In previous information sheets we have highlighted the barrier function of lactic acid bacteria (LAB) in the mucosal tissue, mainly by its role in the production of mucin. Stimulation and support of the immune system by LAB and the gut-lung axis were discussed. Mention was also made of the fact that LAB produce metabolites (in liquid formulation) that can act against pathogens [ProbiTech Info Sheets 1 and 2 and Snippet 1].

The culmination of these and other properties of LAB have now been indicated to be of value in present strategies against SARS-CoV2. Two scientific articles published in May and July 2020 is worth discussing:

1. “Using probiotics to flatten the curve of Coronavirus disease COVID-2019 pandemic” by a team of researchers from Switzerland, United Kingdom and Canada (full reference at the end);
2. “Challenges in the management of SARS-CoV2 infection: The role of oral bacteriotherapy as complementary therapeutic strategy to avoid the progression of COVID-19” by a team of researchers from Italy (full reference at the end).

ARTICLE 1

“The authors are of the opinion that vaccines will not be available in the near future and that additional preventative studies are urgently needed”

• Clinical studies from China indicate that gastrointestinal symptoms are common in COVID-19 and are associated with disease severity. SARS-CoV-2 RNA has been detected in the gastrointestinal tract (GIT) and stool samples from patients and in sewage systems. The GIT (especially the enterocytes*) can therefore act as a reservoir for the virus. *(Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase its surface area – Wikipedia)
• The reason for adding probiotics to the overall prevention and care strategy is founded in science and clinical studies, although none directly on the etiological agent of the COVID-19 pandemic.
• Viruses are etiologic agents of over 90% of upper RTIs. The positive impact of probiotics on prevention of upper RTIs is documented in numerous studies. Examples of several studies are presented.
• LAB are part of the upper respiratory tract microbiota in healthy people. This makes their use for slowing down progression of the coronavirus pandemic worthy of consideration.
• Not all probiotics, even those with gastrointestinal benefits, contribute in every way to reducing the risk of RTIs. See Table 1 for strains that may have relevance to reducing the burden of the Coronavirus pandemic. L. casei and L. rhamnosus GG (amongst others) are mentioned for the ability to reduce incidence and duration of RTIs and to lower the incidence of ventilator-associated pneumonia.
• Mechanisms include enhancement of the intestinal epithelial barrier, competition with pathogens for nutrients and adhesion to the intestinal epithelium, production of anti-microbial substances and modulation of the host immune system. Examples of specific studies are presented.
• Lungs have their own microbiota and a gut-lung connection is described. The gut microbiome has a critical impact on systemic immune responses, even at distant mucosal sites, including the lungs.
• Given the cytokine storm that occurs in many COVID-19 patients, the modulation of the host immune system by the relevant probiotic strains may prove to be very important.
• Effects of probiotics against other Coronavirus strains have been reported.
• Patients are dying from secondary bacterial infections. Oral administration of L. acidophilus (CMCC878) in mice infected with pneumonia causing pathogens, decreased lung damage and systemic inflammation.

CONCLUSION: “Orally administered probiotic strains can reduce the incidence and severity of viral RTIs. Probiotic strains accurately documented for anti-viral and respiratory activities should become part of the armamentarium to reduce the burden and severity of this pandemic”.

Reference:
Baud D, Dimopoulou Agri V, Gibson GR, Reid G and Giannoni E (2020): Using Probiotics to Flatten the Curve of Coronavirus Disease COVID-2019 Pandemic. Front. Public Health 8:186. doi: 10.3389/fpubh.2020.00186

ARTICLE 2

“Gastrointestinal disorders are frequent in COVID-19 and SARS-CoV-2 has been hypothesized to impact on host microbial flora and gut inflammation, infecting intestinal epithelial cells”

• Trial conditions: 70 patients positive for COVID-19, hospitalised and displaying all the symptoms, also requiring non-invasive oxygen therapy.
• 42 patients were treated with the current anti-COVID-19 treatment: hydroxy-chloroquine, azithromycin and tocilizumab (alone or in combination). A second group of 28 patients received the same treatment, added with oral bacteriotherapy, using a multi-strain probiotic formulation. These patients were hospitalized at the same clinic at the same time and were comparable in all aspects.

