Microbiome-Based Hypothesis on Ivermectin’s Mechanism in COVID-19: Ivermectin Feeds Bifidobacteria to Boost Immunity
Sabine Hazan- Progenabiome, LLC, Ventura, CA, United States
Ivermectin is an anti-parasitic agent that has gained attention as a potential COVID-19 therapeutic. It is a compound of the type Avermectin, which is a fermented by-product of Streptomyces avermitilis. Bifidobacterium is a member of the same phylum as Streptomyces spp., suggesting it may have a symbiotic relation with Streptomyces. Decreased Bifidobacterium levels are observed in COVID-19 susceptibility states, including old age, autoimmune disorder, and obesity. We hypothesize that Ivermectin, as a by-product of Streptomyces fermentation, is capable of feeding Bifidobacterium, thereby possibly preventing against COVID-19 susceptibilities. Moreover, Bifidobacterium may be capable of boosting natural immunity, offering more direct COVID-19 protection. These data concord with our study, as well as others, that show Ivermectin protects against COVID-19.
Introduction
SARS-CoV-2 infection has been a global pandemic affecting the world for the last 2+ years. Symptoms include fever, cough, shortness of breath, GI issues, potential pneumonia, and other less common ones, including oral symptoms (Khodavirdipour et al., 2021a; Sharma et al., 2021). Current treatments for SARS-CoV-2 include remdesivir, paxlovid, hydroxychloroquine, nucleoside analogs, antibodies, antibiotics, herbal medicines, tocilizumab, anti-inflammatory drugs (e.g., steroids), and ivermectin (IVM) (Gavriatopoulou et al., 2021). Vaccines have been distributed widely for SAR-CoV-2 infection (Khodavirdipour et al., 2020; Joshi et al., 2021) prevention. In addition to standard nasopharyngeal tests, CRISPR-based methods (Khodavirdipour et al., 2021c) have been used or proposed for SARS-CoV-2 infection testing. Recent mutations have been making SARS-CoV-2 infection more contagious and with a higher rate of Khodavirdipour et al. (2021b) infection. Nonetheless, the pandemic has continued for over 2 years, and a better understanding of all possible therapeutics is essential.
Severity of SARS-CoV-2 has been associated with lower levels of Bifidobacterium (Tao et al., 2020; Xu et al., 2020; Reinold et al., 2021; Yeoh et al., 2021; Zuo et al., 2021; Hazan et al., 2022b). Probiotics have been hypothesized and tested with success for improving SARS-CoV-2 symptoms (Bozkurt and Quigley, 2020; Bozkurt and Bilen, 2021; Khaled, 2021; Khodavirdipour, 2021; Gutiérrez-Castrellón et al., 2022; Khodavirdipour et al., 2022), and they are often enhanced by use with prebiotics (Markowiak and Śliżewska, 2017). Thus, we sought to find medications that increase the level of beneficial gut bacteria, i.e., have a prebiotic effect.
Ivermectin Has Been Shown to Effectively Treat SARS-CoV-2 Infection
Over 40 peer-reviewed studies (Table 1) have demonstrated studies on the effectiveness of IVM in SARS-CoV-2 infection (Alam et al., 2020; Khan et al., 2020; Kishoria et al., 2020; Reaz et al., 2020; Abd-Elsalam et al., 2021; Ahmed et al., 2021; Ahsan et al., 2021; Aref et al., 2021; Behera et al., 2021; Cadegiani et al., 2021; Chaccour et al., 2021; Chahla et al., 2021; Chowdhury et al., 2021; Elalfy et al., 2021; Faisal et al., 2021; Ferreira et al., 2021; Hellwig and Maia, 2021; Krolewiecki et al., 2021; Lima-Morales et al., 2021; López-Medina et al., 2021; Mohan et al., 2021; Morgenstern et al., 2021; Mukarram, 2021; Okumuş et al., 2021; Podder et al., 2021; Rajter et al., 2021; Ravikirti et al., 2021; Rezk et al., 2021; Seet et al., 2021; Shahbaznejad et al., 2021; Shoumann et al., 2021; Abbas et al., 2022; Ascencio-Montiel et al., 2022; Babalola et al., 2022; Beltran Gonzalez et al., 2022; Buonfrate et al., 2022; Hazan et al., 2022a; Kerr et al., 2022; Lim et al., 2022; Mayer et al., 2022; Mustafa et al., 2022; Ozer et al., 2022; Reis et al., 2022; Shimizu et al., 2022; Zubair et al., 2022), with over 80% of studies showing positive outcomes with IVM treatment. Overall, IVM has shown 60–85% improvement in outcomes, including mortality, ventilation, recovery, clearance, and hospital/ICU admissions. The effectiveness could be particularly strong at high doses (Krolewiecki et al., 2021; Buonfrate et al., 2022; Mayer et al., 2022) and for severe SARS-CoV-2 infection (Beltran Gonzalez et al., 2022; Hazan et al., 2022a; Zubair et al., 2022), and one must consider that the effective dose is very affected by food co-administration (Food and Drug Administration, 2022). Thus, there is a tremendous need to ascertain, not whether but how IVM is ideally applied for SARS-CoV-2 infection.
Table 1. Peer-reviewed studies regarding efficacy of Ivermectin in SARS-CoV-2 infection.
