Review Symposium
doi: 10.1111/joim.13050

Benefits of BCG-induced metabolic switch from oxidative
phosphorylation to aerobic glycolysis in autoimmune andnervous system diseases
D. L. Faustman
From the Department of Medicine, Immunobiology Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, MA,
USAThis is an article from the symposium: Linked to BCG symposium.

Abstract. Faustman DL (Massachusetts General
Hospital and Harvard Medical School, Boston,
MA, USA). Benefits of BCG-induced metabolic
switch from oxidative phosphorylation to aerobic
glycolysis in autoimmune and nervous systemdiseases (Review Symposium). J Intern Med 2020;
https://doi.org/10.1111/joim.13050
The most commonly used vaccine worldwide,bacillus Calmette-Gu
erin (BCG), appears to havethe ability to restore blood sugar control in humans
with early onset but long-duration type 1 diabetes
when a repeat vaccination strategy is used. This is
a process that may be driven by a metabolic switchfrom overactive oxidative phosphorylation to accelerated aerobic glycolysis and a reset of the immune
system. BCG is a live, attenuated strain of
Mycobacteria bovis, a cousin of M. tuberculosis.
Humans and Mycobacteria, which are found in theenvironment and in warm-blooded hosts, share along coevolutionary history. In recent times,

Introduction
The bacillus Calmette–Gu
erin (BCG) vaccine is themost commonly used vaccine worldwide, administered primarily for the prevention of tuberculosis
since its introduction in 1921. Recent clinical trials
show that repeat administration of the BCG vaccine may have clinical benefits in autoimmunity,
most notably in clinically isolated syndromes (CIS)[1]/ multiple sclerosis (MS) [2, 3] and in type 1
diabetes [4].
Aerobic glycolysis, one of the two key metabolic
pathways through which cells obtain energy, isassociated with high glucose utilization by immune

humans have had fewer exposures to these andother microorganisms that historically helped
shape the immune response. By ‘re-introducing’
an attenuated form of Mycobacteria via BCG vaccination, humans might benefit from an immunological perspective, a concept supported by a
growing body of data in autoimmunity and robust
data on the nonspecific immune effects of BCG
related to protection from diverse infections andearly mortality. New findings of immune andmetabolic defects in type 1 diabetes that can becorrected with repeat BCG vaccination suggest that
this therapeutic strategy may be applicable inother diseases with inadequate aerobic glycolysis,
including Parkinson’s disease, dementia, depression and other disorders affecting the nervous
system.
Keywords: BCG vaccine, autoimmunity, diabetes
mellitus, type 1, nervous system diseases, aerobic
glycolysis, mycobacterium.

cells. In individuals with type 1 diabetes, aerobic
glycolysis is suppressed and oxidative phosphorylation, a metabolic pathway in which low glucose
utilization, high ketone production and high Krebs
cycle utilization is instead predominant [5, 6].
Repeat vaccination with BCG (i.e. ≥2 vaccinations) appears to address these immune defects
through a ‘reset’ of the immune system achieved by
the induction of beneficial regulatory T cells(Tregs) and the killing of cytotoxic T lymphocytes(CTLs) [4]. BCG also resets cellular metabolism;
namely, by augmenting aerobic glycolysis anddecreasing oxidative phosphorylation in the
immune system [5].

ª 2020 The Association for the Publication of the Journal of Internal Medicine

1BCG-induced immune and metabolic switch / D. L. Faustman

Resetting the metabolism of immune cells in type 1
diabetes appears to control and regulate blood
sugars in a clinically significant way. In a randomized, placebo-controlled clinical trial, BCG treatment led to long-term improvement of blood
sugars, without hypoglycaemia, in adult subjects
with long-standing type 1 diabetes (~20 years disease duration) [5]. Not only was there a statisticallysignificant lowering of HbA1c for ≥ 1 year with
BCG (P = 0.02), but blood sugar lowering wasmaintained for 5 continuous years (P = 0.0002).

hypothesis’ [10], ‘old friends hypothesis’ [11]).
Broadly, these concepts suggest that the increased
incidences of allergies and autoimmune diseases inhumans may be due to fewer exposures to themicrobes that traditionally trained the immune
system to respond appropriately to pathogens.
Thus, the introduction (or, from an evolutionary
perspective, ‘re-introduction’) of an attenuatedform of Mycobacteria into humans via BCG vaccination might be beneficial to immune system
function.

