GENERAL COMMENTARY
published: 29 March 2021
doi: 10.3389/fimmu.2021.620658

Commentary: Beyond “TRIM”
Beneﬁts of b-Glucan by Blood
Glucose and Lipid Balancing
Potentials in Its Defense Against
COVID-19
Nobunao Ikewaki 1,2, Vidyasagar Devaprasad Dedeepiya 3, Masaru Iwasaki 4
and Samuel J. K. Abraham 3,4,5,6*
1 Department of Medical Life Science, Kyushu University of Health and Welfare, Nobeoka, Japan, 2 Institute of Immunology,
Junsei Educational Institute, Nobeoka, Japan, 3 The Mary-Yoshio Translational Hexagon (MYTH), Nichi-In Centre forRegenerative Medicine (NCRM), Chennai, India, 4 School of Medicine, University of Yamanashi, Chuo, Japan, 5 Edogawa
Evolutionary Laboratory of Science (EELS), Edogawa Hospital, Tokyo, Japan, 6 Life-systems through Immunology, Phylogenyand Evolution (LIPE) Division, GN Corporation Co. Ltd., Kofu, Japan

Keywords: COVID-19, trained immunity, b-glucan, blood glucose, fasting plasma glucose, lipid, coagulopathy, TRIM

Edited by:
Vasso Apostolopoulos,
Victoria University, Australia
Reviewed by:
Boris Novakovic,
Royal Children’s Hospital, Australia*Correspondence:
Samuel J. K. Abraham
drsam@nichimail.jp;
drspp@nichimail.jp
Specialty section:
This article was submitted toVaccines and Molecular
Therapeutics,
a section of the journal
Frontiers in Immunology
Received: 27 November 2020
Accepted: 15 March 2021
Published: 29 March 2021
Citation:
Ikewaki N, Dedeepiya VD, Iwasaki M
and Abraham SJK (2021)
Commentary: Beyond “TRIM” Beneﬁtsof b-Glucan by Blood Glucose andLipid Balancing Potentials in Its
Defense Against COVID-19.
Front. Immunol. 12:620658.
doi: 10.3389/fimmu.2021.620658

A Commentary on Could the Induction of Trained Immunity by b-Glucan Serve as a Defense Against
COVID-19? By Geller A and Yan J. Front. Immunol. 2020 11:1782. doi: 10.3389/ﬁmmu.2020.01782

INTRODUCTION
The ‘hypothesis and theory’ article by Geller and Yan (1) is an eye-opener to the innate memory
based Trained Immunity (TRIM) response offered by b-glucans in a prophylactic setting for
immune-modulation to abrogate the symptoms in COVID-19, preventing morbidity and death.
Their review (1) begins with the evolutionary background of TRIM and moves on to its ﬁrst
recognition by the scientiﬁc community based on the non-speciﬁc immune response induced by theBacille Calmette-Gué rin (BCG) vaccine administered for Mycobacterium tuberculosis (TB). The
multi-faceted TRIM offered by b-Glucans by virtue of their antiviral properties through productionof IL-1b, TNF-a, and IFN-g, induction of “central” memory by enabling production of a repertoireof innate cells from hematopoietic stem cells (HSC) in the bone marrow which migrate to peripheral
tissues to generate peripheral memory and the epigenetic regulation through pathways of Dectin-1activation (1) are elaborately narrated.

SIGNIFICANCE OF METABOLIC REGULATION OF TRIM
Geller and Yan (1) primarily focus on the anti-viral response of the metabolic regulation wherein
modulation of the transcription of immunogenic genes occur by metabolic switch from oxidative
phosphorylation toward aerobic glycolysis mediated through the AKT/mTOR/HIF1a pathway.
Besides, it inhibits the LPS mediated upregulation of immune-responsive gene-1 (IRG-1) needed foritaconate generation. As high levels of itaconate and its derivatives inhibit key Type-I interferonproduction during viral infection, itaconate generation inhibited by this metabolic upregulation ofFrontiers in Immunology | www.frontiersin.org

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Ikewaki et al.

b-glucans leads to increased Type I IFN response mediating antiviral response against SARS-CoV-2 (1).

triglycerides to the normal range and increase lower HDL levels toreach their normal levels in human clinical studies (14).