The demonstrated effectiveness of IVM in SARS-CoV-2 cannot be ignored. An important step toward refining our understanding of when and how IVM is successful is that we need to understand all potential mechanisms for IVM against SARS-CoV-2 infection. The purpose of this study is to describe a novel hypothesis for IVM action against SARS-CoV-2 for consideration by the scientific community. While there is limited published evidence for this—as of yet theoretical description—we are soon to publish data showing in vivo administration of IVM increases-relative abundance of Bifidobacterium.
Background to the Hypothesis
IVM discovery was awarded the Nobel prize (Molyneux and Ward, 2015), 35 years post-discovery, for its game-changing impact on the field of antiparasitic agents. IVM is approved by the Food and Drug Administration for treating parasitic infections and comes from the class compounds called macrocyclic lactones, specifically Avermectins. Avermectins are found naturally as a fermentation product of a strain of Streptomyces avermitilis (Laing et al., 2017). While IVM’s mechanisms of action as an anti-parasitic agent are well-established (Ômura and Crump, 2014), its potential in fighting viral infectious disease, including possibly SARS-CoV-2 infection, remains poorly understood.
Streptomyces spp. belong to the same phylum as a critically important constituent of the gut microbiome and common ingredient of probiotics, Bifidobacterium. Bifidobacterium abundance is known to decrease in SARS-CoV-2-infected subjects, as seen in ours and other studies (Tao et al., 2020; Xu et al., 2020; Reinold et al., 2021; Yeoh et al., 2021; Zuo et al., 2021; Hazan et al., 2022b). We have anecdotally observed, through our clinical experiences pre and post Fecal Microbiota Transplant, that certain bacteria in the same phylum may be able to replace each other’s function. Thus, we hypothesized Streptomyces spp. may replace loss of Bifidobacterium.
Bifidobacterium spp. are microaerotolerant anaerobes that degrade monosaccharides, such as glucose and fructose, via the bifid shunt, or the fructose-6-phosphate phosphoketolase pathway and produce more ATP than traditional fermentative pathways (De Vuyst et al., 2014). Bifidobacterium spp. also symbiotically feed other gut microbes via their metabolic by-products and end-products, which, in turn, enhance butyrate production and reduce inflammation (De Vuyst et al., 2014). Streptomyces spp., too, are frequently found in symbiotic relations with other bacteria (Seipke et al., 2012). Thus, it is possible for a symbiotic relation between Streptomyces and Bifidobacterium.
Increased Bifidobacterium levels serve as an important indicator of human health and may promote anti-inflammatory activity (Arboleya et al., 2016; Hughes et al., 2017; Tao et al., 2020). It is interesting to note that these same disorders are key risk factors in severe SARS-CoV-2 infection, and Bifidobacterium abundance is also shown to be low in SARS-CoV-2 infection (Tao et al., 2020; Xu et al., 2020; Reinold et al., 2021; Yeoh et al., 2021; Zuo et al., 2021; Hazan et al., 2022b). Probiotics, which typically contain much Bifidobacterium spp., have been proposed as potentially useful SARS-CoV-2 infection prophylaxis or treatment (Bozkurt and Quigley, 2020; Conte and Toraldo, 2020; Bozkurt and Bilen, 2021; Jabczyk et al., 2021).
The mechanisms for Bifidobacterium boosting “natural immunity,” thereby protecting against SARS-CoV-2 infection effects, may involve its anti-inflammatory properties (Lim and Shin, 2020). Specifically, Bifidobacterium increases Treg responses and reduces cell damage by decreasing the function of TNF-α (the pro-inflammatory “master-switch,” see Figure 1A.) and macrophages (Hughes et al., 2017). Bifidobacterium spp. also increase the anti-inflammatory cytokine interleukin (IL)-10, regulate the helper T cell response (Ruiz et al., 2017), and, in a mouse model of inflammatory bowel disease, B. bifidum and B. animalis reduced pro-inflammatory cytokines and restored intestinal barrier integrity (i.e., decreased potential for “leaky gut”) (Ruiz et al., 2017). In short, Bifidobacterium, through TNF-α and interleukins, can decrease inflammation, leading to increased immunity. Moreover, a decrease in pro-inflammatory cytokines and increase in anti-inflammatory ones can help negate the cytokine storm of SARS-CoV-2 infection.
Figure 1. We hypothesize that IVM treats SARS-CoV-2 infection by decreasing inflammation through enhanced replication of Bifidobacterium, leading to inhibition of TNF-α. (A) Bifidobacterium inhibits inflammation via binding of TNF-α. (B) Expansion of the right side of panel (A), showing IVM contains monosaccharide oleandrose moieties that could feed Bifidobacterium, thereby increasing replication and increasing inhibition of TNF-α and inhibition of inflammation.
Hypothesis and Evaluation
Bifidobacterium is a heterotroph that feeds on a variety of carbon sources, but, most efficiently, simple sugars (oligosaccharides and monosaccharides) (Rivière et al., 2016). IVM is composed of two oleandrose (a monosaccharide) moieties, along with one aglycone moiety (Barton et al., 1999; Figure 1B). A naturally found reversible glycosyltransferase, AveBI, can breakdown or assemble IVM to or from these components (Zhang et al., 2006). Thus, IVM breakdown products include oleandrose, a monosaccharide that may feed Bifidobacterium, thereby promoting its growth (Figure 1B).