RESULTS:

• In nearly all patients treated with oral bacteriotherapy (probiotics) significant improvement in symptoms associated with COVID-19 (diarrhoea, fever, cough, dyspnea¹, asthenia² and myalgia³) was evident within 24-48 hours after commencing with oral bacteriotherapy. *
• Nearly all patients showed remission of diarrhoea and other symptoms within 72 hours, as compared to less than half of the not supplemented group. *
• The estimated risk of developing respiratory failure was eight-fold lower in patients receiving oral bacteriotherapy. *
• The prevalence of patients transferred to ICU as well as mortality was lower in patients treated with oral bacteriotherapy. *

*All datasets are included in the article/supplementary material.

CONCLUSION: “A specific bacterial formulation** showed a statistically significant ameliorating impact on the clinical conditions of patients positive for SARS-CoV-2 infection. These results also stress the importance of the gut-lung axis in controlling the COVID-19 disease”.

Explanation Of The Observations: (Quoted Directly)

• Entry points for the virus into the body, such as ACE2 receptors⁴, are enzymes that are linked to intestinal cells.
• Coronaviruses constantly change their binding patterns as they evolve, and the potential target in the lungs also varies, but not in the small intestine, where it remains constant.
• The cells of the intestinal mucosa (enterocytes) could therefore be a reservoir for coronaviruses.
• This is confirmed by the fact that only 10% of COVID-19 patients present virus complimentary DNA in the blood in the acute phase, while almost 50% of them excrete it in the stools.
• Investigations into the microbiota of patients who have died of COVID-19, revealed a significant decrease in Bifidobacteria as well as LAB, the main families of symbiotic bacteria. On the other hand, there was in increase in opportunistic bacteria.
• Intestinal dysbiosis⁵ has a long-reaching immune impact on the pulmonary immune system and might therefore be an additional risk for respiratory distress induced by COVID-19.
• The success of the oral bacteriotherapy in this regard can be ascribed to the fact that some strains of LAB and Bifidobacteria have a protective role against influenza virus, rhinovirus, respiratory syncytial virus, adenovirus and pneumovirus.
• Please refer to paragraph 1 on page 5 for an explanation of the gut-lung axis and how HO-1 expression prevents an exacerbated immune response in the lung tissue and subsequent damage.

** The probiotic formulation known as Sivomixx^R included the following strains: L. acidophilus (DSM 32241); L. helveticus (DSM 32242); L. paracasei (DSM 32243); L. plantarum (DSM 32244); L. brevis (DSM 27961); Bifidobacterium lactis (DSM 32246 and DSM 32247) and Streptococcus thermophilus (DSM 32345).

Although some of these strains differ from the strains used in our probiotic formulation, it has to be kept in mind that the functions and benefits of the strains might correspond.

The formulation was administered in three equal doses per day with a total of 2.4 x 10¹² bacteria per day.

Reference:

Gabriella d’Ettorre, Giancarlo Ceccarelli , Massimiliano Marazzato, et.al. (2020). Challenges in the Management of SARS-CoV2 Infection: The Role of Oral Bacteriotherapy as Complementary Therapeutic Strategy to Avoid the Progression of COVID-19. Frontiers in Medicine, 7, 389.

Please see the original articles for all the references.

1. Dyspnea:  Dyspnea is the medical term for shortness of breath, sometimes described as “air hunger.” It is an uncomfortable feeling. Shortness of breath can range from mild and temporary to serious and long-lasting (Wikipedia).

2. Asthenia: Abnormal physical weakness or lack of energy (Oxford Dictionary).

3. Myalgia: In medicine, myalgia, also known as muscle pain or muscle ache, is a symptom that presents with a large array of diseases. While the most common cause is the overuse of a muscle or group of muscles, acute myalgia may also be due to viral infections, especially in the absence of a traumatic history (Wikipedia).

4. ACE2 receptors: ACE2 is a protein on the surface of many cell types. It is an enzyme that generates small proteins – by cutting up the larger protein angiotensinogen – that then go on to regulate functions in the cell (Wikipedia).

5. Intestinal dysbiosis: Dysbiosis, which also may be referred to as dysbacteriosis or gut dysbiosis, is a condition that occurs when the normal balance of bacterial flow, or microbiota, is disrupted in the body. Gut dysbiosis most often occurs following a course of antibiotic treatment (Wikipedia).