Butyrate and Fermentable Fiber as Adjunct Therapy for Covid-19 – Food for Thought
Abstract
In just this past year the use of butyrate as adjunct therapy for Covid-19 has gained wider recognition and support in the peer-reviewed literature. Presented here is a review of that literature and comments regarding the use of butyrate as a safe and effective adjunct in treating patients with Covid-19 with the aim of preventing the potentially damaging effects of an overactive immune response (cytokine storm).
Keywords: Covid-19, butyrate, sodium butyrate, inflammation, anti-inflammatory, butyrogenic microbiota, cytokine storm
Introduction
In June, 2020 Archer and Kramer[1] published “Opinion: The Use of Microbial Accessible and Fermentable Carbohydrates and/or Butyrate as Supportive Treatment for Patients With Coronavirus SARS-CoV-2 Infection.” Since that time, many papers have been published supporting the notion that the short chain fatty acid (SCFA) butyrate may help prevent or mitigate symptomatic Covid-19[1–7]. In most papers, butyrate is not suggested as sole treatment, but as an adjunct to existing therapy. Table 1 presents peer-reviewed publications that have appeared since June, 2020 suggesting a direct or indirect role for butyrate in mitigating symptoms and/or severity of Covid-19. The science strongly points to the need for human clinical trials of butyrate as an adjunct, supportive therapy in Covid-19.
Buyrate Direct and Indirect Mechanisms Of Action
Several papers cite butyrate’s known function as a histone deacetylase (HDAC) inhibitor as a proposed mechanism for its anti-Covid-19 activity[8–10]. For example, HDACs can simultaneously suppress ACE2[8,9], the receptor for SARS-CoV-2, and ABO blood group antigens, as non-O individuals appear to be at higher risk for severe Covid-19 than O group individuals. Another HDAC inhibitor, valproic acid, has been suggested as an alternative therapy for Covid-19, as it reduces ACE2, suppresses IL-6, changed macrophages from a proinflammatory (M1) to an anti-inflammatory (M2) type, and decreases the disseminated intravascular coagulopathy frequently seen as a lung complication, as well as myocardial, renal, and cerebral complications in Covid-19[10].
Table 1: References appearing in the peer-reviewed literature since June 2020 suggesting a direct or indirect role for butyrate in mitigating symptoms and/or severity of Covid-19
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Butyrate suggested as a direct treatment for Covid-19 |
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Butyrate as an HDAC Inhibitor or related HDAC Inhibitors as direct treatments for Covid-19 |
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Butyrate via Fiber Digestion (prebiotics), probiotics, or diet as indirect treatment(s) or mitigation factor(s) of Covid-19 |
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Butyrate anti-inflammatory effects in various organ systems |
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Microbiota Changes/Gut Dysbiosis/Leaky Gut (as they affect butyrate) and Covid-19 |
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Numerous papers have addressed butyrate as a possible therapy for Covid-19 via increased fiber digestion (prebiotics), by supplementing the intestinal microbiota with bacteria in part responsible for butyrate production (probiotics), or dietary interventions with high fiber foods and fermented foods as indirect treatment(s) or mitigation factor(s) of Covid-19[11–22]. Interventions in this grouping all relate to a measurable lack of butyrogenic microbiota in Covid-19 patients.
Therapeutic Effects
Butyrate exerts anti-inflammatory effects in other disease states and organ systems that provide insight into its possible therapeutic effects in Covid-19[23–25]. For example, butyrate generated by gut microbiota exerts a therapeutic effect in persons with metabolic syndrome. The hallmarks of metabolic syndrome, obesity, high blood pressure, pre-diabetes and diabetes, are established susceptibility factors for Covid-19. These and other clinical features of metabolic syndrome are improved by increasing colonic butyrate production by the butyrogenic microbiota, many by way of HDAC inhibition[23]. Inflammatory Bowel Disease (IBD) is a group of intestinal disorders, the best known being Crohn’s disease and Ulcerative colitis. Studies suggest that butyrate, using three mechanisms (including the aforementioned HDAC inhibition) to exert anti-inflammatory effects in the colon, may be a prospective therapy for IBD[24].
Evidence strongly suggests that butyrate-producing gut microbiota may prevent/delay the onset of neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD)[25]. Butyrogenic gut microbiota are downregulated in both PD and AD, and dietary factors that modify gut microbiome dysbiosis to favor butyrogenic microbiota may prevent and treat cognitive deficits of Alzheimer’s disease and Parkinson’s disease[25]. Thus, butyrate’s anti-inflammatory properties influence the course of several diseases that are based on inflammation; it would seem reasonable, therefore, to expect that butyrate might also influence inflammation related to Covid-19 infection.
Variables in the Effects of Butyrate
Microbiota changes, gut dysbiosis, and increased intestinal permeability are all conditions that can affect butyrate production and utilization, and as such can affect the disease process progression of Covid-19[26–37]. Many clinical studies have demonstrated a loss of butyrogenic microbiota correlating with increasing severity of Covid-19 symptoms[26,27]. References to dysbiosis in nearly all reported studies of the microbiota profile of those infected with Covid-19 translate to a loss of butyrate producers[28,29,32–34]. Kim[26] suggests that fecal viral load in persons with increased intestinal permeability may gain access to readily infected enterocytes, and result in higher plasma virus loads and viral migration throughout the body. Besides facilitated viral entry through a permeable gut lining, toxins and substances such as LPS and other luminal contents may trigger or exacerbate inflammation and disrupt normal immune control mechanisms such as Tregs.