There may be other mechanisms of action of IVM in SARS-CoV-2 infection treatment. Studies found that IVM has significant potential binding affinity for many proteins within SARS-CoV-2 (Lehrer and Rheinstein, 2020; Saha and Raihan, 2021). Ivermectin could, thus, block the binding of the spike protein’s receptor binding domain within SARS-CoV-2 to the ACE2 receptor (Lehrer and Rheinstein, 2020; Saha and Raihan, 2021). This binding between the spike protein and ACE2 receptor is essential for viral entry. This same study also demonstrated that IVM has the ability to bind a protease on the non-structural protein 3, which serves as a part of the viral replication/transcription complex. This binding prevents the virus using its enzymatic activity to remove ubiquitin, allowing the host anti-viral interferon response to aid viral clearance. Other reviews discuss various proposed mechanisms of IVM in SARS-CoV-2 infection (Heidary and Gharebaghi, 2020; Rizzo, 2020; Kinobe and Owens, 2021).
Discussion
Ours and other data also support a protective role of Bifidobacterium in SARS-CoV-2 infection, possibly through these immune functions of Bifidobacterium. Our study and others (Tao et al., 2020; Xu et al., 2020; Reinold et al., 2021; Yeoh et al., 2021; Zuo et al., 2021; Hazan et al., 2022b) show that the gut microbiome, particularly Bifidobacterium levels, relates to positivity and severity of SARS-CoV-2 infection. Tao et al. (2020) showed that changes in gut microbiota composition might contribute to SARS-CoV-2-induced production of inflammatory cytokines in the intestine, which may lead to the cytokine storm onset.
An increase in Bifidobacterium levels can reduce inflammation levels and TNF-α function, thereby calming the cytokine storm of SARS-CoV-2 infection. Bifidobacterium has been shown to bind TNF-α (Hughes et al., 2017; Dyakov et al., 2020). This binding will absorb TNF-α from the gut, which, in turn, will reduce it in the blood stream, and eventually absorb it from the lungs and other affected areas (the “gut-lung axis”; Cervantes and Hong, 2017; Figure 1).
IVM is known to have antibacterial affects against Staphylococcus aureus and other gram-positive bacteria, which may seem contradictory to its potential to promote growth of another gram-positive bacterium, Bifidobacterium. However, a study by Lazarenko et al. (2012) showed that certain Bifidobacterium spp. can have protective affects against S. aureus infection in mice, thereby acting in an antagonistic relation with S. aureus. Thus, both IVM and Bifidobacterium act against S. auereus, and it is unlikely that IVM would also act against Bifidobacterium.
If this presented hypothesis is true, the timing of IVM administration should be just prior to or at the cytokine storm. Seriously affected SARS-CoV-2-infected patients develop a cytokine storm alongside hypoxemia around Days 10–14, referred to as the “Second week crash” (Bernstein and Cha, 2020; Mehta and Fajgenbaum, 2021; “Second-week crash” is time of peril for some patients with COVID-19). Our study on IVM combination therapy initiated therapy around Day 10, as patients typically presented to the study hypoxic at Day 9 (mean time from the symptom onset to treatment initiation was 9.2 days). This timing resulted in successful treatment, with all 24 severely hypoxic patients, recovering without hospitalizations (Hazan et al., 2022a). In short, IVM should typically be administered at the point of an SpO2 drop, the cytokine storm onset, and/or approximately Days 10–14.
Conclusion
We are hypothesizing the IVM mechanism of action as a therapeutic for COVID-19 is through feeding of Bifidobacterium, which then inhibits cytokine function and tames the cytokine storm (Figure 1). As such, IVM should be administered at the time of the cytokine storm.
Data Availability Statement
The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Author Contributions
The author confirms being the sole contributor of this work and has approved it for publication.
Conflict of Interest
SH declares that she has a pecuniary interest in Topelia Pty Ltd in Australia, and Topelia Pty Ltd in United States where the development of COVID-19 preventative/treatment options are being pursued. She has also filed patents relevant to Coronavirus treatments. She is the founder and owner of Microbiome Research Foundation, ProgenaBiome, and Ventura Clinical Trials.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Acknowledgments
Sonya Dave, provided medical writing services for this manuscript and was funded by ProgenaBiome, LLC (The author’s institution). Thomas J. Borody, provided feedback on the manuscript.
