I have been researching the interaction of the gut microbiome with Covid-19 since the start of the pandemic. Now that concrete information is available, I am incorporating this information into my CORONAVIRUS GUIDE, which I update periodically, but I believe the information is so important that I am posting it as a separate document, for people in a hurry.
The science is complex, but it leads to specific recommended actions, which come at the end of this section.
Your body teems with microbes, tens of trillions of them. Collectively they are called the microbiome. They include bacteria, viruses, fungi, and –for most people in the world—worms and protozoa, like amebas. Bacteria have been the most studied; 99% of them are found in your large intestine. Because two-thirds of your lymphocytes make their home in the small intestine, there has been extensive investigation into the cross-talk between gut bacteria and immune function.
A lot’s been published on the impact of gut bacteria on respiratory health  and on viral infections , so the early months of the pandemic saw considerable speculation about a link between gut microbes and Covid-19. Actual evidence began to emerge late in 2020. It derives from studies of patients in hospital and the numbers are small, but it presents a coherent picture.
First, people hospitalized with Covid-19 show profound changes in the microbiome as measured in stool specimens. Some of these changes may represent the impact of hospitalization, but there is a deeper connection. ACE2, the cellular receptor for the virus, has a special function in the small intestine. It acts as a chaperone for an enzyme that transports amino acids into the body. Damage to intestinal ACE2 creates amino acid deficiencies that impair gut immunity and barrier function , producing abnormalities in the microbiome (this state is called dysbiosis) and increased permeability of the intestinal lining (the so-called “leaky gut.”). Intestinal leakiness in Covid-19 is associated with damage to the heart .
Covid-19 decreases diversity and richness of bacteria in the gut microbiome, with depletion of some beneficial species and overgrowth of others considered undesirable . Covid-19 also increases the richness of yeasts and fungi in the gut (the mycobiome) . The predominant fungal opportunists promoted by Covid-19 are the well-known yeast, Candida albicans, its scary cousin Candida auris (which has received global attention as an invasive drug resistant species ), and the potent allergen, Aspergillus flavus. These organisms persist in stool even after respiratory symptoms have cleared and nose or throat swabs show no active viral infection.
To date, no one has studied the impact of fungi in covid longhaulers, but I’ve been investigating, treating and teaching about yeast and fungal overgrowth for over 40 years and I’ve seen what they can do. Intestinal fungi can exert potent, often undesirable, effects on immunity, inflammation and metabolism that create symptoms in many body systems. Stool testing for bacteria and yeast should be considered in all people with persisting post-covid symptoms.
Some researchers have attempted to correlate specific bacterial disturbances with severity of Covid-19. Two provocative findings have appeared. First, severity correlates with lower levels of a key anti-inflammatory species called Faecalibacterium prausnitzii. Loss of Faecalibacterium prausnitzii and its friends, the Bifidobacteria, persists for weeks after hospitalization, and correlates with increased severity of systemic inflammation  .
The largest and most recent study, from the University of Massachusetts, found that excessive growth of one species, Enterococcus faecalis, in fecal or oral specimens, was the best predictor of severe disease, more accurate than symptoms or underlying medical conditions. The study’s authors note that Enterococcus faecalis is a potent stimulator of inflammation. They believe it actively contributes to worse outcomes for people with Covid-19. Theirs is a reasonable theory, because the use of Enterococcus faecalis as a probiotic provokes the release of gamma-interferon , a major driver of the cytokine storm of severe Covid-19 (This role of gamma-interferon is described in IMMUNITY in the CORONAVIRUS GUIDE).
Possible support for the importance of the oral microbiome in Covid-19 comes from a study done in Bangladesh . In a randomized controlled clinical trial, medical researchers told patients newly diagnosed with Covid 19, to use a povidone/iodine mouth wash (plus a nasal wash and eye drops) or use only warm water to flush their mouth, nose and eyes. The solutions were used every 4 hours for 4 weeks. Povidone iodine reduced the need for hospitalization and oxygen therapy by 84% and the death rate by 86%, compared to warm water. The researchers attributed the benefits to killing of the SARS-CoV-2 virus in the nose, mouth and throat, but by the time they were treated, these patients were already sick with Covid-19, making it likely that the infectious was already systemic. Povidone/iodine kills bacteria as well as viruses and is quite effective at killing Enterococcus faecalis and other oral pathogens, so it is possible that eliminating pro-inflammatory bacteria from the mouth improved the outcome of disease in their patients.
So, here’s the good news:
If an unbalanced microbiome creates sickness in people with Covid-19, restoring balance should lead to milder disease. Overgrowth of Enterococcus faecalis can be reversed. In addition to the use of an iodine-based gargle (which may only be needed once symptoms occur), there are several natural substances and dietary factors that can correct the specific microbiome imbalances described in Covid-19.
