Transient intestinal infection affects host adaptation to nutrient limitation

Recent PNAS study shows that transient intestinal infection not only promotes white adipose tissue (WAT) expansion and host weight gain, but also optimizes host carbohydrate metabolism.

Studies: The infection-induced microbiota promotes host adaptation to nutrient limitation. Image credit: mi_viri / Shutterstock.com

Metabolism and the gut microbiome

The human gut microbiome plays a critical role in host physiology and fitness by regulating metabolism and the immune system. In addition, these microbes obtain energy through the biochemical reactions of proteins, fats and carbohydrates obtained from the human diet.

Several studies have shown the versatile ability of the human microbiome to rapidly adapt to changes in diet. Human diet is therefore one of the main determinants of microbiome diversity and metabolic output.

The gut microbiome diversity of malnourished hosts differs significantly from those accustomed to a high-fat Western diet. A high-fat diet raises blood triglycerides and glucose along with body fat, which in turn increases the risk of diabetes and other health problems. Although an individual’s diet determines the microbial diversity in the gut, these microbes regulate the host’s utilization and storage of dietary energy.

Host metabolism can be regulated favorably or unfavorably by the presence of specific taxa in the microbiome. For example, mucus-decomposing bacteria Akkermansia muciniphila protects the host from obesity and diabetes. On the contrary, Bilophila wadsworthia increases rapidly in response to fat-induced bile acids to increase metabolic syndromes.

In addition to diet, infection and antibiotic treatment also affect the diversity of the host microbiome. For example, overuse of antibiotics is strongly associated with reduced gut microbiota diversity, which is associated with an increased prevalence of various inflammatory and metabolic diseases.

A small degree of pathogen exposure has been found to be beneficial to the host by improving host fitness. This finding was also confirmed by an live an experiment on wild and laboratory mice that revealed that wild mice, which are more often exposed to a wide range of pathogens, are less affected by influenza infection, colon cancer, obesity and metabolic syndromes compared to laboratory mice.

Although dysregulated host metabolism can alter microbiota resistance to pathogens, the potential effects of infection on microbiota regulation of host metabolism remain unclear.

About studying

In the current study, the impact of infection on host metabolism was assessed using Yersinia pseudotuberculosis (Yptb) transient intestinal infection model. Yptb, a food-borne bacterium, causes transient weight loss in infected mice before being cleared from the gut and peripheral tissues within four weeks of infection.

After fifteen weeks of infection, the convalescent mice began to gain significantly more weight than the naïve control mice. However, this weight gain was unrelated to food intake.

Study results

X-ray imaging of Yptb-infected mice fifteen weeks after infection revealed a significant expansion of peripheral body fat. Weight gain was observed in three major depots of WAT, namely mesenteric, perigonadal and subcutaneous.

A higher level of circulating adiponectin, a hormone secreted by WAT, was found in Post-Yptb mice. WAT expansion can be attributed to an increase in adipocyte size and progenitor proliferation.

Evaluation of the proliferation marker Ki-67 four weeks after Yptb revealed the presence of adipocyte progenitors in mesenteric and perigonadal, but not in subcutaneous WAT. Similar expression of Ki-67 was not found in naïve control mice, highlighting the role of Ki-67 for increased adipocyte hyperplasia. These findings suggest that prior intestinal infection may stimulate physiological WAT remodeling and promote long-term weight gain after pathogen clearance.

The authors also observed that infection-induced gut microbiota could shift host metabolism to use carbohydrates, resulting in increased glucose disposal, weight gain, and WAT expansion. This type of infection-optimized carbohydrate metabolism could also promote host fitness based on limited protein and fat availability and prevent malnutrition.
Thus, prior infection appears to promote resistance to malnutrition, particularly if the malnutrition was caused by restricted protein and fat consumption.

Consistent with previous reports, the findings of the current study highlight the importance of environmental stressors for the full development and optimization of host physiology. Nevertheless, the authors failed to elucidate the mechanism associated with infection-induced microbiota in altered distal tissues such as WAT and systemic physiology (carbohydrate metabolism). To extend these findings, the authors are currently investigating how Parasutterella-associated molecular patterns (MAMPs) and/or metabolites synergize to support host metabolism long-term after infection.

Conclusions

The current study elucidated the role of prior infection in mediating host adaptation to nutrient precarity. Importantly, infection-induced gut microflora were found to optimize host metabolism towards carbohydrate utilization.

In resource-poor environments where infection and nutrient scarcity prevail, carbohydrate metabolism optimized for infection could be adaptive. However, infection-induced carbohydrate metabolism could be maladaptive in a ketogenic or high-sugar Western diet.