References
Abbas, K. U., Muhammad, S., and Ding, S. F. (2022). The effect of ivermectin on reducing viral symptoms in patients with mild COVID-19. Indian J. Pharm. Sci. 83, 87–91. doi: 10.36468/pharmaceutical-sciences.spl.416
Abd-Elsalam, S., Noor, R. A., Badawi, R., Khalaf, M., Esmail, E. S., Soliman, S., et al. (2021). Clinical study evaluating the efficacy of ivermectin in COVID-19 treatment: a randomized controlled study. J. Med. Virol. 93, 5833–5838. doi: 10.1002/jmv.27122
Ahmed, S., Karim, M. M., Ross, A. G., Hossain, M. S., Clemens, J. D., Sumiya, M. K., et al. (2021). A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. Int. J. Infect. Dis. 103, 214–216. doi: 10.1016/j.ijid.2020.11.191
Ahsan, T., Rani, B., Siddiqui, R., D‘Souza, G., Memon, R., Lutfi, I., et al. (2021). Clinical variants, characteristics, and outcomes among COVID-19 patients: a case series analysis at a tertiary care hospital in Karachi, Pakistan. Cureus 13:e14761. doi: 10.7759/cureus.14761
Alam, M. T., Murshed, R., Gomes, P. F., Masud, Z., Saber, S., Chaklader, M. A., et al. (2020). Ivermectin as pre-exposure prophylaxis for COVID-19 among healthcare providers in a selected tertiary hospital in Dhaka – an observational study. Eur. J. Med. Health Sci. 2, 1–5. doi: 10.24018/ejmed.2020.2.6.599
Arboleya, S., Watkins, C., Stanton, C., and Ross, R. P. (2016). Gut bifidobacteria populations in human health and aging. Front. Microbiol. 7:1204. doi: 10.3389/fmicb.2016.01204
Aref, Z. F., Bazeed, S. E. E. S., Hassan, M. H., Hassan, A. S., Rashad, A., Hassan, R. G., et al. (2021). Clinical, biochemical and molecular evaluations of ivermectin mucoadhesivenanosuspension nasal spray in reducing upper respiratory symptoms of mild COVID-19. Int. J. Nanomed. 16, 4063–4072. doi: 10.2147/IJN.S313093
Ascencio-Montiel, I. J., Tomás-López, J. C., Álvarez-Medina, V., Gil-Velázquez, L. E., Vega-Vega, H., Vargas-Sánchez, H. R., et al. (2022). A multimodal strategy to reduce the risk of hospitalization/death in ambulatory patients with COVID-19. Arch. Med. Res. 53, 323–328. doi: 10.1016/j.arcmed.2022.01.002
Babalola, O. E., Bode, C. O., Ajayi, A. A., Alakaloko, F. M., Akase, I. E., Otrofanowei, E., et al. (2022). Ivermectin shows clinical benefits in mild to moderate COVID19: a randomized controlled double-blind, dose-response study in Lagos. QJM Int. J. Med. 114, 780–788. doi: 10.1093/qjmed/hcab035
Barton, D. H. R., Nakanishi, K., and Meth-Cohn, O. (1999). Comprehensive Natural Products Chemistry, 1st Edn. Available online at: https://www.elsevier.com/books/comprehensive-natural-products-chemistry/barton/978-0-08-042709-6 (accessed April 13, 2022).
Behera, P., Patro, B. K., Singh, A. K., Chandanshive, P. D., Ravikumar, S. R., Pradhan, S. K., et al. (2021). Role of ivermectin in the prevention of SARS-CoV-2 infection among healthcare workers in India: a matched case-control study. PLoS One 16:e0247163. doi: 10.1371/journal.pone.0247163
Beltran Gonzalez, J. L., González Gámez, M., Mendoza Enciso, E. A., Esparza Maldonado, R. J., Hernández Palacios, D., Dueñas Campos, S., et al. (2022). Efficacy and safety of ivermectin and hydroxychloroquine in patients with severe COVID-19: a randomized controlled trial. Infect. Dis. Rep. 14, 160–168. doi: 10.3390/idr14020020
Bernstein, L., and Cha, A. E. (2020). Second-Week Crash’ is Time of Peril for Some Covid-19 Patients. Available online at: https://www.washingtonpost.com/health/second-week-crash-is-time-of-peril-for-some-covid-19-patients/2020/04/29/3940fee2-8970-11ea-8ac1-bfb250876b7a_story.html (accessed March 8, 2022).
Bozkurt, H. S., and Bilen, Ö (2021). Oral booster probiotic bifidobacteria in SARS-COV-2 patients. Int. J. Immunopathol. Pharmacol. 35:205873842110596. doi: 10.1177/20587384211059677
Bozkurt, H. S., and Quigley, E. M. (2020). The probiotic Bifidobacterium in the management of Coronavirus: a theoretical basis. Int. J. Immunopathol. Pharmacol. 34:205873842096130. doi: 10.1177/2058738420961304
Buonfrate, D., Chesini, F., Martini, D., Roncaglioni, M. C., Ojeda Fernandez, M. L., Alvisi, M. F., et al. (2022). High-dose ivermectin for early treatment of COVID-19 (COVER study): a randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial. Int. J. Antimicrob. Agents 59:106516. doi: 10.1016/j.ijantimicag.2021.106516
Cadegiani, F. A., Goren, A., Wambier, C. G., and McCoy, J. (2021). Early COVID-19 therapy with azithromycin plus nitazoxanide, ivermectin or hydroxychloroquine in outpatient settings significantly improved COVID-19 outcomes compared to known outcomes in untreated patients. New Microbes New Infect. 43:100915. doi: 10.1016/j.nmni.2021.100915
