The gut microbiome of mice is stressed within 24 hours when fed a high-fat diet


In a recent study published in the journal Cell Reportsresearchers in Cincinnati, USA, evaluated the effect of a dietary change to a high-fat diet (HFD) on the gut.

A significant change in diet over time can affect metabolism and physiology. In the United States, a caloric imbalance may be a contributing factor to obesity. From 1999 to 2018, the number of obese people increased from 30.5% to 42.4%, while metabolic diseases such as dyslipidemia and diabetes increased from 25.3% to 34.2%. Long-term variations in diet are known to cause obesity and metabolic diseases, but it is not clear how quickly a change in diet can cause changes in the body.

The study: Changing the diet to a high-fat diet leads to rapid bowel adaptation.  Image credit: Alexei Logvinovich/Shutterstock

Stady: Changing the diet to a high-fat diet leads to a rapid adaptation of the intestine. Image credit: Alexei Logvinovich/Shutterstock

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In this study, the researchers evaluated the response of intestinal epithelial cells to a HFD using physiological and single-cell transcriptome measurements.

The team used an indirect calorimeter to scan wild-type adult mice fed a normal chow or switched to a HFD for seven days and evaluated the effect. First, the amount of oxygen consumed (V.O2) along with the expiration of carbon dioxide (V.Carbon Dioxide) to calculate the respiratory exchange ratio (RER), which showed the primary fuel source metabolized by the body. Also, the team measured the total energy needed for homeostasis, called energy expenditure (EE).

The team also evaluated whether the adaptive response in the proximal intestine to acute HFD caused these whole-body metabolic changes. Intestinal proliferation was examined along with depth of crypts and villus height after one, three, or seven days on the HFD. Single-cell RNA sequencing (scRNA-seq) was also performed on epithelial cells of the jejunum and duodenum of adult mice at all time points. After checking and filtering the quality of the cells, the team combined the datasets of cells obtained from mice that had consumed normal food and mice that had been fed a HFD for one, three, or seven days. Normal food cells were used as the reference data set.

The team further analyzed how each group of cells responded to the HFD using differential gene expression analysis. The transcriptional signature associated with glutamate/glutamine metabolism was also evaluated using genes from the Molecular Signatures Database (MSigDB).


During the first day of HFD feeding, RER levels decreased from approximately 0.9 to 0.8, and these differences were maintained over time. On the first day, energy efficiency increased from approximately 0.2 to 0.5 kcal/min to approximately 0.4 to 0.6 kcal/min. Over the course of seven days, there were no significant differences in the amount of water consumed or ambulatory movements. Mice fed the HFD gained weight while showing higher energy expenditure than on the first day. After one day of eating a HFD, these results showed that the metabolism of the rats had changed in the whole body, and there may have been changes in their intestines as well.

There was an increase in EdU (5-ethynyl-2′-deoxyuridine) incorporation 1 day after HFD consumption. However, the depth of the intestinal crypts or the height of the villi did not change. The team also assessed any changes in intestinal cell death using cleaved caspase-3 staining combined with deoxynucleotidyl transferase-deoxyuridine triphosphate (TUNEL) staining and found no differences at any of the indicated time points. These results showed that the HFD induced a proliferative response within 1 day, but that this did not change the size of the intestinal surface area over the course of 1 week. In addition, all expected cell types were identified, such as EEC cells, enterocytes, enterocyte progenitors (EPs), goblet, Paneth cells, secretory progenitors (SPs), tuft, and stem/early transit (TA) amplification zone cells.

Analysis of HFD-induced transcriptional alterations was performed using Biological Process Ontology Terms (GO-Terms), which showed that genes for fatty acid metabolism pathways had higher expression levels in several cell types after only 1 day of HFD. This indicates that the intestinal epithelium has shifted away from the normally used glutamine/glutamate metabolism. There was also an immediate down-regulation observed 1 day after the HFD. Gene set enrichment analysis (GSEA) showed that most epithelial cells have regulated genes that facilitate fatty acid metabolism, as indicated by normalized enrichment scores (NESs). In particular, NESs associated with fatty acid metabolism increased on one and three days of HFD. This suggests that the body’s metabolism quickly reacts to the excess of shiny fat. By seven days, the NES fatty acid metabolism decreased indicating that the enterocytes had adapted to the change to the HFD.

After 1 day on the HFD, there was upregulation of stress-related genes for all epithelial cell populations. Based on scRNA-seq data, iPS/early-TA, along with Paneth cells, tend to show dramatic changes in gene expression in response to cellular stress. The stem/early stem subset of TA has been found to regulate heat shock protein genes, and the upregulated unfolded protein response (UPR) genes of GSEA. This showed that TA stem/early cells react to a HFD immediately with a stress response.

This study demonstrated a multi-pronged approach to assessing how animals respond to diet changes by evaluating whole-body metabolism, tissue function, morphology, and single-cell transcription. Functional and transcriptional analyzes showed that all types of intestinal epithelial cells were altered within 24 hours. Furthermore, within a week, the intestinal epithelium was modified to increase lipid uptake. Intestinal wall elasticity may have evolved during times of nutrient scarcity but can now be linked to obesity, metabolic disease and inflammation during times of nutrient excess.

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