[BioS 레터]Intestinal-closing,’Corona 19′ and microbiome-Biospectator

Yongbin Choi Visiting Researcher

New Approaches to Treat COVID-19

What is the Gut-Lung axis?

Over the past few years, active research into the health and disease effects of the human microbiome has revealed the importance of numerous microbes (microbiomes; microbiota) present in various parts of the body.

Most of the microbiome research has been focused on the gut microbiome, which has the largest number and quantity of microbial species that make up the gut microbiome, and, incidentally, is relatively simple through fecal samples. Because it can be analyzed easily. However, in addition to the gastrointestinal tract, microbial communities composed of various species exist in the skin, oral cavity, respiratory tract, and lungs, and these are affecting each part and the whole body.

In addition to the fact that intestinal microbes are involved in the physiology and disease of other organs beyond the intestinal tract, it has been reported that these intestinal microbiomes are closely related to microbiomes of other parts of the human body. In particular, the microbiome of the respiratory system and the intestinal tract has a high correlation and shows a similar structure, which is a major inoculum of intestinal microbes and respiratory microbes by microorganisms entering the oral route through inhalation and swallowing. Because it is (Inoculum). However, a similar but different microbiome develops at the same time depending on the anaerobic environment of the intestinal tract and the aerobic environment of the respiratory tract.

Interestingly, the microbiome in the intestine and the microbiome in the respiratory tract can affect the composition of each microorganism through interactions through various pathways in the human body, including metabolites derived from microorganisms in the blood and immune responses, as well as the similarity due to the influx of external microorganisms. Is that there is. The observation that the intestinal microbiome affects the composition of the respiratory and lung microbiome has been continuously reported. For example, it has been reported that changes in diet, the most important factor in the composition of the intestinal microbiome, affect the composition of the lung microbiome, and changes in the composition of the lung microbiome were observed in experimental animals receiving fecal transplantation. There is a bar[1,2].

Conversely, there have also been reports on the effect of changes in the respiratory microbiome through respiratory infections and the like on the composition of the intestinal microbiome. One study reported that the composition of the intestinal microbiome was very different in experimental animals infected with influenza, and in particular, it was observed that the Enterobacteriaceae family increased and the microorganisms of the Lactococcus and Lactobacillus genus decreased. Did[3]. Another study reported that when LPS was injected into the lungs to change the respiratory microbiome and respiratory immune response, an imbalance of the intestinal microbiome appeared. [4]. These interactions between the microbiome in the gut and respiratory tract appear to be due to the close association between the gut and respiratory immune systems.

In fact, in patients with chronic respiratory diseases such as Asthma and Chronic obstructive pulmonary disease (COPD), intestinal diseases such as Inflammatory bowel disease and Irritable bowel syndrome are often found. In the case of COPD patients, the probability of being diagnosed with inflammatory bowel disease is 2 to 3 times higher, and it has been reported that the permeability of the intestinal tract is increased. In addition, functional and structural abnormalities of the intestinal mucosa (Mucosa) have been reported in patients with asthma.[5]. In addition, it has been reported that about 50% of patients with inflammatory bowel disease and 33% of patients with irritable bowel syndrome have symptoms of the respiratory system such as inflammation and decreased lung function.[5]. Considering these epidemiological reports, the immune and inflammatory reactions of the intestine and respiratory tract are very closely related, and accordingly, the intestinal immune response formed by the intestinal microbiome is not only for respiratory diseases such as asthma and COPD, but also COVID-19. Responses to acute respiratory infections may also be affected.

Intestinal microbiome and respiratory infections

If there is a link between intestinal microbes and respiratory microbes, and between the intestinal, respiratory and lung immune responses (Gut-Lung axis), changes in the microbiome in the intestine may be affected by the immune response of the respiratory system and further symptoms of respiratory infections caused by viruses. Could it have an effect? Indeed, research to find answers to these questions has been conducted by a number of research teams over the years.

First of all, in a study published in Frontiers in Immunology in 2018, a significant imbalance of the intestinal microbiome was induced in experimental animals administered with antibiotics (streptomycin, Streptomycin) without any change in the respiratory microbiome. When infected with the Sendai virus, the imbalance of the intestinal microbiome increases the mortality rate due to viral infection through the reduction of regulatory T cells in the lungs and intestines, and the increase of inflammatory cytokines such as interferon-gamma. Reported Sikkim[6].

In addition, it was reported in two independent studies that administration of a strain of the genus Bifidobacterium (Genus) could protect experimental animals from respiratory infections caused by influenza virus, and furthermore, microbial-based probiotics of the genus Lactobacillus were used to increase the frequency of respiratory infections. Clinical trial results have been reported to relieve symptoms and symptoms.[7-11].

In a clinical paper published in the Journal of Allergy and Clinical Immunology in 2014, Lactobacillus rhamnosus (Rhinovirus infection) was investigated in 94 preterm infants.Lactobacillus rhamnosus) A randomized, double-blind comparative clinical trial (NCT00167700) comparing strains and prebiotics (galacto-oligosaccharide-polydextrose mixture, 1:1) with placebo was reported.[8]. The research team confirmed that the frequency and symptoms of rhinovirus infection were significantly reduced in the probiotic and prebiotic groups compared to the placebo group.