Cervantes, J., and Hong, B. (2017). The gut–lung axis in tuberculosis. Pathog. Dis 75, 1–3. doi: 10.1093/femspd/ftx097
Chaccour, C., Casellas, A., Blanco-Di Matteo, A., Pineda, I., Fernandez-Montero, A., Ruiz-Castillo, P., et al. (2021). The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: a pilot, double-blind, placebo-controlled, randomized clinical trial. EClinicalMedicine 32:100720. doi: 10.1016/J.ECLINM.2020.100720
Chahla, R. E., Medina Ruiz, L., Ortega, E. S., Morales Rn, M. F., Barreiro, F., George, A., et al. (2021). Intensive treatment with ivermectin and iota-carrageenan as pre-exposure prophylaxis for COVID-19 in health care workers from Tucuman, Argentina. Am. J. Ther. 28, e601–e604. doi: 10.1097/MJT.0000000000001433
Chowdhury, A., Shahbaz, M., Karim, M., Islam, J., Dan, G., and Shuixiang, H. (2021). A comparative study on ivermectin-doxycycline and hydroxychloroquine-azithromycin therapy on COVID-19 patients. Eurasian J. Med. Oncol. 5, 63–70. doi: 10.14744/ejmo.2021.16263
Conte, L., and Toraldo, D. M. (2020). Targeting the gut-lung microbiota axis by means of a high-fibre diet and probiotics may have anti-inflammatory effects in COVID-19 infection. Ther. Adv. Respir. Dis. 14:1753466620937170. doi: 10.1177/1753466620937170
De Vuyst, L., Moens, F., Selak, M., Rivière, A., and Leroy, F. (2014). Summer Meeting 2013: growth and physiology of bifidobacteria. J. Appl. Microbiol. 116, 477–491. doi: 10.1111/JAM.12415
Dyakov, I. N., Mavletova, D. A., Chernyshova, I. N., Snegireva, N. A., Gavrilova, M. V., Bushkova, K. K., et al. (2020). FN3 protein fragment containing two type III fibronectin domains from B. longum GT15 binds to human tumor necrosis factor alpha in vitro. Anaerobe 65:102247. doi: 10.1016/J.ANAEROBE.2020.102247
Elalfy, H., Besheer, T., El-Mesery, A., El-Gilany, A., Soliman, M. A., Alhawarey, A., et al. (2021). Effect of a combination of nitazoxanide, ribavirin, and ivermectin plus zinc supplement (MANS.NRIZ study) on the clearance of mild COVID-19. J. Med. Virol. 93, 3176–3183. doi: 10.1002/jmv.26880
Faisal, R., Shah, S. F. A., and Hussain, M. (2021). Potential use of azithromycin alone and in combination with ivermectin in fighting against the symptoms of COVID-19. Prof. Med. J. 28, 737–741. doi: 10.29309/TPMJ/2021.28.05.5867
Ferreira, R. M., Beranger, R. W., Sampaio, P. P. N., Mansur Filho, J., and Lima, R. A. C. (2021). Outcomes associated with Hydroxychloroquine and Ivermectin in hospitalized patients with COVID-19: a single-center experience. Rev. Assoc. Médica Bras. 67, 1466–1471. doi: 10.1590/1806-9282.20210661
Food and Drug Administration (2022). STROMECTOL – Food and Drug Administration. Available online at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/050742s030lbl.pdf (accessed May 10, 2022).
Gavriatopoulou, M., Ntanasis-Stathopoulos, I., Korompoki, E., Fotiou, D., Migkou, M., Tzanninis, I.-G., et al. (2021). Emerging treatment strategies for COVID-19 infection. Clin. Exp. Med. 21, 167–179. doi: 10.1007/s10238-020-00671-y
Gutiérrez-Castrellón, P., Gandara-Martí, T., Abreu, Y., Abreu, A. T., Nieto-Rufino, C. D., López-Orduña, E., et al. (2022). Probiotic improves symptomatic and viral clearance in Covid19 outpatients: a randomized, quadruple-blinded, placebo-controlled trial. Gut Microbes 14:2018899. doi: 10.1080/19490976.2021.2018899
Hazan, S., Stollman, N., Bozkurt, H. S., Dave, S., Papoutsis, A. J., Daniels, J., et al. (2022b). Lost microbes of COVID-19: Bifidobacterium,Faecalibacterium depletion and decreased microbiome diversity associated with SARS-CoV-2 infection severity. BMJ Open Gastroenterol. 9:e000871. doi: 10.1136/bmjgast-2022-000871
Hazan, S., Dave, S., Gunaratne, A. W., Dolai, S., Clancy, R. L., McCullough, P. A., et al. (2022a). Effectiveness of ivermectin-based multidrug therapy in severely hypoxic, ambulatory COVID-19 patients. Future Microbiol. 17, 339–350. doi: 10.2217/FMB-2022-0014
Heidary, F., and Gharebaghi, R. (2020). Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen. J. Antibiot. (Tokyo) 73, 593–602. doi: 10.1038/s41429-020-0336-z
Hellwig, M. D., and Maia, A. (2021). A COVID-19 prophylaxis? Lower incidence associated with prophylactic administration of ivermectin. Int. J. Antimicrob. Agents 57:106248. doi: 10.1016/j.ijantimicag.2020.106248
Hughes, K. R., Harnisch, L. C., Alcon-Giner, C., Mitra, S., Wright, C. J., Ketskemety, J., et al. (2017). Bifidobacterium breve reduces apoptotic epithelial cell shedding in an exopolysaccharide and MyD88-dependent manner. Open Biol. 7:160155. doi: 10.1098/RSOB.160155
Jabczyk, M., Nowak, J., Hudzik, B., and Zubelewicz-Szkodzińska, B. (2021). Diet, probiotics and their impact on the gut microbiota during the COVID-19 pandemic. Nutrients 13:3172. doi: 10.3390/NU13093172