These findings in type 1 diabetes suggest that thetherapeutic strategy of repeat BCG vaccination
may have broader applications to other diseases
with inadequate aerobic glycolysis, including a
number of nervous system diseases. Here, we
discuss the recent findings with BCG in type 1
diabetes and the potential for using this Mycobacteria-based vaccine to reset immunometabolism innovel disease settings.

Indeed, BCG is already known to have protective
and therapeutic effects beyond the prevention of
infection with tuberculosis. These effects include
reduced susceptibility to nonmycobacterial infections [12–14], therapeutic effects in bladder cancer(when administered as an intravesical infusion)[15], and a reduced incidence of early mortality [16,17]. These effects appear to be mediated throughboth adaptive immunity and innate immune
responses known as ‘trained immunity’. This latter
immune response is triggered through postvaccination epigenetic changes that shape the immune
system by creating beneficial commensalism at thegene level [18].

Lessons from Mycobacteria: The interplay of immunity andmetabolism with BCG introduction in adults
BCG is a live, attenuated strain of Mycobacterium
bovis. This avirulent Mycobacterium is related tothe pathogenic M. tuberculosis strain, the causative agent of tuberculosis in humans, and to otherstrains in the M. tuberculosis complex. The M. tuberculosis complex shares a long coevolutionary
history with humans, with phylogenetic analysis
suggesting that it has been infecting humans forthousands of years [7].
Throughout this long coevolution, this microorganism – which can be found free-living in soil andwater, as well as in the tissue of warm-blooded
hosts – has helped to shape the human immune
system. Yet, in recent history, improvements insanitation and food safety, the movement awayfrom occupations and living conditions that keep
humans in close interaction with animals and thesoil, and advancements in medicine leading tofewer infections have meant that many humans are
growing up bereft of the wider exposure to microorganisms that helped shape our evolutionary history. How has loss of exposure to these ancient“partners” potentially affected the human immune
system?
One possible answer may be found in the ‘hygiene
hypothesis’ [8] and similar theories (e.g. ‘biome
depletion model’ [9], ‘early immune challenge2ª 2020 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine

Further, alterations in immunometabolism areclosely linked to infections, including infection
with M. tuberculosis. In murine lung tissue,
infected monocytes in tuberculosis granulomas
predominantly utilize serum sugar through a shift
towards glycolysis [19]. In a parallel fashion, these
monocytes exhibit downregulation of enzymes participating in the Krebs cycle and oxidative phosphorylation [19]. In the human, too, infected
immune cells respond to M. tuberculosis byincreasing glucose uptake through a shift to predominant aerobic glycolysis [20].
Similar findings related to central glucose metabolism and aerobic glycolysis have been observed byour group after in vivo administration of repeat
BCG vaccinations in adults with type 1 diabetes [5,6]. These findings are discussed in more detail infurther sections.
Significance of immunity to tuberculosis in diverse human diseasestates: The broader value of BCG vaccination
Over the past two decades, multiple clinical trials
have been launched to evaluate the effects of BCG
vaccination in autoimmunity, allergy and childhood infections [1–6, 16, 17, 21–27]. The findings

