Effects of DHA supplementation and exercise on gut microbiota composition and telomere length in aged obese female mice and overweight/obese postmenopausal women from the OBELEX project

According to the WHO the number of older people has risen dramatically in recent years. Obesity is one of the factors that affect human health causing cellular damage and accelerating the aging process. The use of dietary strategies, as well as exercise programs, can reduce health problems associated with aging, and improve the body composition in order to lessen the damages caused by these conditions. Gut microbiota modulation has been proposed as a novel approach to prevent and control diseases. The aim of the present thesis was divided into four objectives: 1) to characterize gut microbiota changes at four different ages in female mice and study the correlation between these changes and genes related to colon inflammation, intestinal barrier impairment, and gut immune response; 2) to analyze the effect of HFD and exercise on gut bacteria composition and on markers of colon inflammation, gut permeability, and gut immunity in 18-month-old female mice; 3); to examine the influence of DHA and/or exercise on liver telomere length in obese female mice at 18 months old after 1 year of intervention; and finally 4) to evaluate the effectiveness of DHA-rich n-3 PUFA supplementation and/or resistance training, on maintaining telomere integrity and gut microbiota composition in overweight/obese postmenopausal women. In mice, the results showed that the diversity increased as mice got older and there were several changes in gut microbiota composition including an abundance increase of the genera Cyanobacteria, Proteobacteria, Bacteroides, Parabacteroides, Prevotellaceae UCG-100, Akkermansia and P. goldsteinii and B. faecichinchillae; and a decrease of Clostridiaceae, Lactobacillaceae, and Monoglobaceae families, as well as Ligilactobacillus, Limosilactobacillus, and Mucispirillum genera. These changes were linked to changes in gene expression of some markers of permeability (Jam2, Tjp1 and Tjp2), inflammation (Tnf-a, Il-6, Il-10, Ccl2 and Ccl12) and immune response (Cd4, Cd72, Tlr4, Tlr7, Tlr12 and Lbp) in the colon. Execise had a positive effect on bacterial abundance by reducing the levels of Proteobacterias and Akkermansia and increasing levels of Ligilactobacillus and Rikenella. In addition, treadmill exercise improved the expression of some immune receptors like Cd72 and Lbp. Nevertheless, moderate exercise did not appear to reverse all of the changes that were induced by aging and HFD since no effects were observed on either intestinal permeability or inflammation markers. The combination of long-term DHA consumption and moderate exercise appears to slow down telomere shortening and increase the expression of genes that maintain oxidative stress homeostasis (Sirt3, Foxo3, Sod1 and Cat). In spite of this, treatment alone did not seem to have any effect on the results. In the human trial, only women supplemented with DHA-rich n-3 PUFA showed an effect on slowing down telomere shortening. Resistance training alone promoted few changes, including a decrease in Negativicutes and Bacteroidia, and an increased in the Lactobacillaceae family abundance. Moreover, supplementation with DHA-rich n-3 PUFAs contributes to maintain low levels of Holdemania filiformis. In conclusion, these findings suggest that exercise and DHA consumption have potential benefits for gut microbiota composition and telomere length. Exercise appears to positively influence bacterial abundance and immune receptor expression in mice and combined with omega n-3 could keep liver telomere integrity in obese female mice. While DHA consumption may slow down telomere shortening and promote oxidative stress homeostasis in overweight/obese post-menopausal women. However, further research is needed to fully understand the effects of these interventions on microbiota diversity and their potential implications for host health in aging.

Esta tesis doctoral ha podido ser llevada a cabo gracias a la financiación del Ministerio de Economía y Competitividad del Gobierno de España (MINECO-FEDER, BFU2015- 65937-R), del Centro de Investigación Biomédica en Red: Fisiopatología de la Obesidad y la Nutrición (CIBEROBN CB12/03/30002, Insituto de Salud Carlos III) y al Departamento de Universidad, Innovación y Transforacón Digital (PI026 BIOAGEMT) del Gobierno de Navarra.