In addition, another study published in the American Journal of Clinical Nutrition in 2015 found that Lactobacillus paracasei (Lactobacillus paracasei) (Lactobacillus paracasei) Reported the results of a randomized, double-blind comparative clinical trial (ISRCTN08280229) comparing the strain with a placebo.[9]. As a result of the test, administration of the Lactobacillus paracasei strain did not affect the vaccine response, but it was reported that symptoms were shortened after influenza infection (6.4 ± 6.1 vs. 7.3 ± 9.7 (days), P = 0.006). From these results, it seems that the intestinal microbiome can affect the frequency and symptoms of respiratory infections, and in fact, such possibility is being actively discussed.[10,11].

Intestinal microbiome and COVID-19

Since the first report of SARS-CoV-2 (Severe acute respiratory syndrome corona virus 2) at the end of 2019, it has spread rapidly, and the world is still living in the era of the COVID-19 (Coronavirus disease 19) pandemic as of 2021. Given the fact that the gut microbiome affects respiratory infections caused by several viruses, could the gut microbiome be involved in the symptoms and fatality of COVID-19?

In a recent January 2021 study published in Gut, 100 COVID-19 patients and 79 normal subjects analyzed the association between intestinal microbiome composition, COVID-19 symptom severity, blood cytokines and biomarkers. As a result, the composition of the intestinal microbiome of COVID-19 patients was significantly different from that of the normal person, and was reported to have particularly immunomodulatory ability. Faecalibacterium prausnitzii, Eubacterium rectale And Bifidobacteria The composition of the genus strains was lower in COVID-19 patients than in normal subjects, and this change persisted for about 30 days even after COVID-19 cure. The intestinal microbiome of COVID-19 patients showed different cluster characteristics depending on the severity of the patients. In particular, strains that are characteristically reduced in the intestinal microbiome of COVID-19 patients are inflammatory cytokines such as TNF-alpha, CXCL10, and CCL2. There was a high correlation with blood levels of kine and chemokine. Considering that the symptoms of COVID-19 are due to excessive inflammatory reactions rather than simply due to apoptosis due to viral infection, the decrease in immunomodulatory microorganisms in COVID-19 patients is SARS- It was described as increasing the severity by promoting an excessive immune response to CoV-2.[12].

In addition, a paper published in the BioArchive (MedRxiv) on January 6, 2021, is based on modeling based on the composition of the intestinal microbiome, and through analysis of the intestinal microbiome, the symptoms of severe severity in COVID-19 patients were analyzed. Reported that it can be predicted with% accuracy[13].

Global microbiome-based biotech’s COVID-19 related pipeline

In addition to these papers reporting the association between the intestinal microbiome and the severity of COVID-19, attempts to relieve COVID-19 symptoms by modulating the intestinal microbiome are being made by global microbiome-based drug development companies. .

In particular, the U.S. microbiome-based drug development companies, Evelo Biosciences and Kaleiodo Biosciences, respectively, targeting inpatient COVID-19 patients, the two thirds of their candidate substances EDP1815 and 2 A phase 2 clinical trial of KB109 is in progress in a phase clinical trial and for mild COVID-19 patients who have not been hospitalized.[14,15].

The biggest difference between the COVID-19-related pipelines underway at the two companies is the severity and hospitalization of the patient population they target. First of all, in the case of Ivello’s clinical trial, whether EDP1815 can prevent the progression of severe COVID-19 in early patients who were recently hospitalized after being diagnosed with COVID-19, and high-risk patients progressed to severe severity depending on the presence or absence of underlying diseases. It is a clinical trial to see if it can be prevented. On the other hand, a clinical trial in Kaleido verifies whether KB109 can contribute to alleviating symptoms of COVID-19 in patients with mild COVID-19 who have not been hospitalized.

Specifically, Ivelo is the TACTIC-E trial, a phase 2/3 clinical trial conducted in the UK through collaboration with the University of Cambridge, and the Rutgers trial, a phase 2 clinical trial conducted in collaboration with Rutgers University in the US. In progress.

The TACTIC-E trial is a clinical trial designed for 469 patients in each of the three groups: the current treatment control group, the current treatment and EDP1815 treatment groups, the current treatment and the Ambrisentan and Dapagliflozin treatment groups. to be. Ambrisentan is a treatment for pulmonary arterial hypertension, and dapagliflozin is a treatment for diabetes. This clinical trial will verify whether EDP1815, ambricentan, or dapagliflozin can prevent worsening of COVID-19 symptoms and mortality in new COVID-19 patients classified as high-risk groups.Interim results in the second quarter of 2021 (Interim data) will be released.

The Rutgers trial is a double-blind, placebo-comparison clinical trial that compares EDP1815 to placebo in new patients 15 years of age or older who have been hospitalized for COVID-19 within the last 36 hours to see if EDP1815 can prevent worsening of COVID-19-related symptoms. Similar to the TACTIC-E trial, interim results will be announced in the second quarter of 2021.