BCG-induced immune and metabolic switch / D. L. Faustmanfrom these studies have been promising and show
the potential benefits of ‘re-introducing’ beneficial
immune-modulating bacteria – in the form of BCG
vaccination – in the human.
For example, BCG vaccination has been shown toconfer a survival advantage in low-birthweight
infants by offering protection from infections unrelated to tuberculosis, and to confer a long-term
survival advantage in healthy populations [16, 17,
24, 28, 29].
In a double-blind, placebo-controlled study inadults with multiple sclerosis, BCG administration
prevented progression to clinically definite disease
when given after a first demyelinating event (clinically isolated syndrome [CIS]), thereby halting
new-onset disease in the early period (6 months)
after vaccination [1]. Follow-up during the trial
showed that the clinical effect of BCG was evenmore pronounced at 5 years.
In a retrospective study in type 1 diabetes, receiptof two or more BCG vaccinations in childhood was
associated with a lower incidence of type 1 diabetes
by age 12 [25].
A randomized, double-bind, placebo-controlled
Phase I trial in adults with long-standing type 1
diabetes showed that two doses of intradermal BCG
increased beneficial Tregs, killed pathogenic CTLs
and temporarily restored production of a small
amount of pancreatic insulin, but that these favourable biomarker responses did not translate into
lowering of glycated haemoglobin (HbA1c) values, astandard measure of blood sugar control, at the endof the 20-week trial [4]. Long-term follow-up, however, showed that, at 8 years, elevated HbA1c values
in BCG-treated subjects were reduced to the nearnormal range (6.65%; P < 0.002) after an onset
delay of three years [5]. These reductions in HbA1c
were not seen in either the placebo control group nor
in a matched reference group of patients with type 1
diabetes who were receiving the standard of carealone. HbA1c reductions appeared to be permanent
for the next five years after onset of clinical effect,
without further administration of BCG vaccination.
Unlike the expectation with insulin alone, BCGdriven reductions to near-normal blood sugar levelsin this trial were not associated with hypoglycaemic
events [5].
In the same study, a closer look at Tregs from
BCG-treated subjects showed that BCG also

demethylated Treg signature genes [5]. This wasclinically significant, since increased mRNA
expression of the same genes from demethylation
correlated with the change in methylation [5, 30].
Similar to M. tuberculosis and M. leprae, which
create granulomas encircled with Tregs [31], BCG
systemically induces Tregs [4]. Epigenetic reprogramming of the host by M. tuberculosis and otherinfections occurs at key checkpoints, including
methyltransferases, and at key steps in aerobic
glycolysis, such as HIF1a [30, 32–34]. Patients withlong-standing type 1 diabetes who received
repeated BCG vaccinations had both immune andmetabolic changes related to the genes involved in
the reestablishment of tolerance and glucose utilization [5]. These changes in receptor-controlled
glucose utilization appear to have therapeuticutility for lowering blood sugar in type 1 diabetes.
All subjects with type 1 diabetes in this trial had
classic, juvenile-onset diabetes (i.e. early age of
onset), but long disease duration (>15 years).
BCG restores balance in cellular energy production andaccelerates glucose uptake
The impact of BCG on human blood sugars in type1 diabetes appears to be driven through immune
and immunometabolic effects, similar to thoseobserved with M. tuberculosis infection. Mechanistic data demonstrate that BCG can reset theimmune system on the cellular level by inducing
suppressive Tregs [5, 35, 36] and killing theautoreactive CTLs that attack insulin-secreting
pancreatic islet cells [4, 37]. M. tuberculosis similarly induces or ‘turns on’ Tregs through a beneficial host-microbe interaction at the DNA level withchanges in methylation [30, 32–34].
Beyond the immune effects of BCG, recent humandata on BCG vaccination in type 1 diabetes show
BCG’s ability to regulate blood sugar throughchanges in metabolism [5]. The systemic metabolic
shift in glucose metabolism moves from oxidative
phosphorylation, a low cellular glucose state,
towards accelerated and early aerobic glycolysis,a high glucose utilization state [5]. At baseline,
subjects with type 1 diabetes exhibit a derangement in lymphoid system sugar metabolism. BothT cells and monocytes show overzealous oxidative
phosphorylation, possibly linked to prior poor priorhost-microbe interactions. The introduction of
BCG gradually restores this imbalance towards
normal levels. Using mRNA sequencing methods,
we have been able to demonstrate that serial BCGª 2020 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine

3BCG-induced immune and metabolic switch / D. L. Faustman

vaccination in adults with type 1 diabetes
increased key early glycolytic enzymes, upregulated glucose uptake leading to systemic loweringof blood sugars, shunted the accelerated glucose
utilization through the pentose phosphate pathway, decreased utilization of late glycolytic steps(including the Krebs cycle) and decreased oxidative
phosphorylation (Figure 1).
The impact of administering BCG to normal(nonautoimmune) mice has been studied in relation to sugar utilization patterns [5]. When BCG
pretreated nonautoimmune mice were chemicallymade diabetic using streptozocin, these mice experienced hyperglycaemia at significantly lower levels
than untreated mice that were similarly given
streptozocin to induce diabetes. Therefore, evenin animals that are not prone to autoimmunity,
BCG appears to be even able to boost aerobic
glycolysis levels after chemical induction of diabetes, assisting to reduce blood glucose levels.
Why is hypoglycaemia avoided with BCG vaccination in type 1
diabetes?
Upregulation of aerobic glycolysis with BCG vaccination may elucidate the finding of minimal to no
hypoglycaemia in the Phase I trial subjects whoachieved stable, near-normal blood sugars withlong-term follow-up [5].
Patients with long-standing type 1 diabetes who
received two serial BCG vaccinations as part of aneight-year study experienced a correction in blood
sugars that was near-normal after year 3.5, aneffect that persisted for at least five additional years[5]. The insulin requirements for these patientswere reduced, and BCG-related correction of

HbA1c to the 5.7–6.0% range was not associatedwith any increase in hypoglycaemia. For glycolysis
regulated at the natural cell level, glucose transporters are sensitive to ambient sugar and turn off
when serum sugar falls. This appears to be seen
after serial BCG vaccination and stands in contrast
to standard insulin therapy (i.e. insulin pumps,
continuous glucose monitors), where increasing
insulin use to achieve tight blood sugar control canalso increase the risk of hypoglycaemia.
Additionally, in patients with type 1 diabetes,
overutilization of oxidative phosphorylation forcellular metabolism likely results the overproduction of ketones. It has been known for years thatpatients with type 1 diabetes, but not type 2
diabetes, are susceptible to ketosis, even when at
the same level of glucose dysregulation. The mystery behind this phenomenon might be explainedby the baseline defects in lymphoid metabolism intype 1 diabetes. With BCG therapy, accelerated
and regulated glucose transport occurs early at thecell membrane, the pentose phosphate shunt isturned on, and fewer metabolites are funnelled
through the Krebs cycle. This suggests that BCGtreated patients with type 1 diabetes may be lessprone to ketone production, since it occurs at laterstages of glycolysis (Figure 1).
BCG findings in type 1 diabetes support the validity of the hygiene
hypotheses and related theories
Aerobic glycolysis is a metabolic state with highcellular glucose utilization and rapid ATP production. In contrast, oxidative phosphorylation, which
utilizes the mitochondria and Krebs cycle forenergy production, is associated with lower cellularglucose use.

Fig. 1 Lymphocyte aerobic
glycolysis and oxidative
phosphorylation (OXPHOS) in
normal white blood cells (left),in untreated type 1 diabetic
lymphocytes (middle), and intreated lymphocytes fromhuman subjects receiving the
BCG vaccine (right).
4ª 2020 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine

BCG-induced immune and metabolic switch / D. L. Faustman

Individuals with type 1 diabetes have a baseline
deficiency in aerobic glycolysis with diminishedglucose uptake; a reciprocal augmentation ofoxidative phosphorylation is instead present [5].
After BCG vaccinations, the metabolism of theimmune system gradually shifts from overactive
oxidative phosphorylation to regulated glucose
transport through aerobic glycolysis [5].
This metabolic data support the hygiene hypothesis and related theories as a mechanistic insight
into autoimmunity and allergies. These theories
suggest that lack of proper childhood microbial
exposures, that is lack of interactions between thehost immune system and microorganisms, leads todefects in immune tolerance. Our new data on
deficient aerobic glycolysis in type 1 diabetes thatcan be augmented by BCG vaccination [5] support
these hypotheses and also suggest that the lack ofadequate exposure to microbes not only leads todefects in the immune system, but also leads todefects in metabolism.
Microbes within infected cells often try to convert
cells at sites of infections to aerobic glycolysis, aneasy source of sugars for energy. The use ofantibiotics to eliminate immune system-boosting
infections and the use of vaccines and sanitation
measures related to food, water and living environments to prevent infectious diseases might diminish the set point for a better balance of aerobic
glycolysis with oxidative phosphorylation. In animal models, human cells in culture, and humanclinical trials, BCG or a similar approach (i.e.
administration of Complete Freund’s adjuvant[CFA] or of tumour necrosis factor [TNF, which isinduced by BCG]) shows efficacy in diverse autoimmune diseases, including type 1 diabetes, multiple
sclerosis and others [1–5, 37–41]. Therefore, wewould predict that similar states of overzealousoxidative phosphorylation might be present atbaseline in many of these diseases, beyond justtype 1 diabetes. Further, many autoantibodies can,at times, be directed against glycolytic enzymes in
the aerobic glycolysis pathway that is interrupted
in autoimmunity. These autoantibodies could
directly interrupt this pathway or may form in
autoimmune hosts from lack of proper synthesis of
enzymes that appear foreign with subsequent reexpression in life. To date, autoantibodies havebeen found to diverse enzymes in the glycolytic
pathway, including enolase, GADPH, aldolase
pyruvate kinase and others [42].