Joshi, G., Borah, P., Thakur, S., Sharma, P., Mayank, and Poduri, R. (2021). Exploring the COVID-19 vaccine candidates against SARS-CoV-2 and its variants: where do we stand and where do we go? Hum. Vaccines Immunother. 17, 4714–4740. doi: 10.1080/21645515.2021.1995283
Kerr, L., Cadegiani, F. A., Baldi, F., Lobo, R. B., Assagra, W. L. O., Proença, F. C., et al. (2022). Ivermectin prophylaxis used for COVID-19: a citywide, prospective, observational study of 223,128 subjects using propensity score matching. Cureus 14:e21272. doi: 10.7759/cureus.21272
Khaled, J. M. A. (2021). Probiotics, prebiotics, and COVID-19 infection: a review article. Saudi J. Biol. Sci. 28, 865–869. doi: 10.1016/j.sjbs.2020.11.025
Khan, S. I., Khan, S. I., Debnath, C. R., Nath, P. N., Mahtab, M. A., Nabeka, H., et al. (2020). Ivermectin treatment may improve the prognosis of patients with COVID-19. Arch. Bronconeumol. 56, 828–830. doi: 10.1016/j.arbres.2020.08.007
Khodavirdipour, A. (2021). Inclusion of cephalexin in COVID-19 treatment combinations may prevent lung involvement in mild infections: a case report with pharmacological genomics perspective. Glob. Med. Genet. 08, 078–081. doi: 10.1055/s-0041-1726461
Khodavirdipour, A., Asadimanesh, M., and Masoumi, S. A. (2021a). Impact of SARS-CoV-2 genetic blueprints on the oral manifestation of COVID-19: a case report. Glob. Med. Genet. 08, 183–185. doi: 10.1055/s-0041-1735538
Khodavirdipour, A., Chamanrokh, P., Alikhani, M. Y., and Alikhani, M. S. (2022). Potential of Bacillus subtilis against SARS-CoV-2 – a sustainable drug development perspective. Front. Microbiol. 13:718786. doi: 10.3389/fmicb.2022.718786
Khodavirdipour, A., Keramat, F., Hamid Hashemi, S., and YousefAlikhani, M. (2020). SARS-CoV-2; from vaccine development to drug discovery and prevention guidelines. AIMS Mol. Sci. 7, 281–291. doi: 10.3934/molsci.2020013
Khodavirdipour, A., Piri, M., Jabbari, S., and Khalaj-kondori, M. (2021c). Potential of CRISPR/Cas13 system in treatment and diagnosis of COVID-19. Glob. Med. Genet. 08, 007–010. doi: 10.1055/s-0041-1723086
Khodavirdipour, A., Jabbari, S., Keramat, F., and Alikhani, M. Y. (2021b). Concise update on genomics of COVID-19: approach to its latest mutations, escalated contagiousness, and vaccine resistance. Glob. Med. Genet. 08, 085–089. doi: 10.1055/s-0041-1725143
Kinobe, R. T., and Owens, L. (2021). A systematic review of experimental evidence for antiviral effects of ivermectin and an in silico analysis of ivermectin’s possible mode of action against SARS-CoV-2. Fundam. Clin. Pharmacol. 35, 260–276. doi: 10.1111/fcp.12644
Kishoria, N., Mathur, S. L., Parmar, V., Kaur, R. J., Agarwal, H., Parihar, B. S., et al. (2020). Ivermectin as adjuvant to hydroxycholoroquine in patients resistant to standard treatment for Sars-Cov-2: results of an open-label randomized clinical study. Paripex Indian J. Res. 9, 1–4. doi: 10.36106/paripex/4801859
Krolewiecki, A., Lifschitz, A., Moragas, M., Travacio, M., Valentini, R., Alonso, D. F., et al. (2021). Antiviral effect of high-dose ivermectin in adults with COVID-19: a proof-of-concept randomized trial. eClinicalMedicine 37:100959. doi: 10.1016/j.eclinm.2021.100959
Laing, R., Gillan, V., and Devaney, E. (2017). Ivermectin – old drug, new tricks? Trends Parasitol. 33, 463–472. doi: 10.1016/j.pt.2017.02.004
Lazarenko, L., Babenko, L., Sichel, L. S., Pidgorskyi, V., Mokrozub, V., Voronkova, O., et al. (2012). antagonistic action of lactobacilli and bifidobacteria in relation to Staphylococcus aureus and their influence on the immune response in cases of intravaginal Staphylococcosis in mice. Probiotics Antimicrob. Proteins 4, 78–89. doi: 10.1007/s12602-012-9093-z
Lehrer, S., and Rheinstein, P. H. (2020). Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to ACE2. In Vivo 34, 3023–3026. doi: 10.21873/invivo.12134
Lim, H. J., and Shin, H. S. (2020). Antimicrobial and immunomodulatory effects of Bifidobacterium strains: a review. J. Microbiol. Biotechnol. 30, 1793–1800. doi: 10.4014/JMB.2007.07046
Lim, S. C. L., Hor, C. P., Tay, K. H., Mat Jelani, A., Tan, W. H., Ker, H. B., et al. (2022). Efficacy of ivermectin treatment on disease progression among adults with mild to moderate COVID-19 and comorbidities: the I-TECH randomized clinical trial. JAMA Intern. Med. 182:426. doi: 10.1001/jamainternmed.2022.0189
Lima-Morales, R., Méndez-Hernández, P., Flores, Y. N., Osorno-Romero, P., Sancho-Hernández, C. R., Cuecuecha-Rugerio, E., et al. (2021). Effectiveness of a multidrug therapy consisting of Ivermectin, Azithromycin, Montelukast, and Acetylsalicylic acid to prevent hospitalization and death among ambulatory COVID-19 cases in Tlaxcala, Mexico. Int. J. Infect. Dis. 105, 598–605. doi: 10.1016/j.ijid.2021.02.014
