High-fat challenge induced trained innate immunity

Atherosclerosis is characterized by a persistent inflammation of the arterial
wall. Monocyte-derived macrophages are the most abundant immune cells in
atherosclerotic plaques. It has recently been shown that not only immune cells
of the adaptive immune system, but innate immune cells as well are able to
adopt a long-term pro-inflammatory phenotype upon stimulation. This nonspecific
memory of innate immune cells is mediated by epigenetic and metabolic
reprogramming and is termed "trained innate immunity." Previous findings from
our lab have shown that not only bacterial components such as LPS, but also
pro-atherogenic particles such as oxidized LDL can induce trained immunity in
monocytes. Interestingly, this memory-effect of trained immunity indicates that
even temporary triggers could induce the persistent inflammation in
atherosclerosis.

Triglyceride-rich lipoproteins (TRL) have been identified as an important
independent risk factor for atherosclerosis. Moreover, elevated plasma levels
of these lipoproteins are associated with increased pro-inflammatory markers.
TRLs, however, are characterized by alternating plasma levels, with brief
elevations following (fat containing) meals. Notably, a high-fat meal not only
contributes to the transient increase of TRL plasma levels, but also induces a
brief elevation in LPS levels by briefly increasing the permeability of the
gut.

We now aim to investigate whether a single high-fat meal can induce trained
innate immunity, since this concept might explain how brief postprandial
effects can translate into a long-term pro-inflammatory and pro-atherogenic
monocyte phenotype.

The primary objective is to determine whether a high-fat meal can induce a
persistent pro-inflammatory monocyte phenotype, characterized by an increased
cytokine production capacity upon ex vivo stimulation. Secondary objectives
are metabolic and epigenetic reprogramming of monocytes at these time points as
well as the capacity of serum, isolated before and 1-6h after an oral fat load,
to induce an increased cytokine production in healthy human monocytes.

Cross-over high-fat challenge intervention study.

A single high-fat challenge (milkshake containing 95g of fat) and *control*
shake (comparable to an average breakfast).

There is no risk associated with participation. After informed consent 3 mL of
blood will be drawn during the screening visit. A general, medical will be
used. Moreover, participants will be asked to keep a food diary for 3 days.
During the study each participant will consume a high-fat milkshake and
*control* shake after an overnight fast. At baseline t=0h and at visit 1: t=1h,
t=2h, t=4h, t=6h, visit 2: t=24h and visit 3: t=72h after the intervention
shake, a total of 205 mL blood will be collected by using a venflon. The night
before and during the 3-day study period, the participants will receive
standardized meal plans, adjusted to their individual caloric requirements. The
same protocol will be repeated for the *control* shake.