Resveratrol, a polyphenol that enhances activity of ACE2, inhibits the growth of Enterococcus faecalis   and curcumin, another natural ACE2 enhancer, decreases bacterial virulence by breaking up biofilms that support the growth of Enterococcus faecalis  . Both resveratrol and curcumin are basic ingredients in my recommended protocol for preventing severe infection.
Ursolic acid is a dietary compound found in many fruits, vegetables, herbs and spices and is used as a muscle-building supplement by body builders. Like resveratrol and curcumin, ursolic acid has anti-inflammatory, anti-viral and cancer-fighting activity . It also inhibits the growth of Enterococcus faecalis .
Dietary sources of ursolic acid include apple peel, cranberries, bilberries, blueberries, prunes, peppermint, rosemary, oregano, thyme, sage, and marjoram. Dried cranberries are an especially good source . Human clinical trials of ursolic acid show anti-inflammatory effects at doses of 150 mg taken 1 to 3 times a day . Ursolic acid may also inhibit the SARS-CoV-2 main protease   The importance of this enzyme is described in AFTER ENTRY: THE ROLE OF NSPs in the CORONAVIRUS GUIDE).
Just as nutritional strategies can control colonization with the inflammatory organism Enterococcus faecalis, they can support growth of the anti-inflammatory Faecalibacterium prausnitzii, which is fed by fiber-rich foods , fiber supplements   , and certain prebiotics . Daily consumption of chick peas  or of avocados  increases abundance of F prausnitzii in human volunteers.
Although probiotics based on F. prausnitzii do not exist, two commercial probiotics can increase its levels, according to human clinical trials. Bifidobacterium longum BB536 increases the growth of F. prausnitzii at the same time in relieves symptoms of pollen allergy in adults  or upper respiratory infection in young children . Bacillus coagulans GBI-30, 6086 [GanedenBC(30)] was shown to increase growth of F. prausnitzii in men and women over the age of 65 . Bacillus coagulans pre-treatment also enhanced the effect of prebiotics in stimulating growth of F. prausnitzii in a clinical trial of older adults .
The bottom line:
A protocol for building a Covid fighting microbiome fits seamlessly into the program I call INTEGRATED VIRAL MANAGEMENT, described in the CORONAVIRUS GUIDE.
- Diet: a whole foods, plant-based diet, rich in vegetables, fruits, and spices to supply fiber, prebiotic carbohydrates, and polyphenols. Emphasize natural food sources of ursolic acid like berries, especially cranberries, whole apples, prunes, peppermint tea, and savory herbs like rosemary, oregano, thyme, sage and turmeric. Rosemary, thyme and sage are also good sources of rosmarinic acid, a natural promoter of ACE2 activity.
- Supplement with resveratrol and curcumin (more about these in ACE2 ENHANCEMENT and THERAPEUTIC PROFILES in the CORONAVIRUS GUIDE).
- Take a probiotic shown to enhance the growth of Faecalibacterium prausnitzii like Bifidobacterium longum BB536 or Bacillus coagulans.
- If you develop acute symptoms of Covid-19, supplement with ursolic acid 150 mg 3 times a day and use an iodine-based mouthwash (don’t swallow, rinse for 30 seconds and spit it out). The study from Bangladesh used a preparation of standard povidone/iodine 10% (available online and in pharmacies) and diluted it with water to produce a concentration of 1% povidone iodine. There is a commercial iodine spray that approximates that concentration (available at www.Halodine.com).
- If you develop diarrhea or abdominal pain as a symptom of Covid-19, there is a unique probiotic that may actually kill the virus, because of its ability to produce alpha-interferon, the natural substance against which the SARS-CoV-2 virus is most vulnerable. It’s a strain of the soil-derived organism Bacillus subtilis. Please contact my office for more information about this strain, because it is in very short supply.
 Zhang D, Li S, Wang N, Tan HY, Zhang Z, Feng Y. The Cross-Talk Between Gut Microbiota and Lungs in Common Lung Diseases. Front Microbiol. 2020;11:301. Published 2020 Feb 25. doi:10.3389/fmicb.2020.00301
 Li N, Ma WT, Pang M, Fan QL, Hua JL. The Commensal Microbiota and Viral Infection: A Comprehensive Review. Front Immunol. 2019;10:1551. Published 2019 Jul 4. doi:10.3389/fimmu.2019.01551
 Viana SD, Nunes S, Reis F. ACE2 imbalance as a key player for the poor outcomes in COVID-19 patients with age-related comorbidities – Role of gut microbiota dysbiosis. Ageing Res Rev. 2020 Sep;62:101123. doi: 10.1016/j.arr.2020.101123. Epub 2020 Jul 16. PMID: 32683039; PMCID: PMC7365123.
