-2, also known as the severe acute respiratory syndrome coronavirus 2, is the causative agent. Diarrhea, nausea, and vomiting are common GI symptoms observed in a significant number of COVID-19 patients. Additionally, the respiratory and GI tracts express high level of transmembrane protease serine 2 (TMPRSS2) and angiotensin-converting enzyme-2 (ACE2), making them primary sites for human microbiota and targets for SARS-CoV-2 infection. A growing body of research indicates that individuals with COVID-19 and post-acute COVID-19 syndrome (PACS) exhibit considerable alterations in their microbiome. In various human disorders, including diabetes, obesity, cancer, ulcerative colitis, Crohn's disease, and several viral infections, the microbiota play a significant immunomodulatory role. In this review, we investigate the potential therapeutic implications of the interactions between host microbiota and COVID-19. Microbiota-derived metabolites and components serve as primary mediators of microbiota-host interactions, influencing host immunity. We discuss the various mechanisms through which these metabolites or components produced by the microbiota impact the host's immune response to SARS-CoV-2 infection. Additionally, we address confounding factors in microbiome studies. Finally, we examine and discuss about a range of potential microbiota-based prophylactic measures and treatments for COVID-19 and PACS, as well as their effects on clinical outcomes and disease severity.
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Affiliation(s)
- Arezoo Fallah
- Department of Bacteriology and Virology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hamid Sedighian
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Reza Kachuei
- Molecular Biology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Abbas Ali Imani Fooladi
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Tsao YT, Tsai YJ, Chen CY, Chu YC, Tsai YS, Liao YL. Impact of the COVID-19 Pandemic on Microbial Profiles and Clinical Outcomes in Orbital and Preseptal Cellulitis. Microorganisms 2024; 12:2262. [PMID: 39597651 PMCID: PMC11596107 DOI: 10.3390/microorganisms12112262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 10/31/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024] Open
Abstract
Orbital cellulitis and severe preseptal cellulitis are critical periocular infections with potential vision- and life-threatening implications. The COVID-19 pandemic is hypothesized to have had an influence on their presentation and pathogenesis; however, the real impact remains unclear. In this retrospective multicenter cohort study from January 2017 to December 2022, we analyzed 1285 cases with preseptal or orbital cellulitis in pre-pandemic (2017-2019) and pandemic (2020-2022) cohorts. A notable decrease in hospitalized cases during the pandemic period was observed (97 patients in the pre-pandemic group vs. 54 in the pandemic group, p = 0.004), particularly among individuals aged 30-39 (p = 0.028). Sinusitis remained the leading cause, but odontogenic cases increased (p = 0.025). In addition, microbial diversity decreased during the pandemic, with the effective number of species decreasing from 17.07 to 8.87, accompanied by a rise in antibiotic resistance, notably against erythromycin, oxacillin, penicillin, and metronidazole. While visual outcomes appeared worse in the pandemic group, statistical significance was not reached. These findings suggest that the characteristics, etiology, microbial profiles, resistance patterns, and visual outcomes of orbital and preseptal cellulitis have undergone alterations post-COVID-19 pandemic. Vigilance in clinical management and public health measures is crucial, with further research needed to optimize treatment strategies.
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Affiliation(s)
- Yu-Ting Tsao
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan 333423, Taiwan; (Y.-T.T.); (Y.-J.T.); (Y.-C.C.)
| | - Yueh-Ju Tsai
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan 333423, Taiwan; (Y.-T.T.); (Y.-J.T.); (Y.-C.C.)
- Department of Medicine, Chang Gung University College of Medicine, Taoyuan 333323, Taiwan;
| | - Chau-Yin Chen
- Department of Medicine, Chang Gung University College of Medicine, Taoyuan 333323, Taiwan;
- Department of Ophthalmology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
| | - Yen-Chang Chu
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan 333423, Taiwan; (Y.-T.T.); (Y.-J.T.); (Y.-C.C.)
- Department of Medicine, Chang Gung University College of Medicine, Taoyuan 333323, Taiwan;
| | - Yun-Shan Tsai
- School of Traditional Chinese Medicine, Chang Gung University College of Medicine, Taoyuan 333323, Taiwan;
| | - Yi-Lin Liao
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan 333423, Taiwan; (Y.-T.T.); (Y.-J.T.); (Y.-C.C.)
- Department of Medicine, Chang Gung University College of Medicine, Taoyuan 333323, Taiwan;
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8
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Liu S, Yu C, Tu Q, Zhang Q, Fu Z, Huang Y, He C, Yao L. Bacterial co-infection in COVID-19: a call to stay vigilant. PeerJ 2024; 12:e18041. [PMID: 39308818 PMCID: PMC11416760 DOI: 10.7717/peerj.18041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 08/13/2024] [Indexed: 09/25/2024] Open
Abstract
Co-infection with diverse bacteria is commonly seen in patients infected with the novel coronavirus, SARS-CoV-2. This type of co-infection significantly impacts the occurrence and development of novel coronavirus infection. Bacterial co-pathogens are typically identified in the respiratory system and blood culture, which complicates the diagnosis, treatment, and prognosis of COVID-19, and even exacerbates the severity of disease symptoms and increases mortality rates. However, the status and impact of bacterial co-infections during the COVID-19 pandemic have not been properly studied. Recently, the amount of literature on the co-infection of SARS-CoV-2 and bacteria has gradually increased, enabling a comprehensive discussion on this type of co-infection. In this study, we focus on bacterial infections in the respiratory system and blood of patients with COVID-19 because these infection types significantly affect the severity and mortality of COVID-19. Furthermore, the progression of COVID-19 has markedly elevated the antimicrobial resistance among specific bacteria, such as Klebsiella pneumoniae, in clinical settings including intensive care units (ICUs). Grasping these resistance patterns is pivotal for the optimal utilization and stewardship of antibiotics, including fluoroquinolones. Our study offers insights into these aspects and serves as a fundamental basis for devising effective therapeutic strategies. We primarily sourced our articles from PubMed, ScienceDirect, Scopus, and Google Scholar. We queried these databases using specific search terms related to COVID-19 and its co-infections with bacteria or fungi, and selectively chose relevant articles for inclusion in our review.
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Affiliation(s)
- Shengbi Liu
- Department of Clinical Laboratory, Guiqian International General Hospital, Guiyang, People’s Republic of China
| | - Chao Yu
- Department of Clinical Laboratory, Guiqian International General Hospital, Guiyang, People’s Republic of China
| | - Qin Tu
- Department of Clinical Laboratory, Guiqian International General Hospital, Guiyang, People’s Republic of China
| | - Qianming Zhang
- Department of Clinical Laboratory, Guiqian International General Hospital, Guiyang, People’s Republic of China
| | - Zuowei Fu
- Department of Clinical Laboratory, Guiqian International General Hospital, Guiyang, People’s Republic of China
| | - Yifeng Huang
- Department of Clinical Laboratory, Guiqian International General Hospital, Guiyang, People’s Republic of China
| | - Chuan He
- Department of Clinical Laboratory, Guiqian International General Hospital, Guiyang, People’s Republic of China
| | - Lei Yao
- Department of Clinical Laboratory, Guiqian International General Hospital, Guiyang, People’s Republic of China
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9
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Wilson JD, Dworsky-Fried M, Ismail N. Neurodevelopmental implications of COVID-19-induced gut microbiome dysbiosis in pregnant women. J Reprod Immunol 2024; 165:104300. [PMID: 39004033 DOI: 10.1016/j.jri.2024.104300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 06/25/2024] [Accepted: 07/10/2024] [Indexed: 07/16/2024]
Abstract
The global public health emergency of COVID-19 in January 2020 prompted a surge in research focusing on the pathogenesis and clinical manifestations of the virus. While numerous reports have been published on the acute effects of COVID-19 infection, the review explores the multifaceted long-term implications of COVID-19, with a particular focus on severe maternal COVID-19 infection, gut microbiome dysbiosis, and neurodevelopmental disorders in offspring. Severe COVID-19 infection has been associated with heightened immune system activation and gastrointestinal symptoms. Severe COVID-19 may also result in gut microbiome dysbiosis and a compromised intestinal mucosal barrier, often referred to as 'leaky gut'. Increased gut permeability facilitates the passage of inflammatory cytokines, originating from the inflamed intestinal mucosa and gut, into the bloodstream, thereby influencing fetal development during pregnancy and potentially elevating the risk of neurodevelopmental disorders such as autism and schizophrenia. The current review discusses the role of cytokine signaling molecules, microglia, and synaptic pruning, highlighting their potential involvement in the pathogenesis of neurodevelopmental disorders following maternal COVID-19 infection. Additionally, this review addresses the potential of probiotic interventions to mitigate gut dysbiosis and inflammatory responses associated with COVID-19, offering avenues for future research in optimizing maternal and fetal health outcomes.
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Affiliation(s)
- Jacob D Wilson
- NISE Laboratory, School of Psychology, Faculty of Social Science, University of Ottawa, Ottawa, Ontario K1N 9A4, Canada
| | - Michaela Dworsky-Fried
- NISE Laboratory, School of Psychology, Faculty of Social Science, University of Ottawa, Ottawa, Ontario K1N 9A4, Canada
| | - Nafissa Ismail
- NISE Laboratory, School of Psychology, Faculty of Social Science, University of Ottawa, Ottawa, Ontario K1N 9A4, Canada; LIFE Research Institute, Ottawa, Ontario K1N 6N5, Canada; University of Ottawa Brain and Mind Research Institute, Ottawa, Ontario K1H 8M5, Canada.
