Altered gut microbiota patterns in COVID-19: Markers for inflammation and disease severity

Table 1 Different gastrointestinal symptoms in coronavirus disease 2019 patients

SI. No.	Total number of human subjects involved in study	Demographics of the study populations	Vomiting	Diarrhea	Nausea	Remarks/study summary	Ref.
1	191	Adults (46-67 years) hospitalised, Chinese peoples, 91 patients having comorbidity	7 (3.7%)	9 (4.7%)	7 (3.7%)	Identification of several risk factors and a detailed clinical course of illness for mortality of COVID-19 patients	[121]
2	171	Minor aged (1 d-15 years, hospitalised, Chinese children, no such comorbidity	11 (6.4%)	15 (8.8%)	NA	Report of a spectrum of illness from children infected with SARS-CoV-2 virus	[122]
3	1099	Median age group (35-58 years), hospitalised, Chinese patients without any comorbidity	55 (5.0%)	42 (3.8%)	55 (5.0%)	Identification and definition of clinical characteristics and disease severity of hospitalized COVID-19 patients	[37]
4	140	Adults (25-87 year), hospitalised Chinese patients with high comorbidity	7 (5.0%)	18 (12.9%)	24 (17.3%)	Report on hospitalized patients having COVID-19 with abnormal clinical manifestations (fever, fatigue, gastrointestinal symptoms, allergy)	[123]
5	73	Adults hospitalised Chinese patients, comorbidity reported	NA	26 (35.6%)	NA	Clinical significance of SARS-CoV-2 by examining viral RNA in feces of COVID-19 patients during hospitalizations	[124]
6	52	Adults (mean age 59.7 year), critically ill ICU- admitted Chinese patients, comorbidity reported	2 (3.8%)	NA	NA	Retrospective, single-centered, observational study on critically ill, ICU-admitted adult COVID-19 patients	[125]
7	138	Adult (median age 56 years), hospitalised Chinese patients with comorbidities	5 (3.6%)	14 (10.1%)	14 (10.1%)	Clinical characteristics of COVID-19 patients in hospitalized conditions	[126]
8	41	Middle age group (41-58 years) hospitalised Chinese patients with comorbidities	NA	1 (2.6%)	NA	Epidemiological, laboratory, clinical, and radiological features and treatment with clinical outcomes of hospitalized COVID-19 patients	[46]
9	62	Studied patients (median age 41 years) were hospitalised, Chinese ethnicity and comorbidity reported	NA	3 (4.8%)	NA	Most common symptoms at onset of illness with clinical data in confirmed COVID-19 patients	[127]
10	137	Studied patients ( mean age 57-55) ware Chinese and hospitalised, comorbidity was also noted	NA	11 (8%)	NA	Investigation of epidemiological history, clinical characteristics, treatment, and prognosis of COVID-19 patients	[128]
11	81	Chinese patients (mean age was 49.5 years), hospitalised with high comorbidities	4 (4.9%)	3 (3.7%)	NA	Report of confirmed COVID-19 patients with chest computer tomography imaging anomalies	[129]
12	99	Hospitalised, Chinese patients (average age of the patients was 55.5 years), comorbidity was reported	1 (1%)	2 (2.0%)	1 (1%)	Inclusive exploration of epidemiology and clinical features of COVID-19 patients	[130]

NA: Not available; ICU: Intensive care unit; COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.

Table 2 Fecal viral shedding in coronavirus disease 2019 patients

SI. No.	Total number of human subjects in study	Demographics of the study populations	Gastrointestinal symptoms	Confirmed cases of fecal shedding	Remarks/study summary	Ref.
1	205	Patients (mean age of 44 years) were hospitalised, Chinese without any comorbidities	No symptoms	44	Evidence-based study for gastrointestinal infection of SARS-CoV-2 virus and its possible fecal-oral transmission route in humans	[131]
2	73	Different age group (10 mo to 78 years old), hospitalised Chinese patients without report any comorbidities	Gastrointestinal bleeding, diarrhea	39	Description of epidemiological and clinical characteristics of COVID-19 patients	[124]
3	10	Chinese patients have aged 19-40 years, hospitalised and no such comorbidity was reported	Hemoptysis, diarrhea, cough	8	Report of median aged COVID-19 confirmed patients in ICU	[127]
4	14	Patients (18-87 years) were hospitalized, Chinese individuals without any comorbidities	No symptoms	5	Retrospective analysis of laboratory-confirmed COVID-19 cases in hospitalized conditions	[132]
5	66	Chinese patients (median age of 44 years) were hospitalised, comorbidity was not reported	No symptoms	11	Viral RNA detection was performed from throat swabs, stool, urine, and serum samples in different clinical conditions in COVID-19 patients	[133]
6	18	Adults patients (median age, 47 years) from Singapore were hospitalised and comorbidities was noted	No symptoms	4	COVID-19 patient case series using clinical, laboratory, and radiological data	[134]
7	74	Studied paients belonged from China and were hospitalised with comorbidities	No symptoms	41	Analysis of respiratory and fecal samples to determine clinical symptoms and medical treatments of COVID-19 patients	[135]
8	9	Adults Chinese patients were hospitalised without any comorbidities	Diarrhea and urinary irritation	2	Detection of SARS-CoV-2 RNA in urine and blood samples, and anal, oropharyngeal swabs of confirmed COVID-19 patients	[136]

ICU: Intensive care unit; COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.

