Glycolytic regulation of intestinal stem cell self-renewal and differentiation 2022 Li et al

Background and Aims
The Intestinal mucosa undergoes a continual process of proliferation, differentiation, and apoptosis. An imbalance in this highly regimented process within the intestinal crypts is associated with several intestinal pathologies. Although metabolic changes are known to play a pivotal role in cell proliferation and differentiation, how glycolysis contributes to intestinal epithelial homeostasis remains to be defined.

Methods
Small intestines were harvested from mice with specific hexokinase 2 (HK2) deletion in the intestinal epithelium or LGR5+ stem cells. Glycolysis was measured using the Seahorse XFe96 analyzer. Expression of phospho-p38 MAPK, the transcription factor atonal homolog 1 (ATOH1), and intestinal cell differentiation markers lysozyme, mucin 2, and chromogranin A were determined by western blot, qPCR or IF and IHC staining.

Results
HK2 is a target gene of Wnt signaling in intestinal epithelium. HK2 knockout (KO) or inhibition of glycolysis resulted in increased numbers of Paneth, goblet, and enteroendocrine cells and decreased intestinal stem cell self-renewal. Mechanistically, HK2 KO resulted in activation of p38 MAPK and increased expression of ATOH1; inhibition of p38 MAPK signaling attenuated the phenotypes induced by HK2 KO in intestinal organoids. HK2 KO significantly decreased glycolysis and lactate production in intestinal organoids; supplementation of lactate or pyruvate reversed the phenotypes induced by HK2 KO.

Conclusions
Our results show that HK2 regulates intestinal stem cell self-renewal and differentiation through p38 MAPK/ATOH1 signaling pathway. Our findings demonstrate an essential role for glycolysis in maintenance of intestinal stem cell function.

Open access, https://www.cmghjournal.org/article/S2352-345X(22)00263-6/fulltext

 

I'm just hearing about paneth cells and they seem interesting. Here's two papers. First a background primer on how they maintain intestinal homeostasis. Those of us who seem to be in constant dysbiosis might wonder if our paneth cells are working properly.

EMBO Mol Med. 2023 Feb; 15(2): e16427.
Published online 2022 Dec 27. doi: 10.15252/emmm.202216427
PMCID: PMC9906427
PMID: 36573340
Paneth cells as the cornerstones of intestinal and organismal health: a primer
Charlotte Wallaeys, 1 , 2 , † Natalia Garcia‐Gonzalez, 1 , 2 , † and Claude Libert 1 , 2
Author information Article notes Copyright and License information PMC Disclaimer

Go to:
Abstract
Paneth cells are versatile secretory cells located in the crypts of Lieberkühn of the small intestine. In normal conditions, they function as the cornerstones of intestinal health by preserving homeostasis. They perform this function by providing niche factors to the intestinal stem cell compartment, regulating the composition of the microbiome through the production and secretion of antimicrobial peptides, performing phagocytosis and efferocytosis, taking up heavy metals, and preserving barrier integrity. Disturbances in one or more of these functions can lead to intestinal as well as systemic inflammatory and infectious diseases. This review discusses the multiple functions of Paneth cells, and the mechanisms and consequences of Paneth cell dysfunction. It also provides an overview of the tools available for studying Paneth cells.


Second, a paper on how TNF can suppress the paneth cells from working, and cause "leaky gut" where LPS goes into the blood stream and causes an immune reaction.
Apparently the mechanism that it operates through is inhibiting the Unfolded Protein Response.

https://pubmed.ncbi.nlm.nih.gov/39243761/

. 2024 Sep 2:S1931-3128(24)00314-7. doi: 10.1016/j.chom.2024.08.007. Online ahead of print.
Paneth cell TNF signaling induces gut bacterial translocation and sepsis
Charlotte Wallaeys 1 , Natalia Garcia-Gonzalez 1 , Steven Timmermans 1 , Jolien Vandewalle 1 , Tineke Vanderhaeghen 1 , Somara De Beul 1 , Hester Dufoor 1 , Melanie Eggermont 1 , Elise Moens 1 , Victor Bosteels 2 , Riet De Rycke 3 , Fabien Thery 4 , Francis Impens 5 , Serge Verbanck 6 , Stefan Lienenklaus 7 , Sophie Janssens 2 , Richard S Blumberg 8 , Takao Iwawaki 9 , Claude Libert 10
Affiliations

• PMID: 39243761
• DOI: 10.1016/j.chom.2024.08.007

Abstract
The cytokine tumor necrosis factor (TNF) plays important roles in limiting infection but is also linked to sepsis. The mechanisms underlying these paradoxical roles are unclear. Here, we show that TNF limits the antimicrobial activity of Paneth cells (PCs), causing bacterial translocation from the gut to various organs. This TNF-induced lethality does not occur in mice with a PC-specific deletion in the TNF receptor, P55. In PCs, TNF stimulates the IFN pathway and ablates the steady-state unfolded protein response (UPR), effects not observed in mice lacking P55 or IFNAR1. TNF triggers the transcriptional downregulation of IRE1 key genes Ern1 and Ern2, which are key mediators of the UPR. This UPR deficiency causes a significant reduction in antimicrobial peptide production and PC antimicrobial activity, causing bacterial translocation to organs and subsequent polymicrobial sepsis, organ failure, and death. This study highlights the roles of PCs in bacterial control and therapeutic targets for sepsis.

There's long been chat about mecfs-sepsis similarities, this ties in gut issues too.

Here's a model: infection elevates tnf, tnf whacks paneth cells, gut becomes dysbiotic, vagal nerve starts transmitting wrong signals to brain. tnf production doesn't go abck down because of ____? . This would explain things in a centrally mediated way. You could find a peripheral explanation if you wanted to let TNF promote UPR in vasculature or muscles.
Tumor necrosis factor alpha (TNFalpha) induces the unfolded protein response (UPR) in a reactive oxygen species (ROS)-dependent fashion, and the UPR counteracts ROS accumulation by TNFalpha
During exercise the UPR is supposed to start; Hanson finds our bodies don't seem to mount a normal reaction to exercise. Perhaps UPR is already on and so can't be activated for exercise.

Just spit-balling...

 

Me too, I'd never heard of them until I read this. Interesting idea.

Anatomy has the best names. The crypts of Lieberkühn sound like somewhere I might have seen Cabaret Voltaire play in the late '70s.