Research commentary from The Carb-Appropriate Research Review
Dietary intake regulates the circulating inflammatory monocyte pool
Stefan Jordan, Navpreet Tung, Maria Casanova-Acebes, Christie Chang, Claudia Cantoni, Dachuan Zhang, Theresa H. Wirtz, Shruti Naik, Samuel A. Rose, Chad N. Brocker, Anastasiia Gainullina, Barbara B. Maier, Derek LeRoith, Frank J. Gonzalez, Felix Meissner, Jordi Ochando, Adeeb Rahman, Jerry E. Chipuk, Maxim N. Artyomov, Paul S. Frenette, Laura Piccio, Marie-Luise Berres, Emily J. Gallagher, Miriam Merad
Cell – bioRxiv preprint: https://doi.org/10.1101/582346
Caloric restriction is known to improve inflammatory and autoimmune diseases. However, the mechanisms by which reduced caloric intake modulates inflammation are poorly understood. Here we show that short-term fasting reduced monocyte metabolic and inflammatory activity and drastically reduced the number of circulating monocytes. Regulation of peripheral monocyte numbers was dependent on dietary glucose and protein levels. Specifically, we found that activation of the low-energy sensor 5’-AMP-activated protein kinase (AMPK) in hepatocytes and suppression of systemic CCL2 production by peroxisome proliferator-activator receptor alpha (PPARα) reduced monocyte mobilization from the bone marrow. Importantly, while caloric restriction improves chronic inflammatory diseases, fasting did not compromise monocyte emergency mobilization during acute infectious inflammation and tissue repair. These results reveal that caloric intake and liver energy sensors dictate the blood and tissue immune tone and link dietary habits to inflammatory disease outcome.
- Fasting reduces the numbers of peripheral pro-inflammatory monocytes in healthy humans and mice.
- A hepatic AMPK-PPARα energy-sensing axis controls homeostatic monocyte numbers via regulation of steady-state CCL2 production.
- Fasting reduces monocyte metabolic and inflammatory activity.
- Fasting improves chronic inflammatory diseases but does not compromise monocyte emergency mobilization during acute infectious inflammation and tissue repair.
This study is one of my favourites of the year so far and it came to my attention quite serendipitously. I was asked to appear on The AM Show on TV3 (NZ) to talk about fasting and its effects on the immune system and they specifically mentioned this study, which had been released in pre-print only a few days earlier (those journos were on to it this time!)
One of the things that attracted me to the study was that it used a novel combination of outcome testing in humans and backed that up with additional testing in mice where it would have been difficult or unethical to perform in humans. This led to a broader range of results and helped to bridge the divides between mechanisms (mostly shown in animals) and functional outcomes in the human subjects.
The study showed that fasting reduces monocytes (white blood cells) that increase inflammation. However, importantly, these levels were not decreased in those with already lower levels. This suggests that fasting does not simply reduce inflammation, but instead helps the body to properly regulate it.
The authors also looked into the mechanism by which pro-inflammatory monocytes were increased and found that it was unlikely to be driven by cell-death or reductions in monocyte precursors, but instead appeared to be driven by sequestering of the inflammatory monocytes in the bone marrow. This further suggests that the body is adapting to fasting by moderating inflammation where it is unnecessary.
What drove the reduced inflammation?
Overall, energy-restriction drives the monocyte and inflammation-reducing properties of fasting. But importantly, both protein and fasting restore monocyte levels (and therefore return inflammation to pre-fasting levels) but fat does not. Furthermore, the size of the monocyte pool (the total number of inflammation-driving monocytes) depends on the amount of carbohydrate ingested (see figure below).
Because both protein and carbohydrate (but not fats) have a large insulin response, the researchers looked into whether insulin was the reason for the increase in monocyte numbers when animals were fed carbohydrate or protein but not fat. They found, however, that deleting the insulin receptor from mice did not change these results, showing that insulin is unlikely to be the reason. But, blocking glycolysis (the breakdown of carbohydrate for energy in the cell) did reduce monocyte levels to those similar to fasting. This effect is likely to be because of ‘energy-sensing’ within the cell. When energy availability is low (especially low energy from carbohydrate) mammalian 5’-AMP-activated protein kinase (AMPK) is activated and this acts as a signal to reduce monocyte release from bone marrow through various other channels (such as the peroxisome proliferator-activated receptor α (PPARα)).
PPARα itself has been implicated in the anti-inflammatory effects of fasting and in the present study, fasting-induced reduction of monocytes was less efficient in mice which had the PPAR gene knocked out. Additionally, it was found that this signalling pathway was mostly driven by energy-sensing by the liver (via the AMPK-PPARα pathway) in response to caloric and carbohydrate intake. In addition, it was found that a ketogenic diet failed to affect peripheral monocyte numbers.
Fasting also affects many metabolic hormones and in this study, fasting resulted in very similar changes in levels of hormones like ghrelin (increased), and insulin, c-peptide, amylin, GIP, leptin, PP, and PYY (decreased). Most human (and mouse) subjects (67%) also had reduced CCL2 (also known as MCP-1) levels. This hormone is known to bind to a receptor (CCR2) found in abundance on monocytes and helps to regulate the release of monocytes from bone marrow. This provided another inter-related pathway by which fasting reduced monocyte-driven inflammation.
Fasting modifies the metabolic activity of monocytes
Fasting was also seen to have a profound effect on gene expression in monocytes (with more than 2700 genes in mice monocytes being differentially expressed due to fasting). Genetic expression changes unsurprisingly mostly related to cellular energy conservation (eIF2 signalling, protein ubiquitination, and mitochondrial function and oxidative phosphorylation). It was co concluded that “monocytes from fasting mice were reduced in their metabolic activity reflecting a quiescent functional state.”
Fasting and chronic inflammatory disease
It is well known that fasting and calorie-restriction improve chronic inflammatory and autoimmune disorders, such as multiple sclerosis and rheumatoid arthritis.
In this study, gene modules associated with joint inflammation and rheumatoid arthritis were reduced. So, the researchers followed this line of enquiry in mice induced to develop an autoimmune disorder of a pre-clinical model for multiple sclerosis (EAE). A large reduction in myeloid cell accumulation was observed in the spinal cords of fasted mice with EAE, and intermittent fasting significantly improved the clinical symptoms of this disease. Genes related to inflammation and infiltration were also strongly downregulated in monocytes from fasting mice compared to non-fasting mice. This suggests that fasting can reliably improve auto-immune activity.
But….does this reduction in monocytes and inflammation impair the normal immune and repair responses?
The authors had observed reductions in key monocytes and resulting inflammation. While this is seen to be a ‘good’ thing, inflammation and the immune white blood cells (monocytes) are important to proper immune function, resistance to pathogens, and repair from illness and injury. So, the question was asked; would “changes in monocyte functional state also compromise acute inflammatory reactions in response to tissue injury or pathogen invasion?”
It was found that emergency mobilisation of monocytes in
response to a pathogen (Listeria) was no different when fasted to non-fasted. Neither
immunity against Listeria infection nor wound healing were in any way impaired
in fasting mice. This suggests that monocyte resp9nses to infection and injury
are unaffected by fasting.
Take home points:
- Fasting reduces inflammation
- Fasting improves symptoms and clinical progression of an autoimmune disease
- The effects of fasting are due to an inter-related and complex web of biochemical and gene interactions
- These changes are signalled at the cellular level (especially in organs like the liver) by energy-restriction
- Energy restriction and the total volume of carbohydrate consumed are the key drivers of the beneficial effects of fasting
- Fasting did not negatively affect the ability of the body to respond to illness or wounds