BEYOND “TRIM” BENEFITS OFb-GLUCANSMECHANISMS OF ADDITIONAL BENEFITS
OFFERED BY b-GLUCANS IN TRIM AND
METABOLISM

Apart from the metabolic based anti-viral response explained byGeller and Yan (1) or the immune-modulation described by Raoet al. (2) in the defense against COVID-19, we would like toemphasize that regulation of blood glucose and lipid levels by bGlucans as an indispensable tool of defense (3).
Diabetes, dyslipidemia and the immune system are inseparable
and inter-connected factors of worsening the crisis post-COVID-19
infection. While high blood glucose levels lead to constant glucoserecognition by C type lectin receptors which in turn lead toincreased rate of inﬂammatory processes worsening the disease
severity in COVID-19 (4), persistent chronic inﬂammation,
decreased function of vascular endothelial cells and decreased
immune function occurring in COVID-19 may actually underlie
the pathogenesis of diabetes (5). Further, blood sugar levels increase
the levels of clotting factors, causing endothelial dysfunction,enhanced platelet aggregation and activation, favoring a
hypercoagulable pro-thrombotic state increase the risk ofcoagulopathy due to COVID-19 (6). High levels of low-density
lipoprotein (LDL) lead to an increase in inﬂammatory gene
expression and inﬂammasome activation through interaction withmacrophages in atherosclerotic plaques causing worsening of thecytokine storm in COVID-19 (6). Low levels of high-density
lipoprotein (HDL) are involved in the regulation of innate
immune response and negatively regulates T-cell activation andthe expression of inﬂammatory mediators in macrophages anddendritic cells (7). Dyslipidemia also causes endothelial dysfunction.
With endothelial dysfunction induced coagulopathy having been
identiﬁed to be the major cause of organ damage and death in
COVID-19 patients (7), the contribution by high blood glucose andlipid levels cannot be ignored while planning prophylactic andtherapeutic strategies to combat COVID-19 (8).

Immuno-metabolic circuits are critical in TRIM (15). Induction ofglycolysis leads to immunotolerant monocytes as seen in sepsis by
their effects on posttranslational modiﬁcation of effector molecules
such as glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (16).
Insulin resistance that occurs in obesity and diabetes facilitate TRIM
in macrophages to acquire a state that has reduced responses topathogens through metabolic and epigenetic changes. Insulin
sensitization to reverse this state has been hypothesized to be
utilized for inducing therapeutic TRIM response in conditions
like cancer (16).
Apart from the above described beneﬁcial effects that can contributeto the TRIM against COVID-19 by normalization of blood glucose andlipid levels, since b-glucan can reduce the insulin resistance which has
been proven in human studies (17), a therapeutic TRIM response
proving beneﬁcial in COVID-19 will occur when b-glucans areemployed as a prophylactic agents and the state of immunologicaltolerance which exists in individuals with obesity, diabetes anddyslipidemia can perhaps be reversed by these b-glucans (18).

CONCLUSION
Therefore, in view of the excellent suggestion of TRIM induced byb-glucans as an “an efﬁcient, low-cost and safe way” in a long term
prophylactic setting applicable to different age groups of people andthose with vacuous co-existing disease conditions in the defense
against COVID-19 by Geller and Yan (1), we wish to reiterate thatthe metabolic effects of the b-glucans in terms of normalization ofglucose levels, lipid levels and increase of insulin sensitivity
signiﬁcantly contributes to augment the TRIM response. Amidst
the circumstances of a lack of deﬁnitive therapy or vaccine for
COVID-19, Geller and Yan’s timely suggestion of undertaking
clinical trials to conﬁrm the efﬁcacy of TRIM response inducedby b-glucans from various sources (1) needs immediateacknowledgement by the scientiﬁc community, while duly
recognizing their contribution to COVID-19 defense through theabove described potential metabolic pathways and their validation,
for an efﬁcient ﬁght against this devastating pandemic.

b-GLUCANS IN NORMALIZATION OF
GLUCOSE AND LIPID LEVELS IN
CLINICAL STUDIES
b-glucans such as the AFO-202 black yeast derived b-glucan havebeen shown to maintain the fasting plasma glucose (FPG) levels andbring down the high levels in diabetic patients to normal values inhuman clinical studies (9, 10) which has been hypothesized to bebeneﬁcial in the defense against COVID-19 (11). It is noteworthy
that high FPG levels at admission has been proven as a strong
independent predictor of poor outcomes in COVID-19 in several
studies (12, 13). Further, the AFO-202 b-glucan has been shown todecrease LDL levels, very low-density lipoprotein (VLDL) levels andFrontiers in Immunology | www.frontiersin.org

AUTHOR CONTRIBUTIONSNI and SA contributed to conception and design. SA drafted themanuscript. VD and MI performed critical revision of themanuscript. All authors contributed to the article andapproved the submitted version.

