The gastrointestinal tract does not just have a digestive function but is also responsible for achieving immune system homeostasis. The gut-associated lymphoid tissue harbours about 70% of the entire immune system 
. The gut microbiome, its metabolites, and miRNAs influence this homeostasis and also impact mucosal integrity. Weakening of this integrity can result in further inflammation and bacteraemia. As described above, COVID-19 leads to dysbiosis of the gut microbiome, gut inflammation, and weakening of mucosal integrity.
According to the Food and Agriculture Organization of the United Nations World Health Organization, probiotics are defined as “live microorganisms which when administered in adequate amounts confer a health benefit on the host.” Probiotics have been shown to enforce mucosal integrity 
and be beneficial for influenza virus clearing 
. Probiotics could therefore in theory support patients with COVID-19 to lessen inflammation, prevent/reduce the very dangerous cytokine storm, and support clearing of the virus. Several clinical trials are underway to study the impact of probiotics on COVID-19 as an adjunctive therapy.
A study from Italy 
enrolled 70 COVID-19 patients with moderate symptoms (>37.5 °C fever, need of non-invasive oxygen therapy, and according to imaging more than 50% lung involvement) who were treated with hydroxychloroquine (HCQ) 200 mg twice a day, antibiotics (ABX) (azithromycin 500 mg), and Tocilizumab (TCZ), the dosage of which was 8 mg/kg (up to a maximum of 800 mg per dose) with an interval of 12 h two times. A group of randomly picked 28 patients (mean age 59) received probiotics as adjunctive therapy while the remaining 48 patients (mean age 60.5) formed the control group. In this study, Sivomixx®
, Rockville, MD, USA) was used, consisting of Streptococcus thermophilus
DSM 32345, Lactobaccilus acidophilus
DSM 32241, Lactobacillus helveticus
DSM 32242, Lacticaseibacillus paracasei
DSM 32243, Lactobaccilus plantarum
DSM 32244, Lactobacillus brevis
DSM 27961, Bifidobacterium lactis
DSM 32246, and Bifidobacterium lactis
DSM 32247. Patients received three equal doses per day (sum of 2400 billion bacteria), for 14 days. Diarrhoea was resolved for 92.9% of the patients in the probiotic group within three days, whereas in the control group, less than 10% after three days and only about 35% after 7 days. Other symptoms like fever, asthenia, headache, myalgia, and dyspnoea resolved in 100% of the patients after 7 days, but only in about 50% of the control group. The author stated, “After 7 days of treatment, the calculated model showed an 8-fold significantly decreased risk to evolve a respiratory failure” 
. In the probiotic group, 0% of the patients were transferred to the ICU or had a lethal outcome, compared to 4.8% and 9.5%, respectively, in the control group.
The same probiotic Sivomixx®
was used by the same group to enlarge the study 
. This time, 200 patients were enrolled, where 88 received the probiotic at the same dose (3 times daily, a total of 2400 billion bacteria). A similar treatment was provided, including hydroxychloroquine (200 mg twice a day for 7 days), azithromycin (500 mg once a day for 7 days), lopinavir-ritonavir (400/100 mg twice a day), or darunavir–cobicistat (800/150 mg once a day) for 14 days. The risk to be transferred to the ICU was similar in both the control, 21.4% (mean age 64), and probiotic treatment group, 18.1% (mean age 62). There was a significant difference in the mortality between both groups, being 22% in the control group vs. 11% in the probiotic treatment group, clearly demonstrating the potential of this adjuvant treatment.
is being tested in another clinical trial in Italy in conjunction with ozone therapy and the recommend best treatment 
. Systemic autohemotherapy (twice a day) will be combined with 200 billion CFU/day of Sivomixx®
(six sachets twice a day). An estimated 152 participants will be enrolled, and various outcome measures determined, with the primary outcome being the number of patients requiring orotracheal intubation.