 Camargo SMR, Vuille-Dit-Bille RN, Meier CF, Verrey F. ACE2 and gut amino acid transport. Clin Sci (Lond). 2020 Nov 13;134(21):2823-2833. doi: 10.1042/CS20200477. PMID: 33140827.
 Hoel H et al. Elevated markers of gut leakage and inflammasome activation in COVID-19 patients with cardiac involvement J Intern Med 2020 Sep 25. doi: 10.1111/joim.13178.
 Gu S, Chen Y, Wu Z, Chen Y, Gao H, Lv L, Guo F, Zhang X, Luo R, Huang C, Lu H, Zheng B, Zhang J, Yan R, Zhang H, Jiang H, Xu Q, Guo J, Gong Y, Tang L, Li L. Alterations of the Gut Microbiota in Patients with COVID-19 or H1N1 Influenza. Clin Infect Dis. 2020 Jun 4:ciaa709. doi: 10.1093/cid/ciaa709. Epub ahead of print. PMID: 32497191; PMCID: PMC7314193.
 Zuo T, Zhan H, Zhang F, et al. Alterations in Fecal Fungal Microbiome of Patients With COVID-19 During Time of Hospitalization until Discharge. Gastroenterology. 2020;159(4):1302-1310.e5. doi:10.1053/j.gastro.2020.06.048
 Lone SA, Ahmad A. Candida auris-the growing menace to global health. Mycoses. 2019 Aug;62(8):620-637. doi: 10.1111/myc.12904. Epub 2019 Jun 18. PMID: 30773703.
 Zuo T, Zhang F, Lui GCY, Yeoh YK, Li AYL, Zhan H, Wan Y, Chung A, Cheung CP, Chen N, Lai CKC, Chen Z, Tso EYK, Fung KSC, Chan V, Ling L, Joynt G, Hui DSC, Chan FKL, Chan PKS, Ng SC, Alterations in Gut Microbiota of Patients With COVID-19 During Time of Hospitalization, Gastroenterology (2020), doi: https://doi.org/10.1053/j.gastro.2020.05.048.
 Yeoh YK, Zuo T, Lui GC-Y, et al. Gut Epub ahead of print: [please include Day Month Year]. doi:10.1136/ gutjnl-2020-323020….. Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19
 Molina MA, Díaz AM, Hesse C, Ginter W, Gentilini MV, Nuñez GG, Canellada AM, Sparwasser T, Berod L, Castro MS, Manghi MA. Immunostimulatory Effects Triggered by Enterococcus faecalis CECT7121 Probiotic Strain Involve Activation of Dendritic Cells and Interferon-Gamma Production. PLoS One. 2015 May 15;10(5):e0127262. doi: 10.1371/journal.pone.0127262. PMID: 25978357; PMCID: PMC4433276.
 Effect of 1% Povidone Iodine Mouthwash/Gargle, Nasal and Eye Drop in COVID-19 patient.
Bioresearch Communications, Volume 7, Issue 1, January 2021Md. Iqbal Mahmud Choudhury1, NilufarShabnam2, Tazin Ahsan3, Md. Saiful kabir4,
 Chan MM. Antimicrobial effect of resveratrol on dermatophytes and bacterial pathogens of the skin. Biochem Pharmacol. 2002 Jan 15;63(2):99-104. doi: 10.1016/s0006-2952(01)00886-3. PMID: 11841782.
 Hu Y, Chen D, Zheng P, Yu J, He J, Mao X, Yu B. The Bidirectional Interactions between Resveratrol and Gut Microbiota: An Insight into Oxidative Stress and Inflammatory Bowel Disease Therapy. Biomed Res Int. 2019 Apr 24;2019:5403761. doi: 10.1155/2019/5403761. PMID: 31179328; PMCID: PMC6507241.
 Sainudeen S, Nair VS, Zarbah M, Abdulla AM, Najeeb CM, Ganapathy S. Can Herbal Extracts Serve as Antibacterial Root Canal Irrigating Solutions? Antimicrobial Efficacy of Tylophora indica, Curcumin longa, Phyllanthus amarus, and Sodium Hypochlorite on Enterococcus faecalis Biofilms Formed on Tooth Substrate: In Vitro Study. J Pharm Bioallied Sci. 2020 Aug;12(Suppl 1):S423-S429. doi: 10.4103/jpbs.JPBS_127_20. Epub 2020 Aug 28. PMID: 33149499; PMCID: PMC7595561.
 Neelakantan P, Subbarao C, Sharma S, Subbarao CV, Garcia-Godoy F, Gutmann JL. Effectiveness of curcumin against Enterococcus faecalis biofilm. Acta Odontol Scand. 2013 Nov;71(6):1453-7. doi: 10.3109/00016357.2013.769627. Epub 2013 Feb 11. PMID: 23394209.