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REFERENCES

12. Wang S, Ma P, Zhang S, Song S, Wang Z, Ma Y, et al. Fasting blood glucose atadmission is an independent predictor for 28-day mortality in patients with
COVID-19 without previous diagnosis of diabetes: a multi-centre
retrospective study. Diabetologia (2020) 63:2102–11. doi: 10.1007/s00125020-05209-1
13. Zhang B, Liu S, Zhang L, Dong Y, Zhang S. Admission fasting blood glucose
predicts 30-day poor outcome in patients hospitalized for COVID-19
pneumonia. Diabetes Obes Metab (2020) 22:1955–57. doi: 10.1111/dom.14132
14. Ganesh JS, Rao YY, Ravikumar R, Jayakrishnan GA, Iwasaki M, Preethy S,
et al. Beneﬁcial effects of black yeast derived 1-3, 1-6 Beta Glucan-Nichi
Glucan in a dyslipidemic individual of Indian origin–a case report. J Dietary
Suppl (2014) 11(1):1–6. doi: 10.3109/19390211.2013.859211
15. Arts RJ, Joosten LA, Netea MG. Immunometabolic circuits in trained
immunity. Semin Immunol (2016) 28(5):425–30. doi: 10.1016/j.smim.2016.09.002
16. Ieronymaki E, Daskalaki MG, Lyroni K, Tsatsanis C. Insulin Signaling andInsulin Resistance Facilitate Trained Immunity in Macrophages ThroughMetabolic and Epigenetic Changes. Front Immunol (2019) 10:1330.
doi: 10.3389/ﬁmmu.2019.01330
17. Zheng J, Shen N, Wang S, Zhao G. Oat beta-glucan ameliorates insulin
resistance in mice fed on high-fat and high-fructose diet. Food Nutr Res (2013)57:22754. doi: 10.3402/fnr.v57i0.22754
18. Novakovic B, Habibi E, Wang SY, Arts R, Davar R, Megchelenbrink W, et al.
b-Glucan Reverses the Epigenetic State of LPS-Induced ImmunologicalTolerance. Cell (2016) 167:1354–68.e14. doi: 10.1016/j.cell.2016.09.034

1. Geller A, Yan J. Could the Induction of Trained Immunity by b-Glucan Serve
as a Defense Against COVID-19? Front Immunol (2020) 11:1782.
doi: 10.3389/ﬁmmu.2020.01782
2. Rao KS, Suryaprakash V, Senthilkumar R, Preethy S, Katoh S, Ikewaki N, et al.
Role of Immune Dysregulation in Increased Mortality Among a Speciﬁc
Subset of COVID-19 Patients and Immune-Enhancement Strategies for
Combatting Through Nutritional Supplements. Front Immunol (2020)
11:1548. doi: 10.3389/ﬁmmu.2020.01548
3. Chen J, Raymond K. Beta-glucans in the treatment of diabetes and associatedcardiovascular risks. Vasc Health Risk Manage (2008) 4(6):1265–72.
doi: 10.2147/vhrm.s3803
4. de Lucena T, da Silva Santos AF, de Lima BR, de Albuquerque Borborema
ME, de Azevêdo Silva J. Mechanism of inﬂammatory response in associatedcomorbidities in COVID-19. Diabetes Metab Syndrome (2020) 14(4):597–600. doi: 10.1016/j.dsx.2020.05.025
5. Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end products anddiabetic complications. Korean J Physiol Pharmacol: Off J Korean Physiol Soc
Korean Soc Pharmacol (2014) 18(1):1–14. doi: 10.4196/kjpp.2014.18.1.1
6. Hussain A, Bhowmik B, do Vale Moreira NC. COVID-19 and diabetes: Knowledge inprogress. Diabetes Res Clin Pract (2020) 162:108142. doi: 10.1016/j.diabres.2020.108142
7. Hariyanto TI, Kurniawan A. Dyslipidemia is associated with severe
coronavirus disease 2019 (COVID-19) infection. Diabetes Metab Syndrome(2020) 14(5):1463–5. doi: 10.1016/j.dsx.2020.07.054
8. Ikewaki N, Rao KS, Archibold AD, Iwasaki M, Senthilkumar R, Preethy S,
et al. Coagulopathy associated with COVID-19 - Perspectives & Preventive
strategies using a biological response modiﬁer Glucan. Thromb J (2020) 18:27.
doi: 10.1186/s12959-020-00239-6
9. Dedeepiya VD, Sivaraman G, Venkatesh AP, Preethy S, Abraham SJ.
Potential effects of nichi glucan as a food supplement for diabetes mellitus
and hyperlipidemia: preliminary ﬁndings from the study on three patientsfrom India. Case Rep Med (2012) 2012:895370. doi: 10.1155/2012/895370
10. Yano H. Sophy Beta-Glucan is effective in alleviating increased blood sugar
levels. In: Abstract presented at the 55th Conference of the Japanese Society ofNutrition and Dietetics (2008).
11. Ikewaki N, Iwasaki M, Abraham SJK. Biological response modiﬁer glucan
through balancing of blood glucose may have a prophylactic potential in
COVID-19 patients. J Diabetes Metab Disord (2020) 19:1–4. doi: 10.1007/
s40200-020-00664-4

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Conﬂict of Interest: SA is a shareholder in GN Corporation, Japan, which in turnis a shareholder in the manufacturing company of the AFO 202 Beta Glucan
product and an applicant to several patents of relevance.
The remaining authors declare that the research was conducted in the absence ofany commercial or ﬁnancial relationships that could be construed as a potential
conﬂict of interest.
Copyright © 2021 Ikewaki, Dedeepiya, Iwasaki and Abraham. This is an open-accessarticle 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. Nouse, distribution or reproduction is permitted which does not comply with these terms.

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