Impact Factor 3.113 | CiteScore 3.03
More on impact ›

Opinion ARTICLE

Front. Med., 05 June 2020 | https://doi.org/10.3389/fmed.2020.00292

The Use of Microbial Accessible and Fermentable Carbohydrates and/or Butyrate as Supportive Treatment for Patients With Coronavirus SARS-CoV-2 Infection

  • 1Food Science and Human Nutrition Department, Institute of Food and Agricultural Science, University of Florida, Gainesville, FL, United States
  • 2Gastroenterology, Kramer Medical Clinic, Gainesville, FL, United States

In addition to symptoms of fever, cough, and dyspnea, SARS-CoV-2 infection has been reported to also produce gastrointestinal symptoms. These symptoms can include anorexia, nausea, vomiting, and diarrhea. They are not unexpected symptoms, since enterocytes express the ACE2 receptor, and other requisite enzymes for SARS-CoV-2 uptake and replication (1). Viral infection leading to enterocyte death would predictably cause both malabsorption and increased G.I. permeability (2). Up to 50% of coronavirus cases reported from China had G.I. related symptoms (3), with recent corroboration in the United States (4).

After exposure to SARS-CoV-2, the estimated lag before onset of symptoms averages about 5 days. With limited oral intake following the onset of symptoms due to anorexia and other GI perturbations, there is marked alteration in intestinal microbial composition (dysbiosis) resulting in both macro and micronutrient deficiencies (5). The alterations include a decrease in carbohydrate fermentation and precipitous decline in production of short chain fatty acids, most notably butyrate.

Butyrate represents a well-characterized short chain fatty acid and functions as a key modulator of the immune system both in the intestinal tract (6) as well as in the lungs (7), and is instrumental in maintaining the physical integrity and balanced permeability of the gut mucosal lining (8).

Deficiency of short chain fatty acids negatively impacts energy balance resulting in failure of the intestinal epithelial barrier and associated immune defenses. With increased intestinal damage and permeability, pathogenic microbes, their components, and other foreign antigens may enter the body unimpeded. It is, therefore, not surprising that damage to distant organs appears in the heart, liver, kidney, and brain as epithelial barriers collapse and inflammation processes intensify.

Additionally, with lack of nutrients, short chain fatty acids are no longer available to stimulate bone marrow hematopoeisis which is felt to be a critical part of the gut-bone marrow-lung axis. Airway inflammation (7), the hallmark of acute respiratory distress syndrome (ARDS), proceeds unchecked frequently leading to death.

The short chain fatty acid butyrate benefits patients with established allergic lung inflammation (9). Specifically, butyrate has been shown to affect eosinophil trafficking and is able to “blunt migration into the lung, to reduce airway eosinophilia, and to ameliorate impaired lung function” (9).

Under siege by SARS-CoV-2, and perhaps due to over-stimulation of the gut associated lymphoid tissue, host defenses launch a counterattack releasing massive amounts of cytokines, resulting in a “cytokine storm” (10). The cytokine storm attempts to destroy the infecting virus, but, in the process, collateral damage to nearby tissue occurs as well. With SARS-CoV-2 this is particularly true in lung tissue (11). Given that the G.I. tract is the body's largest immunologic organ, it may be, in part, the genesis of the cytokine storm.

The inflammation accompanying SARS-CoV-2 infection is reflected by high blood levels of C-reactive protein, TNF-alpha, and several interleukins, most notably proinflammatory IL-6 (12). Elevated IL-6 in severe Covid-19 patients is a predictor of higher mortality rates (13). Some successes have been reported after treatment of Covid-19 patients with anti-inflammatory agents such as prednisone, and other anti-inflammatory drugs, including the IL-6 antagonist Tocilizumab (12). Butyrate has definitively been found to lower IL-6 levels in both animal and human studies (14, 15).