It has been suggested that therapeutic approaches such as fecal microbial transplant, use of dietary fiber (prebiotics) and next-generation butyrate-producing probiotics be explored further once safety concerns and regulatory hurdles are overcome[26]. Fermentable fiber appears to maximize immune defenses in those who are exposed to SARS-Cov-19 and may, likewise, boost immune defenses in those who are infected.
However, the usefulness of microbial accessible and fermentable carbohydrates may be diminished once dysbiosis is established in Covid-19 patients. The microbiota most frequently reported diminished in Covid-19 infection are butyrate-producers. If butyrate producers are missing or diminished during Covid-related dysbiosis, fermentable fiber may provide little or no benefit as an adjunct in treatment, however, the use of exogenous sources of butyrate may prove beneficial.
Therapeutic Applications of Butyrate
The treatment of inflammatory illness by oral administration of butyrate has been addressed in recent patent applications[38,39]. Human studies have been cited, and while not peer-reviewed, results were promising against inflammation in osteoarthritis, gout, multiple sclerosis, and Parkinson’s disease.
Elevated IL-6 is an accepted marker for cytokine release in serious Covid-19 infections[40]. Since butyrate has been shown to significantly decrease serum IL-6 in other conditions, like idiopathic subfertility[38], the oral administration of butyrate might be clinically relevant in Covid-19 as well.
Systemic levels of butyrate in blood are 1000-fold less than levels found in the colon[41]. Blood levels of butyrate vary significantly among individuals, likely due to variations in diet, body type, metabolism, and other factors. Although blood levels of butyrate are exceedingly low, overwhelming evidence attests to its importance in the periphery in many organ systems[42,43]. It is unclear presently how or whether oral administration of butyrate can affect the blood concentrations significantly, although evidence would strongly support that it does[38,48].
The enteric administration of butyrate has been shown to be safe for human and animals and carries the FDA GRAS designation (Generally Recognized as Safe—GRAS) in human foods[46].
Status of New Formulations
Currently, there are several butyrate formulations available in the United States as dietary supplements, and/or drugs[47–50]. Others are under development[51]. There are additional calls for controlled studies to explore the use of butyrate in other diseases[52], including Parkinson’s disease[54], Alzheimer’s disease[55], and Autism spectrum disorder[56]. There are additional studies on direct antimicrobial and immunomodulatory effects of butyrate[57], and more specific recommendations for orally administered butyrate in Covid-19[58].
Based on microbiome studies showing extreme losses of butyrogenic microbiota in Covid-19, fecal microbiota transplant has been recommended[59] and carried out in a small clinical trial with positive results forming the basis for a larger clinical trial[60]. Previous observations regarding the ability of butyrate to support CD8+ cytotoxic T lymphocytes in their anti-cancer role[61] have become relevant to Covid-19 immunity, as CD8+ memory cells specific for Coronavirus epitopes encountered in the past may have led to milder illness in individuals possessing them[62].
Conclusion
Since proposing butyrate as an adjunct therapy for Covid-19 in June, 2020,[1] support for such use in the peer-reviewed literature has accelerated. Unfortunately, despite the introduction of effective vaccines, SARS-CoV-2 continues to evolve within a largely unvaccinated population worldwide. Covid-19 remains at pandemic levels for most countries, and thus effective, readily available, and affordable treatments are of vital importance. Considering all the diseases that butyrate is thought to prevent or mitigate, it would seem reasonable that greater efforts be directed at developing and testing forms of butyrate and its use as an adjunct for treating COVID-19. Jardou and Lawson[63] hypothesize that butyrate can be administered to persons with Covid-19 to prevent immune system activation and disease progression. They propose a testing scheme to be administered in early stages of Covid-19 to determine if SCFA treatment is warranted based on plasma levels of acetate, propionate, and butyrate, pro-inflammatory cytokines in blood, and/or M1/M2 macrophages[64] ratio. They have further provided a proposed human clinical trial scheme for administration of butyrate[63]. These trials need to be conducted now.
References
Article Type
Opinion Article
Publication history
Received: October 11, 2022
Accepted: October 21, 2022
Published: October 27, 2022
Citation:
Archer DL, Kramer DC (2022) Butyrate and Fermentable Fiber as Adjunct Therapy for Covid-19 – Food for Thought. Clar J Infect Dis Ther 03(02): 232–238.
Douglas L. Archer1 and Dean C. Kramer2
1Food Science and Human Nutrition Department, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, Florida, USA, 32611-0370
2Gastroenterology, Kramer Medical Clinic, Gainesville, Florida, USA, 32605-4477
*Corresponding author
Professor Douglas L. Archer,
Food Science and Human Nutrition Department,
Institute of Food and Agricultural Sciences,
P.O. Box 110370,
University of Florida,
Gainesville, Florida,
USA 32611-0370