Our type 1 diabetes findings strongly show that
infection with an avirulent strain of Mycobacterium
can produce a therapeutic effect on a systemicbasis, lasting greater than 8 years [5], whilst thecollective data on BCG’s heterologous benefits
leads to a new appreciation of the evolutional
synergy of reintroducing avirulent Mycobacterium
into modern humans through BCG vaccination. In
adults with type 1 diabetes, this synergy is illustrated through the systemic immunometabolicchanges after repeat BCG vaccination that appear
to re-establish both blood sugar control and selftolerance through induction of Tregs [5, 6].
Why do the clinical effects of BCG vaccination take several years
to manifest in type 1 diabetes?
Our clinical trials do not yet answer the question of
why the clinical effect of HbA1C reduction after
BCG vaccination is delayed by three years inhumans [5]. However, a human clinical trial that
evaluated BCG in multiple sclerosis had a similarfinding, where BCG’s effects were more pronounced with longer (5 year) follow-up time periods [1]. In addition, in our study of mice withstreptozotocin (STZ)-induced diabetes, a lag time ofat least 6 weeks was needed to see a reduction in
HbA1c [5]. Given the 2.5-year lifespan of a mouse,
this translates into approximately 3.5 years in thehuman. With a live vaccine like BCG, it may be thatthe effects of BCG – such as the initial Treg
induction that occurs approximately 6 weeks after
receipt of the second BCG vaccination in our trials– may need time to become systemic for thecorrection of HbA1c. Further, the shift to aerobic
glycolysis may involve additional cells and organs
beyond those we have examined.
Pancreatic islet regeneration vs correction of immunometabolism
in type 1 diabetes: Which is key?
BCG-induced lowering of HbA1C in type 1 diabetes
appears to be permanent for at least 8 years [5]. In
our study, pancreatic islet regeneration was not
obligatory for correction of blood sugars. The
underlying mechanism, immunometabolism, wassufficient to regulate cellular glucose transport, atleast in adult patients with long-standing type 1
diabetes and no significant residual C-peptide at
the trial start. It is appreciated that the human
lymphoid system, based on overall cell numbers, isthe third largest organ in the human, so systemic
conversion of this organ system to higher glucose
utilization may be enough for a clinical effect. Stillª 2020 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine

5BCG-induced immune and metabolic switch / D. L. Faustmanlacking in the human data is whether BCG can
induce increased sugar utilization through augmented aerobic glycolysis in muscle, liver, fat andother nonlymphoid cells to contribute to the therapeutic effects. In humans with type 1 diabetes,
aerobic glycolysis is deficient at baseline, and BCG
appears to restore the balance between aerobic
glycolysis and oxidative phosphorylation to normal
levels. At this time, however, although somemurine type 2 diabetes data suggest that intravenous BCG administration may be therapeutic in
relation to weight reduction, lowering of blood
sugars and prevention of fatty liver [43], theefficacy of BCG in humans with type 2 diabetes
has not yet been generated through clinical trials.
We have previously shown that BCG or the BCGequivalent (CFA) treatment of NOD mice results in
restored normoglycemia through regeneration of
pancreatic islets [40, 41]. However, in our current
human studies of adults with long-standing type 1
diabetes and negligible C-peptide secretion fromthe pancreas at baseline, this does not seem to be
the primary mechanism. Although HbA1c wasstably corrected to the normal range for over
5 years, stimulated C-peptide remained at almost
undetectable levels and was not high enough toaccount for the observed lowering of HbA1c [5].
In paediatric populations, this might not be thecase. Since the recent BCG trials in type 1 diabetes
have been limited to adults [4, 5], it is possible thatany BCG-driven restoration of normoglycemia inpaediatric populations could be driven by bothpancreatic islet regeneration/ preservation andregulation of immunometabolism. A paediatric trial
is currently planned.
Are timing of BCG administration, number of doses and strain
important?
The timing of BCG administration relative to disease onset, the number of BCG doses given, andthe strain of BCG used for vaccination appear to besignificant factors in determining the efficacy of
BCG treatment in autoimmunity.
In murine models, permanent reversal of type 1
diabetes is observed in nonobese diabetic (NOD)
mice if the BCG therapy is given as BCG or BCGequivalent treatment (i.e. complete Freund’s adjuvant [CFA]) after displaying early signs of diabetes,
new-onset diabetes or full-blown diabetes [40, 41,
44, 45].
6ª 2020 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine

However, giving a single injection of BCG at birth indiabetes-prone humans or NOD mice has noobservable benefits [44–48]. Thus, it appears thatthe disease must be apparent for BCG to beeffective and also suggests that multi-dosing might
be the correct strategy [25, 49]. Indeed, a retrospective study in humans who received BCG vaccination in childhood has shown that a single doseof BCG is not associated with a reduced incidence
of developing type 1 diabetes by age 12, but having
at least two doses appears to have a protective
effect [25].
Studies in the human and mouse also reveal thevariable efficacy of different BCG substrains. The
TICE substrain of BCG is known to have poor
immunoregulatory properties in the NOD mouseand in humans [50]. In an early human type 1
diabetes trial, a single dose of the Connaught
substrain did appear to prevent progression to
new-onset disease [50, 51], whilst subsequent
early trials testing less potent BCG strains, suchas TICE, showed no clinical effect in humans
within the short follow-up windows of these studies[50–52].
In recent decades, a trend towards a higher incidence of immune-mediated diseases, including type1 diabetes [53], allergy [54] and multiple sclerosis[54], has been observed in the developed world. In
contrast, there is a low prevalence of type 1 diabetes
in regions where tuberculosis myocobacteria arefound [55], and there is a negative association
between tuberculosis and multiple sclerosis [56].
In Turkey, retrospective data suggest that receipt of
two or more BCG vaccinations in childhood isprotective against the development of type 1 diabetes, but receipt of only one BCG vaccination is not[25]. In Sweden, receipt of multiple vaccinations of
BCG (at birth, 7 years and 14–15 years) was
mandatory until 1965, when the 7 year booster
was stopped, followed by the 14–15 year booster in1979 and the vaccination of newborns in 1986 [57].
Today, Sweden has amongst the highest reported
incidences of type 1 diabetes in the world, with anaccelerated trend in total cases that started in the
1990s [57]. When looked at in the context of thegradual reduction in BCG vaccination in Sweden,
the acceleration of new type 1 diabetes diagnoses
begins only a few years after the final (newborn) BCG
vaccination was stopped, and incidence was typically highest amongst younger children, whichcorrelates with those with the fewest BCG vaccination exposures [57].

BCG-induced immune and metabolic switch / D. L. Faustman

Can central nervous system diseases benefit from increased
aerobic glycolysis?
If BCG boosts aerobic glycolysis, what other disease states might benefit?
Human diseases that exhibit poor sugar uptake inaffected tissues are well documented in the 18Ffluorodeoxyglucose (18FDG) PET/CAT literature.
This radiographic imaging method utilizes aradioactive sugar to determine the rate of sugar
uptake as a measure of aerobic glycolysis invarious tissues or regions of various tissues. Low
glucose uptake is observed in many central nervous system (CNS) diseases early in the disease
process and is associated with select localized
regions of the brain having diminished glucose
uptake and loss of function associated with theclinical symptoms. Indeed, developing neurons
predominantly use aerobic glycolysis, whilst withsenescence older neurons have a diminished ability to use sugar [58].
Table 1 summarizes sugar uptake defects in the
CNS as measured by 18FDG PET/CAT. Although
not all CNS diseases are associated with diminished aerobic glycolysis, the data show that Parkinson’s disease, Huntington’s disease, Alzheimer’s
disease, multiple sclerosis, depression and ageing
all have CNS regions with diminished sugar utilization or diminished aerobic glycolysis early inthe disease process [59–81].

