A Diet-Microbe-Epithelia Metabolic Trilogue in the Stressed Gut

Gut epithelial integrity is dynamically shaped by microbial signals amenable to environmental and psychological modulation. Here we dissect dietary impact on psychological stress-induced gut microbial remodeling and how this is metabolically linked to stem cell proliferation and epithelial renewal.

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The gut is constantly exposed to a myriad of environmental stimuli that typically include dietary products and resident microbes. Psychological factors are also well known to modulate gut homeostasis, which partially explains an increased burden of gastrointestinal diseases in modern society. How environmental and psychosocial factors jointly impact the integrity of gut epithelia remains largely unexplored. In our latest research we investigated the impact of dietary pattern on chronic restraint stress-induced gut epithelial disturbance. We were intrigued by a contrasting change in epithelial integrity and gut microbial structure in stressed mice fed with a chow or purified diet. Inspired by the close interplay between diet and microbes in the gut mucosal milieu, we further identified a feedforward metabolic circuit between dietary raffinose metabolism and Lactobacillus enrichment that is causally linked with gut epithelial response to chron ic stress and chemical injury. Importantly, we uncovered that fructose produced from this metabolic loop favors intestinal stem cell (ISC) renewal via potentiated glycolysis, depicting a three-way metabolic conversation in the stressed gut between dietary components, the resident bacteria, and the intestinal epithelia.

Dietary pattern impacts restraint stress-induced gut microbial remodeling and epithelial renewal. Dietary raffinose metabolism by Lactobacillus reuteri (L. reuteri) to fructose, which is markedly different in mice fed chow or purified diet, couples stress-induced gut microbial remodeling to intestinal stem cells (ISC) renewal and epithelial homeostasis. At the crypt level, raffinose-derived fructose augments and engages glycolysis to fuel ISC proliferation, underlying less susceptibility to psychological disturbance. F1P, fructose-1-phosphate.


The interconnected modulation of gut microbiota by diet and stress as found in our study provides another interesting piece of information on the highly dynamic nature of this microbial community. These results may explain how nutritional and psychosocial status, two ubiquitous factors from host daily life, interactively affect gut epithelial homeostasis and thereby the risk of functional gut disorders. Given the importance of metabolic signals in mediating the diet-microbe-epithelia trilogue, it is of interest to pursue diet-based metabolic manipulations to strengthen the resilience of ISC maintenance during psychological and chemical insults. It would also be exciting to explore the translational potential of dietary intervention of the detrimental GI impact of psychological stress 1.

The gut microbiota is naturally exposed to multiple remodeling signals from host daily life, such as dietary shifts, drugs and stressful experience2. So how do gut microbes respond to multiple host inputs to adjust their structure? Overall, our work highlights the importance of understanding the highly orchestrated nature of gut microbial metabolism in response to nutritional cues. Dietary pattern seems to take a center stage among daily lifestyle factors affecting the gut microbiota3,4, and the causal links with host pathophysiology in the gut and remote organs have attracted much enthusiasm of our lab and colleagues in the field of life science and medicine5. Unraveling the complexity of dietary component and its crosstalk with the microbial ecology at the gut epithelial interface, as shown here by our current work, could pave the way for precision nutrition and better health strategies6.

 Thanks for reading, and the full paper (“A Diet-Microbial Metabolism Feedforward Loop Modulates Intestinal Stem Cell Renewal in the Stressed Gut”) is available at Nature Communications: https://www.nature.com/articles/s41467-020-20673-4.


  1. Gracie, D.J., et al. Effect of psychological therapy on disease activity, psychological comorbidity, and quality of life in inflammatory bowel disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2, 189-199 (2017).
  2. Maier, L., et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 555, 623-628 (2018).
  3. David, L.A., et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559-563 (2014).
  4. Gentile, C.L. & Weir, T.L. The gut microbiota at the intersection of diet and human health. Science 362, 776-780 (2018).
  5. Liu, Y., Hou, Y., Wang, G., Zheng, X. & Hao, H. Gut Microbial Metabolites of Aromatic Amino Acids as Signals in Host-Microbe Interplay. Trends Endocrinol Metab 31, 818-834 (2020).
  6. Kolodziejczyk, A.A., Zheng, D. & Elinav, E. Diet-microbiota interactions and personalized nutrition. Nat Rev Microbiol 17, 742-753 (2019).

Haiping Hao

Professor, China pharmaceutical university

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