López-Medina, E., López, P., Hurtado, I. C., Dávalos, D. M., Ramirez, O., Martínez, E., et al. (2021). Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: a randomized clinical trial. JAMA 325:1426. doi: 10.1001/jama.2021.3071
Markowiak, P., and Śliżewska, K. (2017). Effects of probiotics, prebiotics, and synbiotics on human health. Nutrients 9:1021. doi: 10.3390/nu9091021
Mayer, M. A., Krolewiecki, A., Ferrero, A., Bocchio, M., Barbero, J., Miguel, M., et al. (2022). Safety and efficacy of a MEURI program for the use of high dose ivermectin in COVID-19 patients. Front. Public Health 10:813378. doi: 10.3389/fpubh.2022.813378
Mehta, P., and Fajgenbaum, D. C. (2021). Is severe COVID-19 a cytokine storm syndrome: a hyperinflammatorydebate. Curr. Opin. Rheumatol. 33, 419–430. doi: 10.1097/BOR.0000000000000822
Mohan, A., Tiwari, P., Suri, T. M., Mittal, S., Patel, A., Jain, A., et al. (2021). Single-dose oral ivermectin in mild and moderate COVID-19 (RIVET-COV): a single-centre randomized, placebo-controlled trial. J. Infect. Chemother. 27, 1743–1749. doi: 10.1016/j.jiac.2021.08.021
Molyneux, D. H., and Ward, S. A. (2015). Reflections on the nobel prize for medicine 2015 – the public health legacy and impact of Avermectin and Artemisinin. Trends Parasitol. 31, 605–607. doi: 10.1016/j.pt.2015.10.008
Morgenstern, J., Redondo, J. N., Olavarria, A., Rondon, I., Roca, S., De Leon, A., et al. (2021). Ivermectin as a SARS-CoV-2 pre-exposure prophylaxis method in healthcare workers: a propensity score-matched retrospective cohort study. Cureus 13:e17455. doi: 10.7759/cureus.17455
Mukarram, M. S. (2021). Ivermectin use associated with reduced duration of Covid-19 febrile illness in a community setting. Int. J. Clin. Stud. Med. Case Rep. 13, 1–9. doi: 10.46998/IJCMCR.2021.13.000320
Mustafa, Z. U., Kow, C. S., Salman, M., Kanwal, M., Riaz, M. B., Parveen, S., et al. (2022). Pattern of medication utilization in hospitalized patients with COVID-19 in three District Headquarters Hospitals in the Punjab province of Pakistan. Explor. Res. Clin. Soc. Pharm. 5:100101. doi: 10.1016/j.rcsop.2021.100101
Okumuş, N., Demirtürk, N., Çetinkaya, R. A., Güner, R., Avcı, İY., Orhan, S., et al. (2021). Evaluation of the effectiveness and safety of adding ivermectin to treatment in severe COVID-19 patients. BMC Infect. Dis. 21:411. doi: 10.1186/s12879-021-06104-9
Ômura, S., and Crump, A. (2014). Ivermectin: panacea for resource-poor communities? Trends Parasitol. 30, 445–455. doi: 10.1016/j.pt.2014.07.005
Ozer, M., Goksu, S. Y., Conception, R., Ulker, E., Balderas, R. M., Mahdi, M., et al. (2022). Effectiveness and safety of Ivermectin in COVID-19 patients: a prospective study at a safety-net hospital. J. Med. Virol. 94, 1473–1480. doi: 10.1002/jmv.27469
Podder, C. S., Chowdhury, N., Sina, M. I., and Haque, W. M. M. U. (2021). Outcome of ivermectin treated mild to moderate COVID-19 cases: a single-centre, open-label, randomised controlled study. IMC J. Med. Sci. 14, 11–18. doi: 10.3329/imcjms.v14i2.52826
Rajter, J. C., Sherman, M. S., Fatteh, N., Vogel, F., Sacks, J., and Rajter, J.-J. (2021). Use of ivermectin is associated with lower mortality in hospitalized patients with Coronavirus disease 2019. Chest 159, 85–92. doi: 10.1016/j.chest.2020.10.009
Ravikirti, Roy, R., Pattadar, C., Raj, R., Agarwal, N., Biswas, B., et al. (2021). Evaluation of ivermectin as a potential treatment for mild to moderate COVID-19: a double-blind randomized placebo controlled trial in Eastern India. J. Pharm. Pharm. Sci. 24, 343–350. doi: 10.18433/jpps32105
Reaz, M., Rahman, M., Iftikher, A., Ahmed, K. G. U., Kabir, A. K. M. H., Sayeed, S. K. J. B., et al. (2020). Ivermectin in combination with doxycycline for treating COVID-19 symptoms: a randomized trial. J. Int. Med. Res. 49:3000605211013550. doi: 10.5061/DRYAD.QJQ2BVQF6
Reinold, J., Farahpour, F., Fehring, C., Dolff, S., Konik, M., Korth, J., et al. (2021). A pro-inflammatory gut microbiome characterizes SARS-CoV-2 infected patients and a reduction in the connectivity of an anti-inflammatory bacterial network associates with severe COVID-19. Front. Cell. Infect. Microbiol. 11:747816. doi: 10.3389/fcimb.2021.747816
Reis, G., Silva, E. A. S. M., Silva, D. C. M., Thabane, L., Milagres, A. C., Ferreira, T. S., et al. (2022). Effect of early treatment with ivermectin among patients with Covid-19. N. Engl. J. Med. 386, 1721–1731. doi: 10.1056/NEJMoa2115869