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10
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Akinsuyi OS, Xhumari J, Ojeda A, Roesch LFW. Gut permeability among Astronauts during Space missions. LIFE SCIENCES IN SPACE RESEARCH 2024; 41:171-180. [PMID: 38670644 DOI: 10.1016/j.lssr.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 02/02/2024] [Accepted: 03/13/2024] [Indexed: 04/28/2024]
Abstract
The space environment poses substantial challenges to human physiology, including potential disruptions in gastrointestinal health. Gut permeability has only recently become widely acknowledged for its potential to cause adverse effects on a systemic level, rendering it a critical factor to investigate in the context of spaceflight. Here, we propose that astronauts experience the onset of leaky gut during space missions supported by transcriptomic and metagenomic analysis of human and murine samples. A genetic map contributing to intestinal permeability was constructed from a systematic review of current literature. This was referenced against our re-analysis of three independent transcriptomic datasets which revealed significant changes in gene expression patterns associated with the gut barrier. Specifically, in astronauts during flight, we observed a substantial reduction in the expression genes that are crucial for intestinal barrier function, goblet cell development, gut microbiota modulation, and immune responses. Among rodent spaceflight studies, differential expression of cytokines, chemokines, and genes which regulate mucin production and post-translational modifications suggest a similar dysfunction of intestinal permeability. Metagenomic analysis of feces from two murine studies revealed a notable reduction probiotic, short chain fatty acid-producing bacteria and an increase in the Gram-negative pathogens, including Citrobacter rodentium, Enterobacter cloacea, Klebsiella aerogenes, and Proteus hauseri which promote LPS circulation, a recipe for barrier disruption and systemic inflammatory activation. These findings emphasize the critical need to understand the underlying mechanisms and develop interventions to maintain gastrointestinal health in space.
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Affiliation(s)
- Oluwamayowa S Akinsuyi
- Institute of Food and Agricultural Sciences, Department of Microbiology and Cell Science, University of Florida, Gainesville 32611, FL, USA
| | - Jessica Xhumari
- Institute of Food and Agricultural Sciences, Department of Microbiology and Cell Science, University of Florida, Gainesville 32611, FL, USA
| | - Amanda Ojeda
- Institute of Food and Agricultural Sciences, Department of Microbiology and Cell Science, University of Florida, Gainesville 32611, FL, USA
| | - Luiz F W Roesch
- Institute of Food and Agricultural Sciences, Department of Microbiology and Cell Science, University of Florida, Gainesville 32611, FL, USA.
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11
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Trandafir LM, Spoiala EL, Ghiga G, Gimiga N, Budescu PD, Lupu VV, Butnariu L, Cojocaru E, Paduraru G. Impact of COVID-19 on Pediatric Inflammatory Bowel Diseases-From Expectations to Reality. J Pers Med 2024; 14:399. [PMID: 38673026 PMCID: PMC11051136 DOI: 10.3390/jpm14040399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 03/26/2024] [Accepted: 03/29/2024] [Indexed: 04/28/2024] Open
Abstract
Viral infections have always been considered a threat to global health, with numerous outbreaks across time. Despite the relative recent experience with coronavirus-associated diseases such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), severe acute respiratory syndrome-2's (SARS-CoV-2) continuous evolution displays a different behavior. With a tropism for both respiratory and digestive mucosa, coronavirus disease 2019 (COVID-19) and inflammatory bowel disease (IBD) seem to share a particular common background. Current literature offers evidence that viral alteration of the immune system, inflammatory intestinal tissue damage, increased intestinal permeability, incomplete viral clearance with viral antigen persistence, and intestinal dysbiosis, might explain SARS-CoV-2-IBD relationship in terms of etiopathogenesis and evolution. The hyperinflammatory state that both entities have in common explains the lack of success of current IBD therapy, raising the need for new personalized therapeutic options, with better outcomes for IBD and COVID-19 as well. This review aims to summarize the current available data on pediatric IBD evolution, management, and outcomes in the post-COVID period, with an emphasis on the particular aspects of the SARS-CoV-2-IBD relationship in children.
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Affiliation(s)
- Laura Mihaela Trandafir
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (L.M.T.); (E.L.S.); (V.V.L.); (G.P.)
| | - Elena Lia Spoiala
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (L.M.T.); (E.L.S.); (V.V.L.); (G.P.)
| | - Gabriela Ghiga
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (L.M.T.); (E.L.S.); (V.V.L.); (G.P.)
| | - Nicoleta Gimiga
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (L.M.T.); (E.L.S.); (V.V.L.); (G.P.)
| | - Paula-Diana Budescu
- Saint Mary Children Hospital, Vasile Lupu Street, no 62-64, 700309 Iasi, Romania;
| | - Vasile Valeriu Lupu
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (L.M.T.); (E.L.S.); (V.V.L.); (G.P.)
| | - Lacramioara Butnariu
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania;
| | - Elena Cojocaru
- Morpho-Functional Sciences II Department, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania;
| | - Gabriela Paduraru
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (L.M.T.); (E.L.S.); (V.V.L.); (G.P.)
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12
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Rhodes RH, Love GL, Da Silva Lameira F, Sadough Shahmirzadi M, Fox SE, Vander Heide RS. Acute neutrophilic vasculitis (leukocytoclasia) in 36 COVID-19 autopsy brains. Diagn Pathol 2024; 19:33. [PMID: 38360666 PMCID: PMC10870569 DOI: 10.1186/s13000-024-01445-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 01/16/2024] [Indexed: 02/17/2024] Open
Abstract
BACKGROUND Hypercytokinemia, the renin-angiotensin system, hypoxia, immune dysregulation, and vasculopathy with evidence of immune-related damage are implicated in brain morbidity in COVID-19 along with a wide variety of genomic and environmental influences. There is relatively little evidence of direct SARS-CoV-2 brain infection in COVID-19 patients. METHODS Brain histopathology of 36 consecutive autopsies of patients who were RT-PCR positive for SARS-CoV-2 was studied along with findings from contemporary and pre-pandemic historical control groups. Immunostaining for serum and blood cell proteins and for complement components was employed. Microcirculatory wall complement deposition in the COVID-19 cohort was compared to historical control cases. Comparisons also included other relevant clinicopathological and microcirculatory findings in the COVID-19 cohort and control groups. RESULTS The COVID-19 cohort and both the contemporary and historical control groups had the same rate of hypertension, diabetes mellitus, and obesity. The COVID-19 cohort had varying amounts of acute neutrophilic vasculitis with leukocytoclasia in the microcirculation of the brain in all cases. Prominent vascular neutrophilic transmural migration was found in several cases and 25 cases had acute perivasculitis. Paravascular microhemorrhages and petechial hemorrhages (small brain parenchymal hemorrhages) had a slight tendency to be more numerous in cohort cases that displayed less acute neutrophilic vasculitis. Tissue burden of acute neutrophilic vasculitis with leukocytoclasia was the same in control cases as a group, while it was significantly higher in COVID-19 cases. Both the tissue burden of acute neutrophilic vasculitis and the activation of complement components, including membrane attack complex, were significantly higher in microcirculatory channels in COVID-19 cohort brains than in historical controls. CONCLUSIONS Acute neutrophilic vasculitis with leukocytoclasia, acute perivasculitis, and associated paravascular blood extravasation into brain parenchyma constitute the first phase of an immune-related, acute small-vessel inflammatory condition often termed type 3 hypersensitivity vasculitis or leukocytoclastic vasculitis. There is a higher tissue burden of acute neutrophilic vasculitis and an increased level of activated complement components in microcirculatory walls in COVID-19 cases than in pre-pandemic control cases. These findings are consistent with a more extensive small-vessel immune-related vasculitis in COVID-19 cases than in control cases. The pathway(s) and mechanism for these findings are speculative.