Conceptually, providing the necessary substrate for the continued production of short chain fatty acids using supplements offers an appealing approach to minimizing the damage caused by SARS-CoV-2. Fructooligosaccharides, arabinoxylose, galactooligosaccharides, and gum guar represent but a few of the readily available carbohydrates capable of fermentation and production of short chain fatty acids. Gastric infusion of short chain fatty acids has been shown in the experimental animal to improve intestinal barrier function (16). The effect of short chain fatty acids, especially butyrate, on gastrointestinal function in animals has been extensively studied with mixed findings, although recent modifications of formulations that modify the release profile have shown superior results (17).

Supplementing SARS-CoV-2 infected patients who are capable of tolerating oral intake with microbial accessible and fermentable carbohydrates could serve as a helpful adjunct in treating SARS-CoV-2 infection. For those patients unable to take food supplements or liquids by mouth, or who display symptoms of gastric upset or dysbiosis, nasogastric gavage of a butyrate solution or rectal administration of butyrate by enema could be considered. The use of butyrate enemas has been reported for multiple conditions including ulcerative colitis, diversion colitis, radiation proctitis, and pouchitis. Studies have yielded varying results making interpretation difficult [reviewed in Hamer et al. (18), Luceri et al. (19)]. The studies reported suffer from the lack of a standard protocol such as varying enema volumes, concentrations of butyrate, and frequency of administration.

The proposed use of butyrate by enema would accomplish two things:

• Direct application of butyrate to the site of the intestinal tract, terminal ileum and right colon that contains one of the highest concentrations of SARS-CoV-2 receptors, and

• Increase butyrate absorption for systemic distribution since the colon is the primary site for both production and absorption of butyrate.

Butyrate therapy has been demonstrated safe when administered by enema (18), per os (20), or intravenously (21). More research into these potential adjunct therapies should be encouraged.

Author Contributions

The authors DK and DA contributed equally to this work and approved it for publication.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

1. Zhang H, Kang Z, Haiyi G, Xu D, Wang J, Li Z, et al. Digestive system is a potential route of COVID-19: an analysis of single-cell coexpression pattern of key proteins in viral entry process. Gut. (2020) 69:1010–8. doi: 10.1136/gutjnl-2020-320953

CrossRef Full Text | Google Scholar

2. Gu J, Han B, Wang J. 2020. COVID-19: gastrointestinal manifestations and potential fecal–oral transmission. Gastroenterology. (2020) 158:1518–9. doi: 10.1053/j.gastro.2020.02.054

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Zhang L, Shang H, Huang C, Chen Y, Zhang S, Yang P, et al. Digestive involvement in SARS-CoV-2 infection: a retrospective multi-center study. Res Square. (2020). doi: 10.21203/rs.3.rs-21375/v1

CrossRef Full Text | Google Scholar

4. Cholankeril G, Podboy A, Aivaliotis VI, Tarlow B, Pham EA, Spencer S, et al. High prevalence of concurrent gastrointestinal manifestations in patients with SARS-CoV-2: early experience from california. Gastroenterology. (2020). doi: 10.1053/j.gastro.2020.04.008. [Epub ahead of print].

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Briguglio M, Pregliasco FE, Lombardi G, Perazzo P, Banfi G. The malnutritional status of the host as virulence factor for SARS- CoV-2. Front. Med. (2020) 7:146. doi: 10.3389/fmed.2020.00146

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Liu H, Wang J, He T, Becker S, Zhang G, Li D, et al. Butyrate: a double-edged sword for health? Adv Nutr. (2018) 9:21–9. doi: 10.1093/advances/nmx009

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Dang AT, Marsland BJ. Microbes, metabolites, and the gut–lung axis. Mucosal Immunol. (2019) 12:843–50. doi: 10.1038/s41385-019-0160-6

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Bach Knudsen KE, Lærke HN, Hedemann MS, Nielsen TS, Ingerslev AK, Gundelund Nielsen, et al. Impact of diet-modulated butyrate production on intestinal barrier function and inflammation. Nutrients. (2018) 10:1499. doi: 10.3390/nu10101499