Rezk, N., ElsayedSileem, A., Gad, D., and Khalil, A. O. (2021). miRNA-223-3p, miRNA- 2909 and cytokines expression in COVID-19 patients treated with ivermectin. Zagazig Univ. Med. J. 28, 573–582. doi: 10.21608/zumj.2021.92746.2329
Rivière, A., Selak, M., Lantin, D., Leroy, F., and De Vuyst, L. (2016). Bifidobacteria and butyrate-producing colon bacteria: importance and strategies for their stimulation in the human gut. Front. Microbiol. 7:979. doi: 10.3389/fmicb.2016.00979
Rizzo, E. (2020). Ivermectin, antiviral properties and COVID-19: a possible new mechanism of action. Naunyn. Schmiedebergs Arch. Pharmacol. 393, 1153–1156. doi: 10.1007/s00210-020-01902-5
Ruiz, L., Delgado, S., Ruas-Madiedo, P., Sánchez, B., and Margolles, A. (2017). Bifidobacteria and their molecular communication with the immune system. Front. Microbiol. 8:2345. doi: 10.3389/fmicb.2017.02345
Saha, J. K., and Raihan, J. (2021). The binding mechanism of ivermectin and levosalbutamol with spike protein of SARS-CoV-2. Struct. Chem. 32, 1985–1992. doi: 10.1007/s11224-021-01776-0
Seet, R. C. S., Quek, A. M. L., Ooi, D. S. Q., Sengupta, S., Lakshminarasappa, S. R., Koo, C. Y., et al. (2021). Positive impact of oral hydroxychloroquine and povidone-iodine throat spray for COVID-19 prophylaxis: an open-label randomized trial. Int. J. Infect. Dis. 106, 314–322. doi: 10.1016/j.ijid.2021.04.035
Seipke, R. F., Kaltenpoth, M., and Hutchings, M. I. (2012). Streptomyces as symbionts: an emerging and widespread theme? FEMS Microbiol. Rev. 36, 862–876. doi: 10.1111/j.1574-6976.2011.00313.x
Shahbaznejad, L., Davoudi, A., Eslami, G., Markowitz, J. S., Navaeifar, M. R., Hosseinzadeh, F., et al. (2021). Effects of ivermectin in patients with COVID-19: a multicenter, double-blind, randomized, controlled clinical trial. Clin. Ther. 43, 1007–1019. doi: 10.1016/j.clinthera.2021.04.007
Sharma, A., Ahmad Farouk, I., and Lal, S. K. (2021). COVID-19: a review on the novel coronavirus disease evolution, transmission, detection, control and prevention. Viruses 13:202. doi: 10.3390/v13020202
Shimizu, K., Hirata, H., Kabata, D., Tokuhira, N., Koide, M., Ueda, A., et al. (2022). Ivermectin administration is associated with lower gastrointestinal complications and greater ventilator-free days in ventilated patients with COVID-19: a propensity score analysis. J. Infect. Chemother. 28, 548–553. doi: 10.1016/j.jiac.2021.12.024
Shoumann, W. M., Hegazy, A. A., Nafae, R. M., Ragab, M. I., Samra, S. R., Ibrahim, D. A., et al. (2021). Use of ivermectin as a potential chemoprophylaxis for COVID-19 in egypt: a randomised clinical trial. J. Clin. Diagn. Res. 15, OC27–OC32. doi: 10.7860/JCDR/2021/46795.14529
Tao, W., Zhang, G., Wang, X., Guo, M., Zeng, W., Xu, Z., et al. (2020). Analysis of the intestinal microbiota in COVID-19 patients and its correlation with the inflammatory factor IL-18. Med. Microecol. 5:100023. doi: 10.1016/j.medmic.2020.100023
Xu, K., Cai, H., Shen, Y., Ni, Q., Chen, Y., Hu, S., et al. (2020). [Management of corona virus disease-19 (COVID-19): the Zhejiang experience]. Zhejiang XueXueBao Yi Xue Ban J. Zhejiang Univ. Med. Sci. 49, 147–157.
Yeoh, Y. K., Zuo, T., Lui, G. C.-Y., Zhang, F., Liu, Q., Li, A. Y., et al. (2021). Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19. Gut 70, 698–706. doi: 10.1136/gutjnl-2020-323020
Zayet, S., Gendrin, V., and Klopfenstein, T. (2020). Natural history of COVID-19: back to basics. New Microbes New Infect. 38:100815. doi: 10.1016/j.nmni.2020.100815
Zhang, C., Albermann, C., Fu, X., and Thorson, J. S. (2006). The in vitro characterization of the iterative avermectin glycosyltransferase AveBI reveals reaction reversibility and sugar nucleotide flexibility. J. Am. Chem. Soc. 128, 16420–16421. doi: 10.1021/JA065950K
Zubair, S. M., Chaudhry, M. W., Zubairi, A. B. S., Shahzad, T., Zahid, A., Khan, I. A., et al. (2022). The effect of ivermectin on non-severe and severe COVID-19 disease and gender-based difference of its effectiveness. Monaldi Arch. Chest Dis. doi: 10.4081/monaldi.2022.2062 [Epub ahead of print].
Keywords: microbiome, COVID-19, SARS-CoV-2, Bifidobacterium, TNF-α (tumor necrosis factor a), ivermectin
Citation: Hazan S (2022) Microbiome-Based Hypothesis on Ivermectin’s Mechanism in COVID-19: Ivermectin Feeds Bifidobacteria to Boost Immunity. Front. Microbiol. 13:952321. doi: 10.3389/fmicb.2022.952321
Received: 25 May 2022; Accepted: 10 June 2022;
Published: 11 July 2022.
Edited by:
Mohammad Yousef Alikhani, Hamadan University of Medical Sciences, IranReviewed by:
Amir Khodavirdipour, University of Tabriz, IranPiyush Baindara, University of Missouri, United States
Copyright © 2022 Hazan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Sabine Hazan, DrHazan@progenabiome.com