BCG Vaccinations Upregulate Myc, a Central Switch for Improved Glucose Metabolism in Diabetes

Abstract

Myc has emerged as a pivotal transcription factor for four metabolic pathways: aerobic glycolysis, glutaminolysis, polyamine synthesis, and HIF-1a/mTOR. Each of these pathways accelerates the utilization of sugar. The BCG vaccine, a derivative of Mycobacteria-bovis, has been shown to trigger a long-term correction of blood sugar levels to near normal in type 1 diabetics (T1D). Here we reveal the underlying mechanisms behind this beneficial microbe-host interaction. We show that baseline glucose transport is deficient in T1D monocytes but is improved by BCG in vitro and in vivo. We then show, using RNAseq in monocytes and CD4 T cells, that BCG treatment over 56 weeks in humans is associated with upregulation of Myc and activation of nearly two dozen Myc-target genes underlying the four metabolic pathways. This is the first documentation of BCG induction of Myc and its association with systemic blood sugar control in a chronic disease like diabetes.

Bacillus Calmette-Guerin 's beneficial impact on glucose metabolism: Evidence for broad based applications

“…We therefore studied the effect of metformin and BCG in vitro in human monocytes ( Figure 5 ). Previous data suggest that metformin interferes with cytokines induced by BCG through innate immunity as well as with glycolysis pathways in innate and adaptive immunity ( Arts et al., 2016 ; Kühtreiber et al., 2020 ).…”

“…This process of adaptive immune training can involve T cells as well as monocytes and centers on metabolic pathways that change aerobic glycolysis. Thus, the use and rate of sugar metabolism is improved after BCG therapy ( Kühtreiber et al., 2018 , 2020 ). The BCG effects observed in human autoimmune clinical trials have a slower onset of disease modifications (over years) but are permanent for >8 years in treated humans ( Kühtreiber et al., 2018 ).…”

“…Lastly, we turn to murine models of T1D and T2D to determine whether BCG's beneficial effect on sugar metabolism is equally observed in two forms of divergent hyperglycemia. To confirm that BCG-induced accelerated glucose transport is due to glycolysis, the inhibitor metformin is used in vitro and in vivo ( Arts et al., 2016 ; Kühtreiber et al., 2020 ).…”

Expanded Scope of Bacillus Calmette-Guerin (BCG) Vaccine Applicability in Disease Prophylaxis, Diagnostics, and Immunotherapeutics

“… 59 In addition, BCG causes an increase in glucose consumption in immune cells due to increased glycolysis and reduced oxidative phosphorylation, 60 , 61 thus helping to achieve glycemic control in type I diabetes patients. Kuhtreiber et al 62 recently reported for the first time, the effect of BCG vaccination in up-regulating the expression of Myc, an important transcription factor utilized by four metabolic pathways: glutaminolysis, HIF-1α/mTOR, glycolysis, and polyamine synthesis, all of which accelerate the utilization of glucose. Through this mechanism, BCG vaccination is able to trigger the correction of elevated blood glucose in type I diabetes patients.…”

“…Through this mechanism, BCG vaccination is able to trigger the correction of elevated blood glucose in type I diabetes patients. 62 In a recently published paper, Klein 63 described the findings of a retrospective analysis of two studies investigating the effect of BCG vaccination on the development of type I diabetes mellitus, and revealed that the administration of a booster dose of the BCG vaccine reinforcing postnatal BCG vaccination had a protective effect against type I diabetes, compared with post-natal BCG administration without booster dose administration. 63 In addition, the study noted that post-natal BCG administration without a booster was in turn better at protecting against type I diabetes than no BCG vaccination at all.…”