Friday, August 1, 2014

Gut flora helps macrophages to flex the muscles

Though I am a little bit tired reviewing papers about gut microbiome, this new paper in Cell is so cute I could not ignore it.

GI tract's proper motility is obviously very important for a good health. It is also quite obvious that food and gut neuronal network regulate GI tract motility and of course, gut muscles. Now this gut muscles are specialized type of muscles called smooth muscles.

This short and very simple paper published in Cell (1) has made very unusual observation. One of the senior authors on this paper is Miriam Merad. She is well known for her work on macrophages.

First, the authors found that gut outer muscular layer harbored Cx3CR1+ macrophages. The development of these muscle associated-macrophages was dependent on CSF-1 (M-CSF) receptor as shown by their absence in CSF receptor-1 or CSF-1 KO mice. 

In addition, intra-peritoneal injection of anti-CSF1 antibody preferentially depleted muscle-associated macrophages.

The parallel set of experiments showed that ex vivo gut motility (peristaltic movements) were modified (accelerated) by anti-CSF1 antibody mediated muscle-associated macrophages depletion.

This was a peculiar observation since this muscle macrophages are sitting deep in the outer muscles layer of the gut and do no directly interact with gut flora, for example.

So, how their depletion affected GI tract motility?

To find the answer, the authors run microarray analysis on purified muscle-associated macrophages and found that molecule, called BMP2, was highly expressed by these macrophages

On the other hand, macrophages depletion affected neurons located in close proximity to the muscle macrophages. These neurons were found to express receptor for BMP2 and to express CSF-1.

It is well described that germ-free mice have GI tract motility issues. Anyone who worked with mice and seen germ-free mice intestine can ascertain that their colon is of enormous size. To further understand the relationship between neurons and macrophages and gut flora, the authors conducted series of experiments with antibiotic-treated mice. Antibiotic treatment diminished BMP2 expression in muscle macrophages and reduced GI peristaltic movement that was reversible with the addition of LPS in drinking water. Interestingly in vitro gut neurons produce more of CSF-1 in response to LPS.

In summary, the authors proposed the following model of physiological gut motility: products of gut microbiota induce neuronal cells (or other cells) in the gut to secrete CSF-1. CSF-1 stimulates development and/or maintenance of muscle-associated macrophages, which in turn secrete BMP2 required for normal gut neuronal activity.

This study represents another example supporting growing evidence that macrophages play more fundamental role in physiology, including already described role in thermoregulation.


No comments:

Post a Comment