"Science": Enterobacteria directly regulate host appetite and body temperature!

It is nothing new that gut bacteria can communicate with the brain
.

 Many studies have shown that the metabolites produced by intestinal bacteria can not only regulate the body's immune function after entering the blood, but also affect the development and behavior of the brain
.

Even what you want to eat, you have to listen to the gut bacteria [1]
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(Maybe, it is the control of intestinal bacteria that we wrote this article) However, the control of intestinal bacteria on the brain may be more direct than we think
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 Recently, an article published in the top journal "Science" stated that enterobacteria can dig out a part of their own cell wall as a token and communicate directly with neurons in the brain [2]
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 Pierre-Marie Lledo from the Pasteur Institute in France and his colleagues found that muropeptides secreted by gut microbiota can enter the blood circulation and accumulate in the brain through pattern recognition receptors expressed by neurons.
The interaction of Nod2 in vivo directly inhibits the activity of hypothalamic neurons, thereby reducing appetite and regulating body temperature and metabolism
.

 Screenshot of the homepage of the paper Why do you say that this is a direct gut-brain communication? Different from the old frequent visitor of gut-brain research - intestinal bacteria metabolites, this time the cell wall peptide is a common component of the cell wall of various bacteria.
It is released by bacteria during growth, reproduction or death.
It can be regarded as a sign of bacterial proliferation.
thing
.

 Previous studies have found small fragments of these bacterial cell walls in the mouse brain [3], and where these cell wall peptides are sent from and what they are sent to the brain for, the case has not yet been closed
.

But everyone agrees that it's the microbes farther away in the gut that are at work
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 Although there are many doubts about cell wall peptides, scientists are not without clues
.

 Muramin is a ligand for the pattern recognition receptor Nod2
.

Studies have shown that the Nod2 signaling pathway plays a role in regulating brain activity and body metabolism, and is associated with bipolar disorder, schizophrenia, Parkinson's disease, etc.
Nod2 deficiency can also lead to diet-induced obesity metabolic dysfunction [2]
.

 Is it possible that intestinal bacteria use the relationship between cell wall peptide and Nod2 to manipulate the brain to do something? So Pierre-Marie Lledo and his colleagues launched this study to solve this mystery
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 They used immunofluorescence technology and mRNA in situ hybridization technology to observe the brain tissue sections of mice, and found that Nod2 is expressed in the brain of mice, and the expression of neurons in different regions is different
.

Nod2 is mainly expressed in neurons in the striatum, thalamus, and hypothalamic regions, while cortical neurons do not express this pattern receptor
.

 Neurons in the brain express Nod2 (cortex: cortex; striatum: striatum; thalamus: thalamus; hypothalamus: hypothalamus) Since it has been ensured that the brain can receive information, it is time to see if the enterobacteria can transmit the cell wall peptide as expected.
send over
.

 The researchers colonized the guts of mice with radiolabeled E.
coli bacteria and observed blood and brain samples from the mice 24 hours later
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The results showed that the cell wall peptides from enterobacteria can cross the intestinal barrier into the blood circulation and accumulate in the brain
.

Also, compared with male mice, the female mice had faster delivery and greater accumulation of murein in their brains and similar levels in the blood
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 In the brain and blood, the levels of murein in female and male mice are different.
So, what is the communication between the murepeptide that runs all the way from the gut and Nod2 in the brain? The researchers found that the interaction of cell wall peptides from enterobacteria with Nod2 expressed by GABAergic neurons in the hypothalamus of mice inhibited the activity of neurons, thereby inhibiting the desire to eat in mice, which is equivalent to a kind of satiety.
In addition, it is also related to maintaining body temperature and body weight stability
.

 Enterobacteriaceae-derived cell wall peptides act on GABAergic neurons through Nod2 and inhibit their activity.
If the Nod2 gene in hypothalamic neurons is conditionally knocked out, the appetite for food and the regulation of body temperature stability in mice will be out of control, and the amount and frequency of food intake will be out of control.
increase, and weight gain significantly
.

 On the other hand, when normal mice were injected with broad-spectrum antibiotics (ABX) to eliminate intestinal bacteria and their wall peptides, the metabolic profiles of appetite, body temperature and body weight regulation were similar to those of Nod2 conditional knockout mice.

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Once ABX was stopped, the mice ate significantly less and their weight was controlled
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And those mice whose neurons had been conditionally knocked out of Nod2 did not make any difference with or without ABX
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 That is to say, the Nod2 on the brain side and the cell wall peptides derived from gut bacteria need to be "online" at the same time to ensure the normal gut-brain communication
.

 When neurons do not express Nod2 or enteric bacteria, they cannot maintain body weight and increase appetite (CRE virus Control: control group; CRE virus Nod2flox: conditional knockout of Nod2).
It is worth noting that the muramin-Nod2 signaling pathway The regulation effect has obvious gender and age differences
.

 In older female mice (about 6 months old), neurons in regions of the hypothalamus (arcuate nucleus, dorsomedial nucleus) responsible for appetite and body temperature regulation were more sensitive to muramidin
.

When the neuron Nod2 is conditionally knocked out, the metabolic activities of female mice such as weight gain, loss of appetite, and temperature homeostasis are more affected, and even older female mice are more likely to develop diabetes and have a significantly longer lifespan.
shorten
.

 In this regard, the researchers believe that this may be related to the faster transmission of wall peptides and higher levels of brain accumulation in female mice, as mentioned earlier
.

In addition, female mice aged around 6 months are equivalent to premenopausal human females, which means that they may also be affected by hormonal changes
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 However, the expression levels of neuronal Nod2 did not differ significantly between mice of different ages and genders
.

 Older female mice showed marked changes in neuronal activity in the arcuate nucleus (ARC) and dorsomedial nucleus (DMH), key regions that regulate feeding behavior and body temperature ) In general, different from the previously discovered gut-brain communication mode, Pierre-Marie Lledo and his colleagues proposed this time that, in addition to metabolites, enterobacteria can also use their cell wall components, cell wall peptides, to achieve The brain communicates directly
.

 After entering the brain through blood circulation, the cell wall peptides secreted by enterobacteria interact with Nod2 expressed in hypothalamic neurons to inhibit the activity of neurons, thereby inhibiting the appetite of mice and regulating metabolic activities such as body temperature and body weight homeostasis
.

 On the other hand, this suggests that neurons can directly monitor changes (increase or decrease) in gut microbiota abundance through changes in the levels of muramin in the brain
.

Once eating behavior or eating habits cause a disproportionate growth or death of certain intestinal bacteria, the flora structure is imbalanced, and the cell wall peptides secreted by the intestinal bacteria will notify the brain
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 The researchers expressed the hope that the existence of this mechanism can be identified in humans as soon as possible to provide new ideas for the treatment of metabolic disorders such as obesity
.

In particular, exploring the effects of age and gender differences may help menopausal women solve the problems of hot flashes and sudden weight gain
.

References: [1] Trevelline BK, Kohl KD.
The gut microbiome influences host diet selection behavior.
Proc Natl Acad Sci US A.
2022 Apr 26;119(17):e2117537119.
doi: 10.
1073/pnas.
2117537119.
Epub 2022 Apr 19.
PMID: 35439064.
[2]https:// Arentsen et al.
, The bacterial peptidoglycan-sensing molecule Pglyrp2 modulates brain development and behavior.
Mol .
Psychiatry 22, 257–266 (2017).
doi: 10.
1038/mp.
2016.
182; pmid: 27843150 Author | Eddie Zhang