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Affiliation(s)
- Roy H Rhodes
- Department of Pathology, Louisiana State University Health Sciences Center, 7th Floor, 2021 Perdido Street, New Orleans, Louisiana, 70112, USA.
| | - Gordon L Love
- Department of Pathology, Louisiana State University Health Sciences Center, 7th Floor, 2021 Perdido Street, New Orleans, Louisiana, 70112, USA
| | - Fernanda Da Silva Lameira
- Department of Pathology, Louisiana State University Health Sciences Center, 7th Floor, 2021 Perdido Street, New Orleans, Louisiana, 70112, USA
- Department of Pathology, Virginia Commonwealth University, Norfolk, Virginia, 23510, USA
| | - Maryam Sadough Shahmirzadi
- Department of Pathology, Louisiana State University Health Sciences Center, 7th Floor, 2021 Perdido Street, New Orleans, Louisiana, 70112, USA
| | - Sharon E Fox
- Department of Pathology, Louisiana State University Health Sciences Center, 7th Floor, 2021 Perdido Street, New Orleans, Louisiana, 70112, USA
- Pathology and Laboratory Medicine Services, Southeast Louisiana Veterans Healthcare System, New Orleans, Louisiana, 70112, USA
| | - Richard S Vander Heide
- Department of Pathology, Louisiana State University Health Sciences Center, 7th Floor, 2021 Perdido Street, New Orleans, Louisiana, 70112, USA
- Marshfield Clinic Health System, Marshfield, Wisconsin, 54449, USA
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13
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Hua S, Latha K, Marlin R, Benmeziane K, Bossevot L, Langlois S, Relouzat F, Dereuddre-Bosquet N, Le Grand R, Cavarelli M. Intestinal immunological events of acute and resolved SARS-CoV-2 infection in non-human primates. Mucosal Immunol 2024; 17:25-40. [PMID: 37827377 DOI: 10.1016/j.mucimm.2023.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/27/2023] [Accepted: 10/04/2023] [Indexed: 10/14/2023]
Abstract
SARS-CoV-2 infection has been associated with intestinal mucosal barrier damage, leading to microbial and endotoxin translocation, heightened inflammatory responses, and aggravated disease outcomes. This study aimed to investigate the immunological mechanisms associated with impaired intestinal barrier function. We conducted a comprehensive analysis of gut damage and inflammation markers and phenotypic characterization of myeloid and lymphoid populations in the ileum and colon of SARS-CoV-2-exposed macaques during both the acute and resolved infection phases. Our findings revealed a significant accumulation of terminally differentiated and activated CD4+ and CD8+ T cells, along with memory B cells, within the gastrointestinal tract up to 43 days after exposure to SARS-CoV-2. This robust infection-induced immune response was accompanied by a notable depletion of plasmacytoid dendritic cells, myeloid dendritic cells, and macrophages, particularly affecting the colon during the resolved infection phase. Additionally, we identified a population of CX3CR1Low inflammatory macrophages associated with intestinal damage during active viral replication. Elevated levels of immune activation and gut damage markers, and perturbation of macrophage homeostasis, persisted even after the resolution of the infection, suggesting potential long-term clinical sequelae. These findings enhance our understanding of gastrointestinal immune pathology following SARS-CoV-2 infection and provide valuable information for developing and testing medical countermeasures.
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Affiliation(s)
- Stéphane Hua
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Krishna Latha
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Romain Marlin
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Keltouma Benmeziane
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Laetitia Bossevot
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Sébastien Langlois
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Francis Relouzat
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Nathalie Dereuddre-Bosquet
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Roger Le Grand
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Mariangela Cavarelli
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France.
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14
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He KY, Lei XY, Zhang L, Wu DH, Li JQ, Lu LY, Laila UE, Cui CY, Xu ZX, Jian YP. Development and management of gastrointestinal symptoms in long-term COVID-19. Front Microbiol 2023; 14:1278479. [PMID: 38156008 PMCID: PMC10752947 DOI: 10.3389/fmicb.2023.1278479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 11/20/2023] [Indexed: 12/30/2023] Open
Abstract
Background Emerging evidence reveals that SARS-CoV-2 possesses the capability to disrupt the gastrointestinal (GI) homeostasis, resulting in the long-term symptoms such as loss of appetite, diarrhea, gastroesophageal reflux, and nausea. In the current review, we summarized recent reports regarding the long-term effects of COVID-19 (long COVID) on the gastrointestine. Objective To provide a narrative review of abundant clinical evidence regarding the development and management of long-term GI symptoms in COVID-19 patients. Results Long-term persistent digestive symptoms are exhibited in a majority of long-COVID patients. SARS-CoV-2 infection of intestinal epithelial cells, cytokine storm, gut dysbiosis, therapeutic drugs, psychological factors and exacerbation of primary underlying diseases lead to long-term GI symptoms in COVID-19 patients. Interventions like probiotics, prebiotics, fecal microbiota transplantation, and antibiotics are proved to be beneficial in preserving intestinal microecological homeostasis and alleviating GI symptoms. Conclusion Timely diagnosis and treatment of GI symptoms in long-COVID patients hold great significance as they may contribute to the mitigation of severe conditions and ultimately lead to the improvement of outcomes of the patients.
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Affiliation(s)
- Kai-Yue He
- School of Life Sciences, Henan University, Kaifeng, China
| | - Xin-Yuan Lei
- School of Life Sciences, Henan University, Kaifeng, China
| | - Lei Zhang
- School of Life Sciences, Henan University, Kaifeng, China
| | - Dan-Hui Wu
- School of Life Sciences, Henan University, Kaifeng, China
| | - Jun-Qi Li
- School of Life Sciences, Henan University, Kaifeng, China
| | - Li-Yuan Lu
- School of Life Sciences, Henan University, Kaifeng, China
| | - Umm E. Laila
- School of Life Sciences, Henan University, Kaifeng, China
| | - Cui-Yun Cui
- Department of Blood Transfusion, Henan Provincial People’s Hospital, Zhengzhou, Henan, China
| | - Zhi-Xiang Xu
- School of Life Sciences, Henan University, Kaifeng, China
| | - Yong-Ping Jian
- School of Life Sciences, Henan University, Kaifeng, China
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15
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Vernia F, Ashktorab H, Cesaro N, Monaco S, Faenza S, Sgamma E, Viscido A, Latella G. COVID-19 and Gastrointestinal Tract: From Pathophysiology to Clinical Manifestations. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1709. [PMID: 37893427 PMCID: PMC10608106 DOI: 10.3390/medicina59101709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 09/10/2023] [Accepted: 09/21/2023] [Indexed: 10/29/2023]
Abstract
Background: Since its first report in Wuhan, China, in December 2019, COVID-19 has become a pandemic, affecting millions of people worldwide. Although the virus primarily affects the respiratory tract, gastrointestinal symptoms are also common. The aim of this narrative review is to provide an overview of the pathophysiology and clinical manifestations of gastrointestinal COVID-19. Methods: We conducted a systematic electronic search of English literature up to January 2023 using Medline, Scopus, and the Cochrane Library, focusing on papers that analyzed the role of SARS-CoV-2 in the gastrointestinal tract. Results: Our review highlights that SARS-CoV-2 directly infects the gastrointestinal tract and can cause symptoms such as diarrhea, nausea/vomiting, abdominal pain, anorexia, loss of taste, and increased liver enzymes. These symptoms result from mucosal barrier damage, inflammation, and changes in the microbiota composition. The exact mechanism of how the virus overcomes the acid gastric environment and leads to the intestinal damage is still being studied. Conclusions: Although vaccination has increased the prevalence of less severe symptoms, the long-term interaction with SARS-CoV-2 remains a concern. Understanding the interplay between SARS-CoV-2 and the gastrointestinal tract is essential for future management of the virus.
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Affiliation(s)
- Filippo Vernia
- Gastroenterology Unit, Division of Gastroenterology, Hepatology, and Nutrition, Department of Life, Health and Environmental Sciences, University of L'Aquila, Piazzale Salvatore Tommasi 1, 67100 L'Aquila, Italy
| | - Hassan Ashktorab
- Department of Medicine, Gastroenterology Division, Howard University College of Medicine, Washington, DC 20060, USA
| | - Nicola Cesaro
- Gastroenterology Unit, Division of Gastroenterology, Hepatology, and Nutrition, Department of Life, Health and Environmental Sciences, University of L'Aquila, Piazzale Salvatore Tommasi 1, 67100 L'Aquila, Italy
| | - Sabrina Monaco
- Gastroenterology Unit, Division of Gastroenterology, Hepatology, and Nutrition, Department of Life, Health and Environmental Sciences, University of L'Aquila, Piazzale Salvatore Tommasi 1, 67100 L'Aquila, Italy
| | - Susanna Faenza
- Gastroenterology Unit, Division of Gastroenterology, Hepatology, and Nutrition, Department of Life, Health and Environmental Sciences, University of L'Aquila, Piazzale Salvatore Tommasi 1, 67100 L'Aquila, Italy
| | - Emanuele Sgamma
- Gastroenterology Unit, Division of Gastroenterology, Hepatology, and Nutrition, Department of Life, Health and Environmental Sciences, University of L'Aquila, Piazzale Salvatore Tommasi 1, 67100 L'Aquila, Italy
| | - Angelo Viscido
- Gastroenterology Unit, Division of Gastroenterology, Hepatology, and Nutrition, Department of Life, Health and Environmental Sciences, University of L'Aquila, Piazzale Salvatore Tommasi 1, 67100 L'Aquila, Italy
| | - Giovanni Latella
- Gastroenterology Unit, Division of Gastroenterology, Hepatology, and Nutrition, Department of Life, Health and Environmental Sciences, University of L'Aquila, Piazzale Salvatore Tommasi 1, 67100 L'Aquila, Italy
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16
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Fortmann SD, Patton MJ, Frey BF, Tipper JL, Reddy SB, Vieira CP, Hanumanthu VS, Sterrett S, Floyd JL, Prasad R, Zucker JD, Crouse AB, Huls F, Chkheidze R, Li P, Erdmann NB, Harrod KS, Gaggar A, Goepfert PA, Grant MB, Might M. Circulating SARS-CoV-2+ megakaryocytes are associated with severe viral infection in COVID-19. Blood Adv 2023; 7:4200-4214. [PMID: 36920790 PMCID: PMC10022176 DOI: 10.1182/bloodadvances.2022009022] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 03/16/2023] Open
Abstract
Several independent lines of evidence suggest that megakaryocytes are dysfunctional in severe COVID-19. Herein, we characterized peripheral circulating megakaryocytes in a large cohort of inpatients with COVID-19 and correlated the subpopulation frequencies with clinical outcomes. Using peripheral blood, we show that megakaryocytes are increased in the systemic circulation in COVID-19, and we identify and validate S100A8/A9 as a defining marker of megakaryocyte dysfunction. We further reveal a subpopulation of S100A8/A9+ megakaryocytes that contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein and RNA. Using flow cytometry of peripheral blood and in vitro studies on SARS-CoV-2-infected primary human megakaryocytes, we demonstrate that megakaryocytes can transfer viral antigens to emerging platelets. Mechanistically, we show that SARS-CoV-2-containing megakaryocytes are nuclear factor κB (NF-κB)-activated, via p65 and p52; express the NF-κB-mediated cytokines interleukin-6 (IL-6) and IL-1β; and display high surface expression of Toll-like receptor 2 (TLR2) and TLR4, canonical drivers of NF-κB. In a cohort of 218 inpatients with COVID-19, we correlate frequencies of megakaryocyte subpopulations with clinical outcomes and show that SARS-CoV-2-containing megakaryocytes are a strong risk factor for mortality and multiorgan injury, including respiratory failure, mechanical ventilation, acute kidney injury, thrombotic events, and intensive care unit admission. Furthermore, we show that SARS-CoV-2+ megakaryocytes are present in lung and brain autopsy tissues from deceased donors who had COVID-19. To our knowledge, this study offers the first evidence implicating SARS-CoV-2+ peripheral megakaryocytes in severe disease and suggests that circulating megakaryocytes warrant investigation in inflammatory disorders beyond COVID-19.