It is interesting to speculate whether BCG, byaugmenting aerobic glycolysis, could correct these
low glucose uptake states in the CNS to restore
neuron health and perhaps induce broader clinicalbenefits beyond the already promising multiple
sclerosis data [1–3]. Augmented sugar utilization in
the CNS may perhaps be an additional reason –beyond the potential protective effects against
neuroinflammation provided by the BCG vaccine[27] – why BCG administered to new-onset multiple
sclerosis patients is associated with marked clinical improvement in Phase II clinical trials [1].
Interestingly, a review of the literature by Raisonand colleagues has suggested that lack of contact
with previously available triggers of anti-inflammatory and immunoregulatory signalling throughincreased sanitation is associated with the possible
pathophysiology and onset of major depressive
disorder [82]. This perhaps implies that greater
microbial exposure through BCG vaccination isneeded to augment aerobic glycolysis, similar tothe developing autoimmune data in human clinical
trials.
Concluding remarks
In type 1 diabetes, microbial exposure throughrepeat BCG vaccination appears to systemicallytrigger a switch from oxidative phosphorylation, astate of poor cellular glucose utilization, toincreased aerobic glycolysis, a state of high cellular

Table 1 Altered glucose metabolism in central nervous system (CNS) disorders
Glucose
DiseaseMetabolism

Location

Parkinson’s disease

DeficientDisease regions

References[59–64]

Huntington’s disease

Deficient

Striatum[65, 66]

Dementia

DeficientDisease regions[67]

Alzheimer’s disease

DeficientDisease regions[68–71]

Multiple sclerosis

DeficientDisease regions[72]

Depression

Deficient

Cortical regions[73, 74]

Ageing/Development

Deficient

Young brains high glucose, old brains low glucose[58, 75]

Obsessive Compulsive DisorderAccelerated

Bilateral caudate nuclei, Orbital frontal cortex[76]

Schizophreniaa

Accelerated

Cortico-striato-thalamic frontal lobe

[77–80]

Low glucose uptake is observed in many central nervous system (CNS) disorders early in the disease process, including in
Parkinson’s, Huntington’s and Alzheimer’s diseases as well as in dementia, multiple sclerosis and depression. Might BCG
vaccination be able to correct glucose metabolism – and therefore provide a therapeutic effect – by augmenting aerobic
glycolysis to restore metabolic balance, similar to the developing data in human autoimmunity?
aSome studies have shown the opposite, finding deficient glucose transport in the low frontal lobe [81].
ª 2020 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine

7

BCG-induced immune and metabolic switch / D. L. Faustman

glucose utilization. Correction of this metabolic
defect in type 1 diabetes using the BCG vaccine
results in white blood cells using more serum
sugar and appears to drive clinically important
effects; namely, the stable, long-term lowering of
HbA1c for > 5 years without hypoglycaemia after
an initial onset delay of three years. These findings
support the hygiene hypothesis and suggest thatearly-life exposure to microbes that promote aerobic glycolysis is both beneficial to immune systemdevelopment and could even be corrective later inlife as a treatment approach to diverse diseases.
Since certain CNS diseases are also known to be
associated with too little lymphoid sugar utilization, this raises the intriguing hypothesis that BCG
vaccination or a similar intervention to reset cell
metabolism could be an attractive therapeuticstrategy in these disorders. Taken with otherknown benefits of BCG benefits related to reduced
mortality [16, 17] and reduced susceptibility toinfection [12–14], these findings also support
reconsideration of vaccine policy in nations thatno longer mandate BCG vaccination due to low
tuberculosis incidence. Mycobacteria, at least in
the form of the attenuated BCG strain, are indeed‘old friends’ that we may want to welcome back.
Acknowledgements
The author would like to acknowledge The Iacocca
Foundation and the many other contributors supporting the BCG clinical trial programme in type 1
diabetes. The author would also like to acknowledge D. Briscoe for help with review and editing of
this paper.
Conflict of interest statement
None to report.

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Correspondence: Denise L. Faustman, MD, PhD, Department ofMedicine, Immunobiology Laboratories, Massachusetts General
Hospital and Harvard Medical School, Boston, MA, USA.
(fax: 617-726-4095; e-mail: faustman@helix.mgh.harvard.edu).