15th July 19:22
Fasting (via FOXO) upregulates innate antimicrobials like cathelicidin (diabetes stress calories diet kidney)
Fasting upregulates innate antimicrobials?
Well, you heard it from me first. I stated quite a while back that
fasting upregulates OCTN2 and this should, in turn, upregulate carnitine
uptake, butyrate uptake and histone acetylation leading to enhanced
expression of those genes under HDAC control - including defensins and
This little paper identifies differential antimicrobial peptide (AMP)
regulation in the skin and illuminates another fasting signal (FOXO)
involved in the regulation.
Given the angiogenic, pro- and anti-inflammatory, and other properties
of cathelicidin, this may place the peptide as uniquely central in
maintaining the health of aging people. (Note I didn't add other
organisms to the list; human cathelicidin has a unique transcriptional
I would also simply note how logical it is to assume that as nutrient
intake drops, there's less largesse to spread around. The body
naturally becomes less tolerant of its retinue of hangers on - the Kato
Kaelin's of the microbial world, so-to-speak.
This may explain why a liquid diet or intermittent fasting is beneficial
for diseases like Crohn's where AMP production can be deficient. One
item not mentioned by the article is that cathelicidin also has
antiviral properties. Intermittent fasting is helpful in M.S. and
enhanced antiviral activities might explain why. Fasting during periods
in adolescence might also help purge the body, leading to a lower
incidence of viral-related issues later in life like cancers and
Nutrition Has a Direct Influence on the Immune System
ScienceDaily (Jan. 20, 2010) ‹ Bonn researchers have discovered an
elementary mechanism which regulates vital immune functions in healthy
people. In situations of hunger which mean stress for the body's cells,
the body releases more antimicrobial peptides in order to protect
itself. The scientists will publish their results in the journal Nature.
T cells, B cells, antibodies are known as the 'SWAT team' of our immune
system that intervenes when viruses and bacteria make us ill. With
'heavy molecular artillery' they wipe out intruders effectively.
However, at the same time the defence systems cause collateral damage in
the body's own tissue, which has to be repaired first.
In order for the immune system not to be consistently in a state of red
alert and possibly cause chronic inflammation this way, there is a
second defence system switched in series between body and outside world.
This is absolutely necessary because on the barrier tissue such as lungs
and skin there are trillions of bacteria. The majority of these
microorganisms have been living with our body's cells as good neighbours
for millions of years. There's more to come: the complex symbiosis of
very different microorganisms supplies us with important natural
substances such as vitamin B12.
Good germs, bad germs
At the same time there are always a few mischief-makers among the
numerous peaceful bacteria which can make us sick. In this situation,
even before the pathogenic germs invade our body, a mechanism is set in
motion which acts completely independently of the classic immune defence
systems. The biomedical researchers from the LIMES Institute at the
University of Bonn have been able to show in fruit flies but also in
human tissue that this natural immune defence system is linked directly
to the metabolic status via the insulin signalling pathway.
If we have not eaten for a while or have to climb many stairs, the
energy level of our cells drops and with it the level of insulin. The
researchers from Bonn have now discovered that in the case of a low
insulin level the FOXO transcription factor is activated. A
transcription factor can switch genes on and off. FOXO switches genes
for immune defence proteins on when energy is needed. These
antimicrobial peptides (AMP) -- not to be confused with antibodies --
are subsequently jettisoned by the body's cells. They destroy possible
pathogens by dissolving their cell walls.
'This happens every minute every day,' the director of studies Prof.
Michael Hoch from the LIMES Institute explains. 'What is fascinating
about this is that a function of the immune system directly depends on
how much and what we eat.' In situations of hunger which mean stress for
the body cells, the body releases antimicrobial peptides as a precaution
in order to protect itself. 'The barrier between body and outside world
is apparently fortified in a potentially dangerous situation in which we
have too little energy,' Professor Hoch presumes.
Ancient defence mechanism helps us to get old?
FOXO and the antimicrobial peptide genes which it switches on occur in
almost all groups of animals. That is why the researchers believe that
the direct link between the food supply and the immunological defence
probably developed during the early stage of evolution of metazoan
The research of the Bonn biologists could also be clinically relevant.
For a number of common diseases such as type II diabetes or obesity
(adiposity) are the result of an increased intake of calories.
Furthermore, such diseases are accompanied by increased inflammation of
the barrier tissue, a disturbed immune system and an overall reduced
life span. 'Our results present new starting points for understanding of
these diseases,' Professor Joachim Schultze from the LIMES Institute,
who also is involved in the research project, says.
The scientists at LIMES will concentrate next on the relationship
between calorie intake and life span. Examinations of nematodes, fruit
flies and mice have shown that a reduced calorie intake can increase
life span. Professor Hoch says: 'We now want to find out whether this is
due to an foxo-dependent improvement of the barrier functions of the
natural immune system.'
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Adapted from materials provided by University of Bonn, via EurekAlert!,
a service of AAAS.
1. Becker et al. FOXO-dependent regulation of innate immune homeostasis.
Nature, 2010; 463 (7279): 369 DOI: 10.1038/nature08698
Nature. 2010 Jan 21;463(7279):369-73
FOXO-dependent regulation of innate immune homeostasis.
Becker T, Loch G, Beyer M, Zinke I, Aschenbrenner AC, Carrera P,
Inhester T, Schultze JL, Hoch M.
Development, Genetics & Molecular Physiology Unit, LIMES Institute,
University of Bonn, Carl-Troll-Strasse 31, D-53115 Bonn, Germany.
The innate immune system represents an ancient host defence mechanism
that protects against invading microorganisms. An important class of
immune effector molecules to fight pathogen infections are antimicrobial
peptides (AMPs) that are produced in plants and animals. In Drosophila,
the induction of AMPs in response to infection is regulated through the
activation of the evolutionarily conserved Toll and immune deficiency
(IMD) pathways. Here we show that AMP activation can be achieved
independently of these immunoregulatory pathways by the transcription
factor FOXO, a key regulator of stress resistance, metabolism and
ageing. In non-infected animals, AMP genes are activated in response to
nuclear FOXO activity when induced by starvation, using insulin
signalling mutants, or by applying small molecule inhibitors. AMP
induction is lost in foxo null mutants but enhanced when FOXO is
overexpressed. Expression of AMP genes in response to FOXO activity can
also be triggered in animals unable to respond to immune challenges due
to defects in both the Toll and IMD pathways. Molecular experiments at
the Drosomycin promoter indicate that FOXO directly binds to its
regulatory region, thereby inducing its transcription. In vivo studies
in Drosophila, but also studies in human lung, gut, kidney and skin
cells indicate that a FOXO-dependent regulation of AMPs is
evolutionarily conserved. Our results indicate a new mechanism of
cross-regulation of metabolism and innate immunity by which AMP genes
can be activated under normal physiological conditions in response to
the oscillating energy status of cells and tissues. This regulation
seems to be independent of the pathogen-responsive innate immunity
pathways whose activation is often associated with tissue damage and
repair. The sparse production of AMPs in epithelial tissues in response
to FOXO may help modulating the defence reaction without harming the
host tissues, in particular when animals are suffering from energy
shortage or stress.
* Research Support, Non-U.S. Gov't