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Affiliation(s)
- Seth D. Fortmann
- Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, AL
- Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, AL
| | - Michael J. Patton
- Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, AL
- Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, Birmingham, AL
| | - Blake F. Frey
- Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, AL
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL
| | - Jennifer L. Tipper
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - Sivani B. Reddy
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL
| | - Cristiano P. Vieira
- Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, AL
| | - Vidya Sagar Hanumanthu
- Division of Clinical Immunology and Rheumatology, Department of Medicine and Microbiology, University of Alabama at Birmingham, Birmingham, AL
| | - Sarah Sterrett
- Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - Jason L. Floyd
- Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, AL
| | - Ram Prasad
- Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, AL
| | - Jeremy D. Zucker
- Biological Sciences Division, Pacific Northwest National Laboratories, Richland, WA
| | - Andrew B. Crouse
- Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, Birmingham, AL
| | - Forest Huls
- Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, Birmingham, AL
| | - Rati Chkheidze
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL
| | - Peng Li
- Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL
| | - Nathaniel B. Erdmann
- Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - Kevin S. Harrod
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - Amit Gaggar
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - Paul A. Goepfert
- Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - Maria B. Grant
- Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, AL
| | - Matthew Might
- Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, Birmingham, AL
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17
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Lerner A, Benzvi C, Vojdani A. SARS-CoV-2 Gut-Targeted Epitopes: Sequence Similarity and Cross-Reactivity Join Together for Molecular Mimicry. Biomedicines 2023; 11:1937. [PMID: 37509576 PMCID: PMC10376948 DOI: 10.3390/biomedicines11071937] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/02/2023] [Accepted: 07/06/2023] [Indexed: 07/30/2023] Open
Abstract
The gastrointestinal tract can be heavily infected by SARS-CoV-2. Being an auto-immunogenic virus, SARS-CoV-2 represents an environmental factor that might play a role in gut-associated autoimmune diseases. However, molecular mimicry between the virus and the intestinal epitopes is under-investigated. The present study aims to elucidate sequence similarity between viral antigens and human enteric sequences, based on known cross-reactivity. SARS-CoV-2 epitopes that cross-react with human gut antigens were explored, and sequence alignment was performed against self-antigens implicated in enteric autoimmune conditions. Experimental SARS-CoV-2 epitopes were aggregated from the Immune Epitope Database (IEDB), while enteric antigens were obtained from the UniProt Knowledgebase. A Pairwise Local Alignment tool, EMBOSS Matcher, was employed for the similarity search. Sequence similarity and targeted cross-reactivity were depicted between 10 pairs of immunoreactive epitopes. Similar pairs were found in four viral proteins and seven enteric antigens related to ulcerative colitis, primary biliary cholangitis, celiac disease, and autoimmune hepatitis. Antibodies made against the viral proteins that were cross-reactive with human gut antigens are involved in several essential cellular functions. The relationship and contribution of those intestinal cross-reactive epitopes to SARS-CoV-2 or its potential contribution to gut auto-immuno-genesis are discussed.
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Affiliation(s)
- Aaron Lerner
- Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, Ramat Gan 52621, Israel;
- Research Department, Ariel University, Ariel 40700, Israel
| | - Carina Benzvi
- Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, Ramat Gan 52621, Israel;
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18
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Xue W, Honda M, Hibi T. Mechanisms of gastrointestinal barrier dysfunction in COVID-19 patients. World J Gastroenterol 2023; 29:2283-2293. [PMID: 37124884 PMCID: PMC10134419 DOI: 10.3748/wjg.v29.i15.2283] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/13/2023] [Accepted: 03/29/2023] [Indexed: 04/14/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a major global public health event, resulting in a significant social and economic burden. Although COVID-19 was initially characterized as an upper respiratory and pulmonary infection, recent evidence suggests that it is a complex disease including gastrointestinal symptoms, such as diarrhea, nausea, and vomiting. Moreover, it remains unclear whether the gastrointestinal symptoms are caused by direct infection of the gastrointestinal tract by SARS-CoV-2 or are the result of systemic immune activation and subsequent dysregulation of homeostatic mechanisms. This review provides a brief overview of the mechanisms by which SARS-CoV-2 disrupts the integrity of the gastrointestinal barrier including the mechanical barrier, chemical barrier, microbial barrier, and immune barrier.
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Affiliation(s)
- Weijie Xue
- Department of Transplantation and Pediatric Surgery, Kumamoto University, Kumamoto 860-8556, Japan
| | - Masaki Honda
- Department of Transplantation and Pediatric Surgery, Kumamoto University, Kumamoto 860-8556, Japan
| | - Taizo Hibi
- Department of Transplantation and Pediatric Surgery, Kumamoto University, Kumamoto 860-8556, Japan
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19
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Gareau MG, Barrett KE. Role of the microbiota-gut-brain axis in postacute COVID syndrome. Am J Physiol Gastrointest Liver Physiol 2023; 324:G322-G328. [PMID: 36880667 PMCID: PMC10042594 DOI: 10.1152/ajpgi.00293.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/27/2023] [Accepted: 02/28/2023] [Indexed: 03/08/2023]
Abstract
The COVID-19 pandemic has resulted in the infection of hundreds of millions of individuals over the past 3 years, coupled with millions of deaths. Along with these more acute impacts of infection, a large subset of patients has developed symptoms that collectively comprise "postacute sequelae of COVID-19" (PASC, also known as long COVID), which can persist for months and maybe even years. In this review, we outline the current knowledge on the role of impaired microbiota-gut-brain (MGB) axis signaling in the development of PASC and the potential mechanisms involved, which may lead to a better understanding of disease progression and treatment options in the future.
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Affiliation(s)
- Mélanie G Gareau
- School of Veterinary Medicine, University of California, Davis, Davis, California, United States
| | - Kim E Barrett
- School of Medicine, University of California, Davis, Sacramento, California, United States
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20
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Saviano A, Brigida M, Petruzziello C, Zanza C, Candelli M, Morabito Loprete MR, Saleem F, Ojetti V. Intestinal Damage, Inflammation and Microbiota Alteration during COVID-19 Infection. Biomedicines 2023; 11:1014. [PMID: 37189632 PMCID: PMC10135602 DOI: 10.3390/biomedicines11041014] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 03/20/2023] [Accepted: 03/22/2023] [Indexed: 03/29/2023] Open
Abstract
BACKGROUND The virus SARS-CoV-2 is responsible for respiratory disorders due to the fact that it mainly infects the respiratory tract using the Angiotensin-converting enzyme 2 (ACE2) receptors. ACE2 receptors are also highly expressed on intestinal cells, representing an important site of entry for the virus in the gut. Literature studies underlined that the virus infects and replicates in the gut epithelial cells, causing gastrointestinal symptoms such as diarrhea, abdominal pain, nausea/vomiting and anorexia. Moreover, the SARS-CoV-2 virus settles into the bloodstream, hyperactivating the platelets and cytokine storms and causing gut-blood barrier damage with an alteration of the gut microbiota, intestinal cell injury, intestinal vessel thrombosis leading to malabsorption, malnutrition, an increasing disease severity and mortality with short and long-period sequelae. CONCLUSION This review summarizes the data on how SARS-CoV-2 effects on the gastrointestinal systems, including the mechanisms of inflammation, relationship with the gut microbiota, endoscopic patterns, and the role of fecal calprotectin, confirming the importance of the digestive system in clinical practice for the diagnosis and follow-up of SARS-CoV-2 infection.