A clinical trial in Mexico sponsored by AB Biotics, SA, has finished (May 2021), but no data have been published yet 
. In this intervention study, 300 COVID-19 patients with mild symptoms were enrolled. To a randomly selected group, a probiotic was given (Lactobacillus plantarum
CECT 30292, Lactobacillus plantarum
CECT 7484, Lactobacillus plantarum
CECT 7485 y Pediococcus acidilactici
CECT 7483) once a day for 30 days. Various primary and secondary outcomes were determined, for example, severity progression, stay at ICU (frequency and length), mortality, and changes in the faecal microbiome.
A Canadian clinical trial has now finished (June 2021) as well, but no data have been published yet 
. Nasal irrigation with Probiorinse (2.4 billion colony forming units (CFU) of Lactococcus Lactis
W136, (NPN: 80085895)) twice daily for 14 days was used as an intervention. A total of 23 COVID-19 patients were enrolled and changes in severity were monitored for up to 28 days. Another Canadian clinical trial monitored the duration of symptoms, severity, and changes in the oral and faecal microbiome of an estimated 84 patients 
. A probiotic (undefined) was given to the treatment group for 25 days.
An interventional multi-centre clinical study in Spain is evaluating the probiotic Lactobacillus Coryniformis
K8, using a dose of 3 × 109
CFU/day for 2 months, on health care workers 
. The estimated enrolment is 314 participants, and the incidence and severity of COVID-19 will be measured. In the United States at Duke University, a study is being performed looking at the microbiome of exposed household members from COVID-19 patients. The intervention will be made by providing a probiotic consisting of Lactobacillus rhamnosus
GG. In total, 182 participants are expected to enrol 
. A clinical trial in Austria aims to use Omni-Biotic®
10 AAD (Bifidobacterium bifidum
W23, Bifidobacterium lactis
W51, Enterococcus faecium
W54, Lactobacillus acidophilus
W37, Lactobacillus acidophilus
W55, Lactobacillus paracasei
W20, Lactobacillus plantarum
W1, Lactobacillus plantarum
W62, Lactobacillus rhamnosus
W71, and Lactobacillus salivarius
W24) as an invention for COVID-19-related diarrhoea 
. It is planned that an estimated 120 patients will be enrolled.
Another way to influence the gut microbiome more radically is faecal microbiota transplant (FMT). Two cases were reported, from an 80- and a 19-year-old man, who received an FMT to treat a Clostridioides difficile
infection (CDI) 
. Both had severe comorbidities. Unknowingly, both were at the onset of developing COVID-19 at the time point of the FMT. Despite the risk factors of both patients in developing severe COVID-19 symptoms, both experienced rather mild symptoms. This gave rise to a hypothesis that FMT can be used to reduce the risk of severe illness progression. A clinical trial was started to investigate this hypothesis 
6. Is There a Link between Changes in the Gut Microbiome in COVID-19 Patients and Chronic COVID-19 Symptoms?
Evidence is accumulating that the gut microbiome is changing for COVID-19 patients and as described above, in a large proportion of patients, these changes (dysbiosis) seem to last. There is compelling evidence that gut microbial dysbiosis can lead to or drive various health problems and is associated with a lower quality of life. It might be no coincidence that more reports are being published describing the long-term effects of COVID-19. Lopez-Leon et al. showed in a meta-analysis that about 80% of COVID-19 patients developed at least one symptom 
. The main symptoms of this chronic COVID-19 syndrome (CCS) (1) were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnoea (24%); however, joint pain, sleeping problems, depression, and diarrhoea were reported as well. Fatigue, headache, attention disorders, joint pain, headaches, sleeping problems, depression, and diarrhoea have been linked to dysbiosis in the gut microbiome 
. There seems to be an intriguing overlap between these symptoms and more research in this area might reveal new treatment options for CCS. For a more detailed discussion, see 
. A not yet peer-reviewed article (MedRxiv) shows a loss of diversity in the gut microbiome in chronic COVID-19 patients who experienced severe acute COVID-19 symptoms 
, underpinning the importance of studying this potential connection between gut dysbiosis and chronic COVID-19.