 Ramírez-Rodríguez AM, González-Ortiz M, Martínez-Abundis E, Acuña Ortega N. Effect of Ursolic Acid on Metabolic Syndrome, Insulin Sensitivity, and Inflammation. J Med Food. 2017 Sep;20(9):882-886. doi: 10.1089/jmf.2017.0003. Epub 2017 Jun 9. PMID: 28598231.
 Medina-Vera I, Sanchez-Tapia M, Noriega-López L, Granados-Portillo O, Guevara-Cruz M, Flores-López A, Avila-Nava A, Fernández ML, Tovar AR, Torres N. A dietary intervention with functional foods reduces metabolic endotoxaemia and attenuates biochemical abnormalities by modifying faecal microbiota in people with type 2 diabetes. Diabetes Metab. 2019 Apr;45(2):122-131. doi: 10.1016/j.diabet.2018.09.004. Epub 2018 Sep 25. PMID: 30266575.
 Benus RF, van der Werf TS, Welling GW, Judd PA, Taylor MA, Harmsen HJ, Whelan K. Association between Faecalibacterium prausnitzii and dietary fibre in colonic fermentation in healthy human subjects. Br J Nutr. 2010 Sep;104(5):693-700. doi: 10.1017/S0007114510001030. Epub 2010 Mar 29. PMID: 20346190.
 Dewulf EM, Cani PD, Claus SP, Fuentes S, Puylaert PG, Neyrinck AM, Bindels LB, de Vos WM, Gibson GR, Thissen JP, Delzenne NM. Insight into the prebiotic concept: lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women. Gut. 2013 Aug;62(8):1112-21. doi: 10.1136/gutjnl-2012-303304. Epub 2012 Nov 7. PMID: 23135760; PMCID: PMC3711491.
 Ramirez-Farias C, Slezak K, Fuller Z, Duncan A, Holtrop G, Louis P. Effect of inulin on the human gut microbiota: stimulation of Bifidobacterium adolescentis and Faecalibacterium prausnitzii. Br J Nutr. 2009 Feb;101(4):541-50. doi: 10.1017/S0007114508019880. Epub 2008 Jul 1. PMID: 18590586.
 Fernando WM, Hill JE, Zello GA, Tyler RT, Dahl WJ, Van Kessel AG. Diets supplemented with chickpea or its main oligosaccharide component raffinose modify faecal microbial composition in healthy adults. Benef Microbes. 2010 Jun;1(2):197-207. doi: 10.3920/BM2009.0027. PMID: 21831757.
 Avocado Consumption Alters GastrointestinalBacteria Abundance and Microbial MetaboliteConcentrations among Adults withOverweight or Obesity: A RandomizedControlled TrialSharon V Thompson,1Melisa A Bailey,1Andrew M Taylor,2Jennifer L Kaczmarek,1AnnemarieR Mysonhimer,2Caitlyn G Edwards,1Ginger E Reeser,3Nicholas A Burd,1,3Naiman A Khan,1,3,4and Hannah D Holscher, J Nutr2020;00:1–10.
 Odamaki T, Xiao JZ, Iwabuchi N, Sakamoto M, Takahashi N, Kondo S, Miyaji K, Iwatsuki K, Togashi H, Enomoto T, Benno Y. Influence of Bifidobacterium longum BB536 intake on faecal microbiota in individuals with Japanese cedar pollinosis during the pollen season. J Med Microbiol. 2007 Oct;56(Pt 10):1301-1308. doi: 10.1099/jmm.0.47306-0. PMID: 17893165.
 Lau AS, Yanagisawa N, Hor YY, Lew LC, Ong JS, Chuah LO, Lee YY, Choi SB, Rashid F, Wahid N, Sugahara H, Xiao JZ, Liong MT. Bifidobacterium longum BB536 alleviated upper respiratory illnesses and modulated gut microbiota profiles in Malaysian pre-school children. Benef Microbes. 2018 Jan
 Nyangale EP, Farmer S, Cash HA, Keller D, Chernoff D, Gibson GR. Bacillus coagulans GBI-30, 6086 Modulates Faecalibacterium prausnitzii in Older Men and Women. J Nutr. 2015 Jul;145(7):1446-52. doi: 10.3945/jn.114.199802. Epub 2015 May 6. PMID: 25948780.
 Nyangale EP, Farmer S, Keller D, Chernoff D, Gibson GR. Effect of prebiotics on the fecal microbiota of elderly volunteers after dietary supplementation of Bacillus coagulans GBI-30, 6086. Anaerobe. 2014 Dec;30:75-81. doi: 10.1016/j.anaerobe.2014.09.002. Epub 2014 Sep 16. Erratum in: Anaerobe. 2015 Aug;34:187. PMID: 25219857.