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Affiliation(s)
- Angela Saviano
- Emergency Department, Fondazione Policlinico Universitario A. Gemelli, 00168 Roma, Italy; (A.S.)
| | - Mattia Brigida
- Department of Gastroenterology, Policlinico Tor Vergata, 00133 Roma, Italy
| | - Carmine Petruzziello
- Emergency Department and Internal Medicine, San Carlo di Nancy Hospital, 00165 Roma, Italy
| | - Christian Zanza
- Foundation “Ospedale Alba-Bra” and Department of Anesthesia, Critical Care and Emergency Medicine, Michele and Pietro Ferrero Hospital, 12060 Verduno, Italy
| | - Marcello Candelli
- Emergency Department, Fondazione Policlinico Universitario A. Gemelli, 00168 Roma, Italy; (A.S.)
| | | | - Faiz Saleem
- Emergency Department, Fondazione Policlinico Universitario A. Gemelli, 00168 Roma, Italy; (A.S.)
| | - Veronica Ojetti
- Emergency Department, Fondazione Policlinico Universitario A. Gemelli, 00168 Roma, Italy; (A.S.)
- Internal Medicine, Catholic University of the Sacred Heart, 00168 Roma, Italy
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21
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Tsounis EP, Triantos C, Konstantakis C, Marangos M, Assimakopoulos SF. Intestinal barrier dysfunction as a key driver of severe COVID-19. World J Virol 2023; 12:68-90. [PMID: 37033148 PMCID: PMC10075050 DOI: 10.5501/wjv.v12.i2.68] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/08/2022] [Accepted: 01/16/2023] [Indexed: 03/21/2023] Open
Abstract
The intestinal lumen harbors a diverse consortium of microorganisms that participate in reciprocal crosstalk with intestinal immune cells and with epithelial and endothelial cells, forming a multi-layered barrier that enables the efficient absorption of nutrients without an excessive influx of pathogens. Despite being a lung-centered disease, severe coronavirus disease 2019 (COVID-19) affects multiple systems, including the gastrointestinal tract and the pertinent gut barrier function. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can inflict either direct cytopathic injury to intestinal epithelial and endothelial cells or indirect immune-mediated damage. Alternatively, SARS-CoV-2 undermines the structural integrity of the barrier by modifying the expression of tight junction proteins. In addition, SARS-CoV-2 induces profound alterations to the intestinal microflora at phylogenetic and metabolomic levels (dysbiosis) that are accompanied by disruption of local immune responses. The ensuing dysregulation of the gut-lung axis impairs the ability of the respiratory immune system to elicit robust and timely responses to restrict viral infection. The intestinal vasculature is vulnerable to SARS-CoV-2-induced endothelial injury, which simultaneously triggers the activation of the innate immune and coagulation systems, a condition referred to as “immunothrombosis” that drives severe thrombotic complications. Finally, increased intestinal permeability allows an aberrant dissemination of bacteria, fungi, and endotoxin into the systemic circulation and contributes, to a certain degree, to the over-exuberant immune responses and hyper-inflammation that dictate the severe form of COVID-19. In this review, we aim to elucidate SARS-CoV-2-mediated effects on gut barrier homeostasis and their implications on the progression of the disease.
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Affiliation(s)
- Efthymios P Tsounis
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University Hospital of Patras, Patras 26504, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University Hospital of Patras, Patras 26504, Greece
| | - Christos Konstantakis
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University Hospital of Patras, Patras 26504, Greece
| | - Markos Marangos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, Patras 26504, Greece
| | - Stelios F Assimakopoulos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, Patras 26504, Greece
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22
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Eleftheriotis G, Tsounis EP, Aggeletopoulou I, Dousdampanis P, Triantos C, Mouzaki A, Marangos M, Assimakopoulos SF. Alterations in gut immunological barrier in SARS-CoV-2 infection and their prognostic potential. Front Immunol 2023; 14:1129190. [PMID: 37006316 PMCID: PMC10050566 DOI: 10.3389/fimmu.2023.1129190] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 03/06/2023] [Indexed: 03/17/2023] Open
Abstract
Although coronavirus disease 2019 (COVID-19) is primarily associated with mild respiratory symptoms, a subset of patients may develop more complicated disease with systemic complications and multiple organ injury. The gastrointestinal tract may be directly infected by SARS-CoV-2 or secondarily affected by viremia and the release of inflammatory mediators that cause viral entry from the respiratory epithelium. Impaired intestinal barrier function in SARS-CoV-2 infection is a key factor leading to excessive microbial and endotoxin translocation, which triggers a strong systemic immune response and leads to the development of viral sepsis syndrome with severe sequelae. Multiple components of the gut immune system are affected, resulting in a diminished or dysfunctional gut immunological barrier. Antiviral peptides, inflammatory mediators, immune cell chemotaxis, and secretory immunoglobulins are important parameters that are negatively affected in SARS-CoV-2 infection. Mucosal CD4+ and CD8+ T cells, Th17 cells, neutrophils, dendritic cells, and macrophages are activated, and the number of regulatory T cells decreases, promoting an overactivated immune response with increased expression of type I and III interferons and other proinflammatory cytokines. The changes in the immunologic barrier could be promoted in part by a dysbiotic gut microbiota, through commensal-derived signals and metabolites. On the other hand, the proinflammatory intestinal environment could further compromise the integrity of the intestinal epithelium by promoting enterocyte apoptosis and disruption of tight junctions. This review summarizes the changes in the gut immunological barrier during SARS-CoV-2 infection and their prognostic potential.
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Affiliation(s)
- Gerasimos Eleftheriotis
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Efthymios P. Tsounis
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
- Laboratory of Immunohematology, Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Periklis Dousdampanis
- Department of Renal Diseases, “Agios Andreas” Patras State General Hospital, Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Athanasia Mouzaki
- Laboratory of Immunohematology, Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Markos Marangos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Stelios F. Assimakopoulos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
- *Correspondence: Stelios F. Assimakopoulos,
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23
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Ralli T, Saifi Z, Rathee A, Aeri V, Kohli K. Decoding the bidirectional relationship between gut microbiota and COVID-19. Heliyon 2023; 9:e13801. [PMID: 36811017 PMCID: PMC9936796 DOI: 10.1016/j.heliyon.2023.e13801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 02/09/2023] [Accepted: 02/13/2023] [Indexed: 02/19/2023] Open
Abstract
From late 2019, whole world has been facing COVID-19 pandemic which is caused by SARS-CoV-2 virus. This virus primarily attacks the respiratory tract and enter host cell by binding with angiotensin 2 converting enzyme receptors present on alveoli of the lungs. Despite its binding in the lungs, many patients have reported gastrointestinal symptoms and indeed, RNA of the virus have been found in faecal sample of patients. This observation gave a clue of the involvement of gut-lung axis in this disease development and progression. From several studies reported in past two years, intestinal microbiome has shown to have bidirectional link with lungs i.e., gut dysbiosis increases the tendency of infection with COVID-19 and coronavirus can also cause perturbations in intestinal microbial composition. Thus, in this review we have tried to figure out the mechanisms by which disturbances in the gut composition can increase the susceptibility to COVID-19. Understanding these mechanisms can play a crucial role in decreasing the disease outcomes by manipulating the gut microbiome using prebiotics, probiotics, or combination of two. Even, faecal microbiota transplantation can also show better results, but intensive clinical trials need to be done first.
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Affiliation(s)
- Tanya Ralli
- Department of Pharmaceutics, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi 110062, India
| | - Zoya Saifi
- Department of Pharmaceutics, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi 110062, India
| | - Anjali Rathee
- Department of Pharmacognosy, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi 110062, India
| | - Vidhu Aeri
- Lloyd Institute of Management and Technology, Plot No-11, Knowledge Park-II, Greater Noida, Uttar Pradesh 201306, India
| | - Kanchan Kohli
- Department of Pharmaceutics, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi 110062, India
- Research and Publications, Llyod Institute of Management and Technology, Knowledge Park II, Greater Noida, Uttar Pradesh, India
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24
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Ferroptosis in Rat Lung Tissue during Severe Acute Pancreatitis-Associated Acute Lung Injury: Protection of Qingyi Decoction. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:5827613. [PMID: 36820405 PMCID: PMC9938780 DOI: 10.1155/2023/5827613] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/06/2022] [Accepted: 11/25/2022] [Indexed: 02/13/2023]
Abstract
Qingyi decoction (QYD) has anti-inflammatory pharmacological properties and substantial therapeutic benefits on severe acute pancreatitis (SAP) in clinical practice. However, its protective mechanism against SAP-associated acute lung injury (ALI) remains unclear. In this study, we screened the active ingredients of QYD from the perspective of network pharmacology to identify its core targets and signaling pathways against SAP-associated ALI. Rescue experiments were used to determine the relationship between QYD and ferroptosis. Then, metabolomics and 16s rDNA sequencing were used to identify differential metabolites and microbes in lung tissue. Correlation analysis was utilized to explore the relationship between core targets, signaling pathways, metabolic phenotypes, and microbial flora, sorting out the potential molecular network of QYD against SAP-associated lung ALI. Inflammatory damage was caused by SAP in the rat lung. QYD could effectively alleviate lung injury, improve respiratory function, and significantly reduce serum inflammatory factor levels in SAP rats. Network pharmacology and molecular docking identified three key targets: ALDH2, AnxA1, and ICAM-1. Mechanistically, QYD may inhibit ferroptosis by promoting the ALDH2 expression and suppress neutrophil infiltration by blocking the cleavage of intact AnxA1 and downregulating ICAM-1 expression. Ferroptosis activator counteracts the pulmonary protective effect of QYD in SAP rats. In addition, seven significant differential metabolites were identified in lung tissues. QYD relatively improved the lung microbiome's abundance in SAP rats. Further correlation analysis determined the correlation between ferroptosis, differential metabolites, and differential microbes. In this work, the network pharmacology, metabolomics, and 16s rDNA sequencing were integrated to uncover the mechanism of QYD against SAP-associated ALI. This novel integrated method may play an important role in future research on traditional Chinese medicine.