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Theiler A, Bärnthaler T, Platzer W, Richtig G, Peinhaupt M, Rittchen S, et al. Butyrate ameliorates allergic airway inflammation by limiting eosinophil trafficking and survival. J Allergy Clin Immunol. (2019) 144:764–76. doi: 10.1016/j.jaci.2019.05.002

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. (2020) 395:1033–4. doi: 10.1016/S0140-6736(20)30628-0

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao J, et al. The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing. medRxiv. (2020). doi: 10.1101/2020.02.23.20026690

CrossRef Full Text | Google Scholar

12. Zhang W, Zhao Y, Zhang F, Wang Q, Li T, Liu Z, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): the experience of clinical immunologists from China. Clin Immunol. (2020) 214:108393. doi: 10.1016/j.clim.2020.108393

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. (2020) 395:1054–62. doi: 10.1016/S0140-6736(20)30566-3

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Liu J, Zhu H, Li B, Lee C, Alganabi M, Zheng S, et al. Beneficial effects of butyrate in intestinal injury. J Pediatr Surg. (2020). doi: 10.1016/j.jpedsurg.2020.02.036

CrossRef Full Text | Google Scholar

15. Liu T, Li J, Liu Y, Xiao N, Suo H, Xie K, et al. Short-chain fatty acids suppress lipopolysaccharide-induced production of nitric oxide and proinflammatory cytokines through inhibition of NF-κB pathway in RAW264.7 cells. Inflammation. (2012) 35:1676–84 doi: 10.1007/s10753-012-9484-z

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Dio H, Jiao AR, Yu B, Mao XB, Chen DW. Gastric infusion of short-chain fatty acids can improve intestinal barrier function in weaned piglets. Genes Nutr. (2020) 14:4. doi: 10.1186/s12263-019-0626-x

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Onrust L, Baeyen S, Haesebrouck F, Ducatelle R, Van Immerseel F. Effect of in feed administration of different butyrate formulations on Salmonella Enteritidis colonization and cecal microbiota in broilers. Vet Res. (2020) 51:56. doi: 10.1186/s13567-020-00780-2

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Hamer HM, Jonkers D, Venema K, Vanhoutvin SA, Troost FJ, Brummer RJ. Review article: the role of butyrate on colonic function. Alim. Pharmacol. Therapeut. (2008) 27:104–19. doi: 10.1111/j.1365-2036.2007.03562.x

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Luceri C, Femia AP, Fazi M, Di Martino C, Zolfanelli F, Dolara P, et al. Effect of butyrate enemas on gene expression profiles and endoscopic/histopathological scores of diverted colorectal mucosa: a randomized trial. Dig Liver Dis. (2016) 48:27–33. doi: 10.1016/j.dld.2015.09.005

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Edelman MJ, Bauer K, Khanwani S, Tait N, Trepel J, Karp J, et al. Clinical and pharmacologic study of tributyrin: an oral butyrate prodrug. Cancer Chemo Pharmacol. (2003) 51:439–44. doi: 10.1007/s00280-003-0580-5

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Miller AA, Kurschel E, Osieka R, Schmidt CG. Clinical pharmacology of sodium butyrate in patients with acute leukemia. Eur J Cancer Clin Oncol. (1987) 23:1283–7. doi: 10.1016/0277-53798790109-X

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: SCFAs, butyrate, adjunct therapy, cytokine storm, anti-inflammatory

Citation: Archer DL and Kramer DC (2020) The Use of Microbial Accessible and Fermentable Carbohydrates and/or Butyrate as Supportive Treatment for Patients With Coronavirus SARS-CoV-2 Infection. Front. Med. 7:292. doi: 10.3389/fmed.2020.00292

Received: 29 April 2020; Accepted: 22 May 2020;
Published: 05 June 2020.

Edited by:

Angel Lanas, University of Zaragoza, Spain

Reviewed by:

Levinus Albert Dieleman, University of Alberta, Canada

Copyright © 2020 Archer and Kramer. 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: Douglas L. Archer, dlarcher@ufl.edu