Table 3 Analysis of gut microbiota in coronavirus disease 2019 patients in different cohorts

SI. No.	Cohort composition	No of Patients	Demographics of the study populations	Country	Significant gut microbiota found	Study conclusion	Reference
1	A pilot study with 15 healthy individuals (controls) and 15 patients with COVID-19	15	Study performed with hospitalised patients (median age 55 years), Chinese ethnicity and comorbidities were reported	Hong Kong	Abundance of Clostridium hathewayi, Clostridium ramosum, Coprobacillus, which are correlated with COVID-19 severity	Change in the fecal microbiome of COVID-19 patients during hospitalization, compared to healthy individuals (controls)	[48]
2	The two-hospitals cohort, serial stool samples collected from 27 COVID-19 patients among 100	27	Adults hospitalised Chinese patients, comorbidities were noted	Hong Kong	Faecalibacterium prausnitzii, Eubacteriumrectale and bifidobacteria	Gut microbiome involved in COVID-19 severity	[38]
3	United States cohort (majority African American)	50	Studied patients (mean age 62.3 years) were hospitalised with comorbidities, American ethnicity	United States	Some of the significant genera (Corynebacterium Peptoniphilus, Campylobacter, etc.)	No significant associations found between the composition microbiome and disease severity from COVID-19 patient gut microbiota	[50]
4	The study used 53 COVID-19 patients and 76 healthy individuals. 81 fecal samples collected during hospitalization	53	Adults Chinase hospitalised patients, no such comorbidities were noted	China	Elevated gut microbes such as Rothia mucilaginosa, Granulicatella spp, etc.	COVID-19 infection linked with change of the microbiome in COVID-19 patients	[137]
5	15 patients Cohort	15	Study performed adults hospitalised patients with comorbidities, Chinese ethnicity	Hong Kong	Elevated bacterial species Collinsella tanakaei, Collinsella aerofaciens, Morganella morganii, Streptococcus infantis	The study found fecal viral (SARS-CoV-2) activity	[54]
6	Two-hospital cohort with a total of 100 patients. Stool samples collected from 27 patients	27	Hospitalised adults patients were from China, comorbidities were noted	Hong Kong	Several gut microbiota such as Faecalibacterium prausnitzii, Eubacterium rectale, and bifidobacteria	Gut microbiota associated disease severity and inflammation in COVID-19 patients	[38]
7	98 COVID-19 patients (3 asymptomatic, 34 moderate, 53 mild, 3 critical, 5 severe), serial fecal samples collected from 37 COVID-19 patients	37	Adults (mean age 37 years) patients, hospitalised condition from Chinese ethnicity, comorbidities were reported	Hong Kong	A total of 10 virus species in fecal matter (9 DNA virus species and 1 RNA virus, pepper chlorotic spot virus)	Analysis of gut virome (RNA and DNA virome) in COVID-19 patients	[47]
8	Study of fecal samples from 30 COVID-19 patients	30	Patients (mean age 46 years) were hospitalised from Chinese groups, comorbidities were noted	Hong Kong	Increased proportions of fungal pathogens (Candida albicans, Candida auris, Aspergillus flavus, Aspergillus niger) in fecal samples	Analysis of fecal fungal microbiome of COVID-19 patients	[48]

COVID-19: Coronavirus disease 2019.

Table 4 List of clinical trials initiated to understand the role of gut microbiota in coronavirus disease 2019 and its therapeutic implications