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25
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SeyedAlinaghi S, Afzalian A, Pashaei Z, Varshochi S, Karimi A, Mojdeganlou H, Mojdeganlou P, Razi A, Ghanadinezhad F, Shojaei A, Amiri A, Dashti M, Ghasemzadeh A, Dadras O, Mehraeen E, Afsahi AM. Gut microbiota and COVID-19: A systematic review. Health Sci Rep 2023; 6:e1080. [PMID: 36721396 PMCID: PMC9881458 DOI: 10.1002/hsr2.1080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/24/2022] [Accepted: 01/11/2023] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND AND AIMS Alteration in humans' gut microbiota was reported in patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The gut and upper respiratory tract (URT) microbiota harbor a dynamic and complex population of microorganisms and have strong interaction with host immune system homeostasis. However, our knowledge about microbiota and its association with SARS-CoV-2 is still limited. We aimed to systematically review the effects of gut microbiota on the SARS-CoV-2 infection and its severity and the impact that SARS-CoV-2 could have on the gut microbiota. METHODS We searched the keywords in the online databases of Web of Science, Scopus, PubMed, and Cochrane on December 31, 2021. After duplicate removal, we performed the screening process in two stages; title/abstract and then full-text screening. The data of the eligible studies were extracted into a pre-designed word table. This study adhered to the PRISMA checklist and Newcastle-Ottawa Scale Bias Assessment tool. RESULTS Sixty-three publications were included in this review. Our study shows that among COVID-19 patients, particularly moderate to severe cases, the gut and lung microbiota was different compared to healthy individuals. In addition, the severity, and viral load of COVID-19 disease would probably also be influenced by the gut, and lung microbiota's composition. CONCLUSION Our study concludes that there was a significant difference in the composition of the URT, and gut microbiota in COVID-19 patients compared to the general healthy individuals, with an increase in opportunistic pathogens. Further, research is needed to investigate the probable bidirectional association of COVID-19 and human microbiome.
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Affiliation(s)
- SeyedAhmad SeyedAlinaghi
- Iranian Research Center for HIV/AIDS, Iranian Institute for Reduction of High Risk BehaviorsTehran University of Medical SciencesTehranIran
| | - Arian Afzalian
- School of MedicineTehran University of Medical SciencesTehranIran
| | - Zahra Pashaei
- Iranian Research Center for HIV/AIDS, Iranian Institute for Reduction of High Risk BehaviorsTehran University of Medical SciencesTehranIran
| | - Sanaz Varshochi
- School of MedicineTehran University of Medical SciencesTehranIran
| | - Amirali Karimi
- School of MedicineTehran University of Medical SciencesTehranIran
| | | | | | - Armin Razi
- School of MedicineTehran University of Medical SciencesTehranIran
| | | | - Alireza Shojaei
- Iranian Research Center for HIV/AIDS, Iranian Institute for Reduction of High Risk BehaviorsTehran University of Medical SciencesTehranIran
| | - Ava Amiri
- Iranian Research Center for HIV/AIDS, Iranian Institute for Reduction of High Risk BehaviorsTehran University of Medical SciencesTehranIran
| | - Mohsen Dashti
- Department of RadiologyTabriz University of Medical SciencesTabrizIran
| | | | - Omid Dadras
- Iranian Research Center for HIV/AIDS, Iranian Institute for Reduction of High Risk BehaviorsTehran University of Medical SciencesTehranIran
- Department of Global Public Health and Primary CareUniversity of BergenBergenNorway
| | - Esmaeil Mehraeen
- Department of Health Information TechnologyKhalkhal University of Medical SciencesKhalkhalIran
| | - Amir Masoud Afsahi
- Department of RadiologyUniversity of California, San Diego (UCSD)CaliforniaUSA
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26
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Li J, Ghosh TS, McCann R, Mallon P, Hill C, Draper L, Schult D, Fanning LJ, Shannon R, Sadlier C, Horgan M, O’Mahony L, O’Toole PW. Robust cross-cohort gut microbiome associations with COVID-19 severity. Gut Microbes 2023; 15:2242615. [PMID: 37550964 PMCID: PMC10411309 DOI: 10.1080/19490976.2023.2242615] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 07/07/2023] [Accepted: 07/26/2023] [Indexed: 08/09/2023] Open
Abstract
Although many recent studies have examined associations between the gut microbiome and COVID-19 disease severity in individual patient cohorts, questions remain on the robustness across international cohorts of the biomarkers they reported. Here, we performed a meta-analysis of eight shotgun metagenomic studies of COVID-19 patients (comprising 1,023 stool samples) and 23 > 16S rRNA gene amplicon sequencing (16S) cohorts (2,415 total stool samples). We found that disease severity (as defined by the WHO clinical progression scale) was associated with taxonomic and functional microbiome differences. This alteration in gut microbiome configuration peaks at days 7-30 post diagnosis, after which the gut microbiome returns to a configuration that becomes more similar to that of healthy controls over time. Furthermore, we identified a core set of species that were consistently associated with disease severity across shotgun metagenomic and 16S cohorts, and whose abundance can accurately predict disease severity category of SARS-CoV-2 infected subjects, with Actinomyces oris abundance predicting population-level mortality rate of COVID-19. Additionally, we used relational diet-microbiome databases constructed from cohort studies to predict microbiota-targeted diet patterns that would modulate gut microbiota composition toward that of healthy controls. Finally, we demonstrated the association of disease severity with the composition of intestinal archaeal, fungal, viral, and parasitic communities. Collectively, this study has identified robust COVID-19 microbiome biomarkers, established accurate predictive models as a basis for clinical prognostic tests for disease severity, and proposed biomarker-targeted diets for managing COVID-19 infection.
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Affiliation(s)
- Junhui Li
- School of Microbiology, University College Cork, Cork, Ireland
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Tarini Shankar Ghosh
- School of Microbiology, University College Cork, Cork, Ireland
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Rachel McCann
- Centre for Experimental Pathogen Host Research, School of Medicine, University College Dublin, St Vincent’s University Hospital, Dublin, Ireland
| | - Patrick Mallon
- Centre for Experimental Pathogen Host Research, School of Medicine, University College Dublin, St Vincent’s University Hospital, Dublin, Ireland
| | - Colin Hill
- School of Microbiology, University College Cork, Cork, Ireland
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Lorraine Draper
- School of Microbiology, University College Cork, Cork, Ireland
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - David Schult
- Department of Internal Medicine II, Klinikum Rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Liam J. Fanning
- Department of Medicine, University College Cork, Cork, Ireland
| | - Robert Shannon
- Department of Infectious Diseases, Cork University Hospital, Cork, Ireland
| | - Corinna Sadlier
- Department of Medicine, University College Cork, Cork, Ireland
- Department of Infectious Diseases, Cork University Hospital, Cork, Ireland
| | - Mary Horgan
- Department of Medicine, University College Cork, Cork, Ireland
- Department of Infectious Diseases, Cork University Hospital, Cork, Ireland
| | - Liam O’Mahony
- School of Microbiology, University College Cork, Cork, Ireland
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- Department of Medicine, University College Cork, Cork, Ireland
| | - Paul W. O’Toole
- School of Microbiology, University College Cork, Cork, Ireland
- APC Microbiome Ireland, University College Cork, Cork, Ireland
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27
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Wang M, Zhang Y, Li C, Chang W, Zhang L. The relationship between gut microbiota and COVID-19 progression: new insights into immunopathogenesis and treatment. Front Immunol 2023; 14:1180336. [PMID: 37205106 PMCID: PMC10185909 DOI: 10.3389/fimmu.2023.1180336] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 04/17/2023] [Indexed: 05/21/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a global health crisis. Increasing evidence underlines the key role of competent immune responses in resisting SARS-CoV-2 infection and manifests the disastrous consequence of host immune dysregulation. Elucidating the mechanisms responsible for deregulated host immunity in COVID-19 may provide a theoretical basis for further research on new treatment modalities. Gut microbiota comprises trillions of microorganisms colonizing the human gastrointestinal tract and has a vital role in immune homeostasis and the gut-lung crosstalk. Particularly, SARS-CoV-2 infection can lead to the disruption of gut microbiota equilibrium, a condition called gut dysbiosis. Due to its regulatory effect on host immunity, gut microbiota has recently received considerable attention in the field of SARS-CoV-2 immunopathology. Imbalanced gut microbiota can fuel COVID-19 progression through production of bioactive metabolites, intestinal metabolism, enhancement of the cytokine storm, exaggeration of inflammation, regulation of adaptive immunity and other aspects. In this review, we provide an overview of the alterations in gut microbiota in COVID-19 patients, and their effects on individuals' susceptibility to viral infection and COVID-19 progression. Moreover, we summarize currently available data on the critical role of the bidirectional regulation between intestinal microbes and host immunity in SARS-CoV-2-induced pathology, and highlight the immunomodulatory mechanisms of gut microbiota contributing to COVID-19 pathogenesis. In addition, we discuss the therapeutic benefits and future perspectives of microbiota-targeted interventions including faecal microbiota transplantation (FMT), bacteriotherapy and traditional Chinese medicine (TCM) in COVID-19 treatment.
