Animal models with humanized microbiota, exploring the role of dietary interventions

Worldwide obesity is a public health problem, and despite all the strategies implemented to revert the situation, no suitable solution has been found yet. According to the World Health Organization (WHO), globally, in 2016, more than 1,900 million adults were overweight and over 650 million were obese. [1]

Obesity is associated with decreased life expectancy of an estimated 5–20 years lost, depending on the severity of the condition and comorbid disorders. The WHO defines obesity as excessive fat accumulation that might impair health and is diagnosed at a BMI ≥30kg/m².[2]

As I discussed in my previous post, in addition to nutritional, lifestyle and genetic factors, it has been suggested that obesity may also result from perturbation of the gut microbiome. [3] [4]

The human microbiome encompasses a vast reservoir of genetic information that exceeds by a factor of 100 to 1 the genetic information encoded in the human genome. Most of this genetic information is found in the gastrointestinal tract and the definition of our “second genome” is increasingly accepted. This genetic information comes from over 1000 bacterial strains residing in the gastrointestinal tract.

Accumulating data from the microbiota characterization in both human studies and animal models indicates that alteration (dysbiosis) of the intestinal microbiota is associated with the development and progression of metabolic pathologies such as obesity. [3][5][6]

Nevertheless, the studies attempting to demonstrate causality and not only association are limited in number. For this reason, further research is needed to understand the role of gut microbiota in disease.

Fecal microbiota transplantation (FMT) is one of the most commonly used approaches for investigating the causal connection between the gut microbiome and diseases in animal models. Some recent research indicates how the transplanted microbiota can influence physiological changes and may have a major role in the development of pathologies, such as Clostridium Difficile infection [7], Inflammatory bowel diseases (IBD)[8], diabetes [9], obesity[10], aging [11], cancer [12] and others.

During the progress of PREVENTOMICS project, the researchers involved have been able to have access to fecal samples provided by volunteers who participated in the dietary interventions. Using these samples, LEITAT researchers characterized the volunteers gut microbiota, before and after the dietary interventions, and developed a microbiota humanized animal model. The main objective of this study was to assess whether the changes induced by the dietary intervention in the microbiota influenced the physiological change and metabolism associated with overweight and obesity.

In this present study the animals gained between 20-30% of their initial body weight, afterthat the diet was changed to Control diet and FMT was performed every 2 days during the first week and once every 7 days for the following 3 weeks.

Samples from volunteers before starting the dietary interventions and fecal samples from the same individuals at the end of the intervention were used for the FMT. The intervention groups, Control (CT), Personalized Nutrition (PN) and Personalized Plan (PP), have been replicated in the animal model. The animals were monitored throughout the intervention and variables of interest such as weight gain, diet consumption, biochemical parameters associated with obesity, microbiota samples at different time points, plasma samples for metabolomic characterization, and different organs and tissues for immunohistochemical and mRNA analysis were obtained.

All data generated in this humanized animal model are currently being analysed and work is underway to publish the results in a scientific journal. Some of the preliminary results after analysing endpoint plasmas indicated that the mouse metabolism receiving FMT from people at the end point of the dietary interventions was different from the metabolism of mice receiving FMT from the same people before the start of the intervention. Indeed, this suggests that the changes in the microbiota induced by the dietary intervention are transferred to the animal model through the modification of the mouse metabolism.

However, at the phenotypic level we did not observe significant changes in body weight loss between groups comparing mice that received FMT from the same individuals before and after the dietary intervention. We are currently studying more in depth the relationship between the observed metabolic changes, obesity and other co-morbidities.

It is necessary to further analyse the results and put these findings in context with the human intervention results. However, after the first analysis approach, the results point to the fact that microbiota plays a key role in the dietary interventions as the microbiota of the post-intervention volunteers has the capacity to modify the animal model metabolism.