SI. No.	Objective of clinical trials	Clinical trials No.	Description of clinical trials	Remarks
1	Evaluate the combination of probiotics (P. acidilactici and L. plantarum) to reduce the viral load of moderate or severe COVID-19 patients	NCT04517422	It was a randomized controlled trial, 300 participants, treatment by dietary supplement (probiotics)	Observational study of adult and older adult, trial completed
2	To explore the natural history of mild-to-moderate COVID-19 illness and safety of a novel glycan (KB109) and self-supportive care	NCT04414124	It was a randomized, prospective, open-label, parallel-group controlled clinical study of 350 participants	Observational study of adults (both male and female), trial completed
3	Investigate the physiologic effects of the novel glycan (KB109) on patients with COVID-19 illness on gut microbiota structure and function in the outpatient	NCT04486482	It was a randomized, open-label clinical study of 49 participants	Observational study of adults patients with mild-to-moderate COVID-19 infections, trial completed
4	Evaluate the clinical contribution of the gut microbiota and its diversity on the COVID-19 disease severity and the viral load	NCT05107245	It was case-control, diagnostic study of 143 participants	Observational study on the diagnostic evaluation of the human intestinal microbiota, trial completed
5	Studied the effects of Lactobacillus coryniformis K8 intake on the prevalence and severity of COVID-19 in health professional	NCT04366180	A randomized, interventional study of 314 participants	Investigation of probiotic effects to healthcare personnel exposed to COVID-19 infection
6	Investigate to exploring the role of nutritional support by probiotics to COVID-19 outpatients (adult)	NCT04907877	Randomized, evidence based study of 300 participants	Used of probiotics as dietary supplement that enhance specific immune response of patients having COVID-19 respiratory infection
7	Use of dietary supplement (Omni-Biotic® 10 AAD) can decrease the intestinal inflammation and improves dysbiosis for COVID-19 patients	NCT04420676	It was a randomized Interventional study of 30 participants	This study performed as double blind, placebo-controlled study
8	Evaluate the probiotics efficacy to decrease the COVID-19 infection symptoms and duration of COVID-19 positive patients	NCT04621071	The double-blind, randomized, controlled trial of 17 participants	This study performed to explored the effects of dietary supplement: Probiotics (2 strains 10 × 109 UFC), trial completed
9	Impact analysis of probiotic strain L. reuteri DSM 17938 for specific Abs response against SARS-CoV-2 infection	NCT04734886	It was control, randomized trial of 161 participants	To assess the upon and after COVID-19 infection in healthy adults, trial completed
10	To evaluate the primary efficacy of live microbials (probiotics) for boosting up the immunity of SARS-CoV-2 infected persons (unvaccinated)	NCT04847349	It was double-blind, randomized, controlled trial of 54 participants	Efficacy analysis of dietary supplement (combination of live microbials) as anti COVID-19 infection, trial completed
11	Evaluate the follow -up of Symprove (probiotic) to COVID-19 positive patients	NCT04877704	The randomized clinical trial was performed with 60 patients	Observational study to supervision of hospitalized COVID-19 patients
12	Study was performed to evaluate the possible effect of a probiotic mixtures in the improvement of COVID-19 infection symptoms	NCT04390477	It was randomized case control, clinical trial of 41 participants	Observational study of dietary supplement: Probiotic to COVID-19 patients
13	The probiotic ( Omni-Biotic Pro Vi 5) use for investigate the side effect of post-COVID syndrome	NCT04813718	It was a randomized trial of 20 participants	It was a therapeutic target study of probiotic for treatment of acute COVID-19 and prevention of post COVID infections
14	To evaluate the effect of a probiotic strain on the occurrence and severity of COVID-19 in hospitalised elderly population	NCT04756466	Randomized control trial of 201 participants	It was observational study, probiotic sued for improve the immune response of elderly patients
15	This study assesses the beneficial effects of the nutritional supplementation (ABBC1) to individuals taken the COVID-10 vaccine	NCT04798677	It was a double-blinded, placebo-controlled, randomized clinical study of 90 participants	Used as knowing the microbiome modulating properties, observational study
16	To investigate the consequence of Ligilactobacillus salivarius MP101 to hospitalised elderly individuals	NCT04922918	Non-randomised study of 25 participants	Observational study of aged patients having highly affected by COVID-19
17	Study was performed to explored the effect of the probiotic Lactobacillus rhamnosus GG	NCT04399252	It was a randomized double-blind, placebo-controlled trail of 182 participants	Observational study of individuals microbiome of household contacts exposed to COVID-19
18	Treatment approaches by probiotics to human gut microbiome and growing the anti-inflammatory response for COVID-19 infected patients	NCT04854941	It was a randomized controlled open-label study of 200 participants	The optimizing treatment approaches based observational study, trial completed
19	To evaluate the capability of the novel nutritional supplement (probiotics and other vitamins) to COVID-19 infected and hospitalised patients	NCT04666116	Randomized, single blind clinical trial of 96 participants	Used of dietary supplementation with probiotics aims to reduce the viral load
20	Using of probiotics for COVID 19 transmission reduction to health care professionals	NCT04462627	It was a non-randomized trial of 500 participants	Analysis and reduction of COVID-19 viral load to health care professionals

P. acidilactici: Pediococcus acidilactici; L. plantarum: Lactobacillus plantarum; COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.