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Affiliation(s)
- Man Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
- *Correspondence: Man Wang, ; Chunmei Li,
| | - Yuan Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Chunmei Li
- Department of Radiology, Qingdao Municipal Hospital, Qingdao, China
- *Correspondence: Man Wang, ; Chunmei Li,
| | - Wenguang Chang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Lei Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
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28
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Vakili K, Fathi M, Yaghoobpoor S, Sayehmiri F, Nazerian Y, Nazerian A, Mohamadkhani A, Khodabakhsh P, Réus GZ, Hajibeygi R, Rezaei-Tavirani M. The contribution of gut-brain axis to development of neurological symptoms in COVID-19 recovered patients: A hypothesis and review of literature. Front Cell Infect Microbiol 2022; 12:983089. [PMID: 36619768 PMCID: PMC9815719 DOI: 10.3389/fcimb.2022.983089] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 10/25/2022] [Indexed: 12/24/2022] Open
Abstract
The gut microbiota undergoes significant alterations in response to viral infections, particularly the novel SARS-CoV-2. As impaired gut microbiota can trigger numerous neurological disorders, we suggest that the long-term neurological symptoms of COVID-19 may be related to intestinal microbiota disorders in these patients. Thus, we have gathered available information on how the virus can affect the microbiota of gastrointestinal systems, both in the acute and the recovery phase of the disease, and described several mechanisms through which this gut dysbiosis can lead to long-term neurological disorders, such as Guillain-Barre syndrome, chronic fatigue, psychiatric disorders such as depression and anxiety, and even neurodegenerative diseases such as Alzheimer's and Parkinson's disease. These mechanisms may be mediated by inflammatory cytokines, as well as certain chemicals such as gastrointestinal hormones (e.g., CCK), neurotransmitters (e.g., 5-HT), etc. (e.g., short-chain fatty acids), and the autonomic nervous system. In addition to the direct influences of the virus, repurposed medications used for COVID-19 patients can also play a role in gut dysbiosis. In conclusion, although there are many dark spots in our current knowledge of the mechanism of COVID-19-related gut-brain axis disturbance, based on available evidence, we can hypothesize that these two phenomena are more than just a coincidence and highly recommend large-scale epidemiologic studies in the future.
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Affiliation(s)
- Kimia Vakili
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mobina Fathi
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shirin Yaghoobpoor
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Sayehmiri
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yasaman Nazerian
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Ashraf Mohamadkhani
- Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Pariya Khodabakhsh
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Gislaine Z. Réus
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Ramtin Hajibeygi
- Department of Cardiology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mostafa Rezaei-Tavirani
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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29
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Neag MA, Vulturar DM, Gherman D, Burlacu CC, Todea DA, Buzoianu AD. Gastrointestinal microbiota: A predictor of COVID-19 severity? World J Gastroenterol 2022; 28:6328-6344. [PMID: 36533107 PMCID: PMC9753053 DOI: 10.3748/wjg.v28.i45.6328] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/26/2022] [Accepted: 11/17/2022] [Indexed: 12/02/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19), caused by a severe acute respiratory syndrome coronavirus 2 infection, has raised serious concerns worldwide over the past 3 years. The severity and clinical course of COVID-19 depends on many factors (e.g., associated comorbidities, age, etc) and may have various clinical and imaging findings, which raises management concerns. Gut microbiota composition is known to influence respiratory disease, and respiratory viral infection can also influence gut microbiota. Gut and lung microbiota and their relationship (gut-lung axis) can act as modulators of inflammation. Modulating the intestinal microbiota, by improving its composition and diversity through nutraceutical agents, can have a positive impact in the prophylaxis/treatment of COVID-19.
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Affiliation(s)
- Maria Adriana Neag
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca 400337, Romania
| | - Damiana-Maria Vulturar
- Department of Pneumology, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca 400332, Romania
| | - Diana Gherman
- Department of Radiology, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca 400347, Romania
| | - Codrin-Constantin Burlacu
- Faculty of Medicine, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca 400347, Romania
| | - Doina Adina Todea
- Department of Pneumology, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca 400332, Romania
| | - Anca Dana Buzoianu
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca 400337, Romania
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30
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Matthews PC, Campbell C, Săndulescu O, Matičič M, Ruta SM, Rivero-Juárez A, van Welzen BJ, Tan BK, Garcia F, Gherlan GS, Çınar G, Hasanoğlu İ, Gmizić I, Nicolini LA, Santos L, Sargsyants N, Velikov P, Habibović S, Fourati S, Židovec-Lepej S, Herder V, Dudman S, Miron VD, Irving W, Şahin GÖ. Acute severe hepatitis outbreak in children: A perfect storm. What do we know, and what questions remain? Front Pharmacol 2022; 13:1062408. [PMID: 36506522 PMCID: PMC9732095 DOI: 10.3389/fphar.2022.1062408] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 11/04/2022] [Indexed: 11/27/2022] Open
Abstract
During the first half of 2022, the World Health Organization reported an outbreak of acute severe hepatitis of unknown aetiology (AS-Hep-UA) in children, following initial alerts from the United Kingdom (UK) where a cluster of cases was first observed in previously well children aged <6 years. Sporadic cases were then reported across Europe and worldwide, although in most countries incidence did not increase above the expected baseline. There were no consistent epidemiological links between cases, and microbiological investigations ruled out known infectious causes of hepatitis. In this review, we explore the evidence for the role of viral infection, superimposed on a specific host genetic background, as a trigger for liver pathology. This hypothesis is based on a high prevalence of Human Adenovirus (HAdV) 41F in affected children, together with metagenomic evidence of adeno-associated virus (Adeno-associated viruses)-2, which is a putative trigger for an immune-mediated liver injury. Roles for superantigen-mediated pathology have also been explored, with a focus on the potential contribution of SARS-CoV-2 infection. Affected children also had a high frequency of the MHC allele HLA-DRB1*04:01, supporting an immunological predisposition, and may have been vulnerable to viral coinfections due to disruption in normal patterns of exposure and immunity as a result of population lockdowns during the COVID-19 pandemic. We discuss areas of ongoing uncertainty, and highlight the need for ongoing scrutiny to inform clinical and public health interventions for this outbreak and for others that may evolve in future.