Unlike Evelo, Kaleido recently announced the interim results of KB109, its COVID-19 clinical pipeline, through IR data in January 2021. Kaleido has a clinical pipeline for metabolic diseases and autoimmune diseases based on MMT (Microbiome metabolic therapy), a strategy platform for controlling the composition and metabolism of intestinal microbes using synthetic glycans. Among them, KB109 is an MMT candidate material that can promote the synthesis of short-chain fatty acid, a substance derived from intestinal microorganisms with immunomodulatory ability.

This clinical trial targets a total of 176 unhospitalized mild COVID-19 patients, the safety and tolerability of KB109 in the SSC (Supportive self-care) control group and the SSC and KB109 treatment groups, as well as the relief of COVID-19 symptoms. It is a clinical trial comparing duration. Kaleido includes 8 major symptoms including cough, chills, muscle pain, fever, headache, loss of taste and breath, shortness of breath, and sore throat, and 13 symptoms including abdominal pain, diarrhea, fatigue, stuffy nose, and chest pain. It was defined as, and the duration of the symptom relief was measured and analyzed by dividing according to the presence or absence of comorbidity. As a result, the median period for alleviation of the eight major symptoms was 8 days in the SSC group without underlying disease, 27 days in the SSC group with underlying disease, and 15 days in the SSC and KB109 group with underlying disease. In mild COVID-19 patients with underlying diseases, KB109 reported that it could reduce the time it takes to relieve major COVID-19-related symptoms by about 12 days. In addition, the median period for remission of 13 symptoms was 14 days in the SSC group without underlying disease, 27 days in the SSC group with underlying disease, and 18 days in the SSC and KB109 group with underlying disease. Similarly, in mild COVID-19 patients with underlying diseases, KB109 reported that 13 COVID-19 symptoms could be relieved by about 9 days.

It should be noted that in mild COVID-19 patients without underlying diseases, no shortening of the symptom relief period was observed following the administration of KB109, and the incidence of GI symptoms was rather high in the KB109 group (47). % vs 33%). Kaleido said all trial participants have been enrolled and that final data will be released within the first quarter of 2021.

Recently, as the mechanism of the influence of the intestinal microbiome on various organs of the human body has been revealed, concepts such as the Gut-brain Axis and the Gut-Liver Axis have emerged. In addition, research on the Gut-Lung Axis is also being actively conducted. The microbiome of the intestine and lungs is closely connected through the immune system. In particular, the immune regulation by the intestinal microbiome is important for the immune response against chronic respiratory diseases such as asthma and COPD, as well as respiratory infections caused by various viruses and pathogens. It looks like you can get involved. However, further evidence for this possibility and research on specific mechanisms should be continued.

references

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2. Liu et al. 16S rDNA analysis of the effect of fecal microbiota transplantation on pulmonary and intestinal flora. 3 Biotech 7:370. (2017).

3. Looft et al. Collateral effects of antibiotics on mammalian gut microbiomes. Gut Microbes 3, 463–467. (2012).

4. Sze et al. Changes in the bacterial microbiota in gut, blood, and lungs following acute LPS instillation into mice lungs. PLoS ONE 9:e111228. (2014).

5. Budden et al. Emerging pathogenic links between microbiota and the gut-lung axis. Nature Reviews Microbiology Vol 15 (2016).

6. Grayson et al. Intestinal Microbiota Disruption Reduces Regulatory T Cells and Increases Respiratory Viral Infection Mortality Through Increased IFNγ Production. Front Immunol. 2018 Jul 10;9:1587 (2018)

7. Wu, S. et al. Microbiota regulates the TLR7 signaling pathway against respiratory tract influenza A virus infection. Curr. Microbiol. 67, 414–422 (2013).

8. Luoto, R. et al. Prebiotic and probiotic supplementation prevents rhinovirus infections in preterm infants: a randomized placebo-controlled trial. J. Allergy Clin. Immunol. 133, 405–413 (2014).

9. Jespersen, L. et al. Effect of Lactobacillus paracasei subsp. paracasei, L. casei 431 on immune response to influenza vaccination and upper respiratory tract infections in healthy adult volunteers: a randomized, double-blind, placebo-controlled, parallel-group study. Am. J. Clin. Nutr. 101, 1188–1196 (2015).

10. King et al. Effectiveness of probiotics on the duration of illness in healthy children and adults who develop common acute respiratory infectious conditions: a systematic review and meta-analysis. Br. J. Nutr. 112, 41–54 (2014).

11. West, NP et al. Probiotic supplementation for respiratory and gastrointestinal illness symptoms in healthy physically active individuals. Clin. Nutr. 33, 581-587 (2014).

12. Yeoh YK, et al. Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19. Gut 2021;0:1–9. (2021)

13. Ward et al. The Intestinal an oral microbiomes are robust predictors of COVID-19 severity; The main predictor of COVID-19 related fatality. MedRxiV 2021.01.05.20249061 (2021)

14. Evelo Bioscience. January 2021 Presentation. https://ir.evelobio.com/

15. Kaleido Bioscience. Corporate Overview Presentation-January 2021.https://investors.kaleido.com/events-presentations