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Affiliation(s)
- Philippa C. Matthews
- The Francis Crick Institute, London, United Kingdom
- Division of Infection and Immunity, University College London, London, United Kingdom
- Department of Infection, University College London Hospitals, London, United Kingdom
| | - Cori Campbell
- Nuffield Department of Medicine, University of Oxford, Oxford, England
| | - Oana Săndulescu
- Department of Infectious Diseases, National Institute for Infectious Diseases-Prof. Dr. Matei Balş, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Mojca Matičič
- Faculty of Medicine, Clinic for Infectious Diseases and Febrile Illnesses, University Medical Centre Ljubljana, University of Ljubljana, Ljubljana, Slovenia
| | - Simona Maria Ruta
- Virology Department, Stefan S. Nicolau Institute of Virology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
| | - Antonio Rivero-Juárez
- Hospital Universitario Reina Sofía, Instituto Maimónides de Investigación Biomédica de Córdoba, Universidad de Córdoba, Córdoba, Spain
| | - Berend Joost van Welzen
- Department of Internal Medicine and Infectious Diseases, University Medical Centre Utrecht, Utrecht, Netherlands
| | - Boun Kim Tan
- INSERM U1052, Department of Intensive Care Unit, Hôpital Lyon Sud, Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | - Federico Garcia
- Microbiology Department, Instituto de Investigacion Ibs.Granada and Ciber de Enfermedades Infecciosas (CIBERINFEC), University Hospital San Cecilio, Granada, Spain
| | - George Sebastian Gherlan
- Department of Infectious Diseases, “Dr. Victor Babes” Clinical Hospital of Infectious and Tropical Diseases, Bucharest, Romania
| | - Güle Çınar
- Department of Infectious Diseases and Clinical Microbiology, Ankara University Faculty of Medicine, Ankara, Turkey
| | - İmran Hasanoğlu
- Department of Infectious Disease and Clinical Microbiology, Ankara City Hospital, Ankara Yıldırım Beyazıt University, Ankara, Turkey
| | - Ivana Gmizić
- Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Belgrade, Serbia
| | - Laura Ambra Nicolini
- Division of Infectious Diseases , Ospedale Policlinico San Martino, Genova, Italy
| | - Lurdes Santos
- Nephrology and Infectious Diseases R&D, Infectious Diseases Intensive Care Unit, Faculty of Medicine of University of Porto, Centro Hospitalar Universitário São João, I3S - Instituto de Investigação e Inovaçãoem Saúde, University of Porto, Porto, Portugal
| | - Narina Sargsyants
- Ministry of Health, National Centre for Infectious Diseases, National Institute of Health, Yerevan, Armenia
| | - Petar Velikov
- Infectious Diseases Hospital Prof. Ivan Kirov and Department of Infectious Diseases, Parasitology and Tropical Medicine, Medical University of Sofia, Sofia, Bulgaria
| | - Selma Habibović
- Department of Microbiology, Public Health Institute Novi Pazar, Novi Pazar, Serbia
| | - Slim Fourati
- Department of Virology, INSERM, Henri Mondor Hospital, Assistance Publique-Hôpitaux de Paris, Institut Mondor de Recherche Biomédicale, Université Paris-Est, Créteil, France
| | - Snježana Židovec-Lepej
- Department of Immunological and Molecular Diagnostics, University Hospital for Infectious Diseases “Dr Fran Mihaljevic”, Zagreb, Croatia
| | - Vanessa Herder
- Medical Research Council-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, United Kingdom
| | - Susanne Dudman
- Department of Microbiology, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Victor Daniel Miron
- National Institute for Mother and Child Health “Alessandrescu-Rusescu”, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - William Irving
- NIHR Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, United Kingdom
| | - Gülşen Özkaya Şahin
- Department of Laboratory Medicine, Section of Clinical Microbiology, Region Skåne, Lund, Sweden
- Department of Translational Medicine, Lund University, Malmö, Sweden
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31
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Assante G, Tourna A, Carpani R, Ferrari F, Prati D, Peyvandi F, Blasi F, Bandera A, Le Guennec A, Chokshi S, Patel VC, Cox IJ, Valenti L, Youngson NA. Reduced circulating FABP2 in patients with moderate to severe COVID-19 may indicate enterocyte functional change rather than cell death. Sci Rep 2022; 12:18792. [PMID: 36335131 PMCID: PMC9637119 DOI: 10.1038/s41598-022-23282-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 10/25/2022] [Indexed: 11/08/2022] Open
Abstract
The gut is of importance in the pathology of COVID-19 both as a route of infection, and gut dysfunction influencing the severity of disease. Systemic changes caused by SARS-CoV-2 gut infection include alterations in circulating levels of metabolites, nutrients and microbial products which alter immune and inflammatory responses. Circulating plasma markers for gut inflammation and damage such as zonulin, lipopolysaccharide and β-glycan increase in plasma along with severity of disease. However, Intestinal Fatty Acid Binding Protein / Fatty Acid Binding Protein 2 (I-FABP/FABP2), a widely used biomarker for gut cell death, has paradoxically been shown to be reduced in moderate to severe COVID-19. We also found this pattern in a pilot cohort of mild (n = 18) and moderately severe (n = 19) COVID-19 patients in Milan from March to June 2020. These patients were part of the first phase of COVID-19 in Europe and were therefore all unvaccinated. After exclusion of outliers, patients with more severe vs milder disease showed reduced FABP2 levels (median [IQR]) (124 [368] vs. 274 [558] pg/mL, P < 0.01). A reduction in NMR measured plasma relative lipid-CH3 levels approached significance (median [IQR]) (0.081 [0.011] vs. 0.073 [0.024], P = 0.06). Changes in circulating lipid levels are another feature commonly observed in severe COVID-19 and a weak positive correlation was observed in the more severe group between reduced FABP2 and reduced relative lipid-CH3 and lipid-CH2 levels. FABP2 is a key regulator of enterocyte lipid import, a process which is inhibited by gut SARS-CoV-2 infection. We propose that the reduced circulating FABP2 in moderate to severe COVID-19 is a marker of infected enterocyte functional change rather than gut damage, which could also contribute to the development of hypolipidemia in patients with more severe disease.
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Affiliation(s)
- G Assante
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK
- Faculty of Life Sciences & Medicine, King's College, London, UK
| | - A Tourna
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK
- Faculty of Life Sciences & Medicine, King's College, London, UK
| | - R Carpani
- Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - F Ferrari
- Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - D Prati
- Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - F Peyvandi
- Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
- Department of Pathophysiology and Transplantation, Università Degli Studi Di Milano, Milan, Italy
| | - F Blasi
- Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
- Department of Pathophysiology and Transplantation, Università Degli Studi Di Milano, Milan, Italy
| | - A Bandera
- Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
- Department of Pathophysiology and Transplantation, Università Degli Studi Di Milano, Milan, Italy
| | - A Le Guennec
- Randall Centre for Cell & Molecular Biophysics, King's College, London, UK
| | - S Chokshi
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK
- Faculty of Life Sciences & Medicine, King's College, London, UK
| | - V C Patel
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK
- Faculty of Life Sciences & Medicine, King's College, London, UK
- Institute of Liver Studies, King's College Hospital, London, UK
| | - I J Cox
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK.
- Faculty of Life Sciences & Medicine, King's College, London, UK.
| | - L Valenti
- Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
- Department of Pathophysiology and Transplantation, Università Degli Studi Di Milano, Milan, Italy.
| | - N A Youngson
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK.
- Faculty of Life Sciences & Medicine, King's College, London, UK.
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32
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Shen S, Gong M, Wang G, Dua K, Xu J, Xu X, Liu G. COVID-19 and Gut Injury. Nutrients 2022; 14:nu14204409. [PMID: 36297092 PMCID: PMC9608818 DOI: 10.3390/nu14204409] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/11/2022] [Accepted: 10/18/2022] [Indexed: 01/28/2023] Open
Abstract
COVID-19 induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently a pandemic and it has led to more than 620 million patients with 6.56 million deaths globally. Males are more susceptible to COVID-19 infection and associated with a higher chance to develop severe COVID-19 than females. Aged people are at a high risk of COVID-19 infection, while young children have also increased cases. COVID-19 patients typically develop respiratory system pathologies, however symptoms in the gastrointestinal (GI) tract are also very common. Inflammatory cell recruitments and their secreted cytokines are found in the GI tract in COVID-19 patients. Microbiota changes are the key feature in COVID-19 patients with gut injury. Here, we review all current known mechanisms of COVID-19-induced gut injury, and the most acceptable one is that SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) receptor on host cells in the GI tract. Interestingly, inflammatory bowel disease (IBD) is an inflammatory disorder, but the patients with IBD do not have the increased risk to develop COVID-19. There is currently no cure for COVID-19, but anti-viruses and monoclonal antibodies reduce viral load and shorten the recovery time of the disease. We summarize current therapeutics that target symptoms in the GI tract, including probiotics, ACE2 inhibitors and nutrients. These are promising therapeutic options for COVID-19-induced gut injury.
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Affiliation(s)
- Sj Shen
- UNSW Microbiome Research Centre, St George and Sutherland Clinical Campus, University of New South Wales, Sydney, NSW 2217, Australia
| | - Muxue Gong
- School of Clinical Medicine, Bengbu Medicine College, Bengbu 233030, China
| | - Gang Wang
- Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW 2007, Australia
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Jincheng Xu
- Stomatology Department, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, China
- School of Dental Medicine, Bengbu Medical College, Bengbu 233030, China
| | - Xiaoyue Xu
- School of Population Health, University of New South Wales, Sydney, NSW 2052, Australia
| | - Gang Liu
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
- Centre for Inflammation, Centenary Institute, Camperdown, NSW 2050, Australia
- Correspondence:
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33
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Clerbaux LA, Fillipovska J, Muñoz A, Petrillo M, Coecke S, Amorim MJ, Grenga L. Mechanisms Leading to Gut Dysbiosis in COVID-19: Current Evidence and Uncertainties Based on Adverse Outcome Pathways. J Clin Med 2022; 11:5400. [PMID: 36143044 PMCID: PMC9505288 DOI: 10.3390/jcm11185400] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/24/2022] [Accepted: 09/09/2022] [Indexed: 02/06/2023] Open
Abstract
Alteration in gut microbiota has been associated with COVID-19. However, the underlying mechanisms remain poorly understood. Here, we outlined three potential interconnected mechanistic pathways leading to gut dysbiosis as an adverse outcome following SARS-CoV-2 presence in the gastrointestinal tract. Evidence from the literature and current uncertainties are reported for each step of the different pathways. One pathway investigates evidence that intestinal infection by SARS-CoV-2 inducing intestinal inflammation alters the gut microbiota. Another pathway links the binding of viral S protein to angiotensin-converting enzyme 2 (ACE2) to the dysregulation of this receptor, essential in intestinal homeostasis-notably for amino acid metabolism-leading to gut dysbiosis. Additionally, SARS-CoV-2 could induce gut dysbiosis by infecting intestinal bacteria. Assessing current evidence within the Adverse Outcome Pathway framework justifies confidence in the proposed mechanisms to support disease management and permits the identification of inconsistencies and knowledge gaps to orient further research.
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Affiliation(s)
| | | | - Amalia Muñoz
- European Commission, Joint Research Centre (JRC), 2440 Geel, Belgium
| | | | - Sandra Coecke
- European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy
| | - Maria-Joao Amorim
- Instituto Gulbenkian de Ciência, 2780-156 Oerias, Portugal
- Católica Medical School, Católica Biomedical Research Centre, Universidade Católica Portuguesa, 1649-023 Lisbon, Portugal
| | - Lucia Grenga
- Département Médicaments et Technologies pour la Santé, Commissariat à l’Énergie Atomique et Aux Énergies Alternatives (CEA), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Paris-Saclay, 30200 Bagnols-sur-Cèze, France
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