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Genomics Assignment 2: Paper Review
Evaluating 'Lactobacillus plantarum strain maintains growth of infant mice during chronic undernutrition' (Schwarzer et al.)
In their 2016 publication, Schwarzer et al. demonstrate that a particular strain of Lactobacillus plantarum promotes growth of juvenile mice during days 21-56 post birth. Throughout the study, Schwarzer et al. compare longitudinal growth and systemic growth of wild type (WT) and germ free (GF) mice when exposed to breeding diets and nutritionally depleted diets after weaning (21 days post birth).
Schwarzer et al. performed an array of experiments, first to demonstrate that microbiota have an impact on infant growth and finally to pinpoint a particular Lactobacillus plantarum strain as a major factor in growth while subject to nutritionally depleted diets. First, they found that presence of microbiota was a factor in growth by comparing weight and body length of WT and GF juveniles fed a standard breeding diet. They saw that GF mice weighed less and were shorter than their WT counterparts, despite eating similar quantities of food. Because systemic growth is driven by the somatotropic axis, they investigated circulating levels of growth hormone (GH), insulin growth factor-1 (IGF-1), and IGF-1 binding protein-3 (IGFBP-3) and found lower levels of IGF-1 and IGFBP-3 in GF mice when compared to WT mice. They tested the role of IGF-1 in growth by injecting WT mice with an inhibitor of IGF-1R called picropodophyllin (PPP), which slowed growth of mice. Their results indicate that microbiota is involved in production of IGF-1, which is necessary for growth. To test chronic nutritionís influence on juvenile growth, they compared growth of WT and GF mice raised on nutritionally depleted diets and saw that WT mice lost less weight than GF mice and were able to recover weight when fed a normal diet, but GF mice were not. To test effects of microbiota on the somatotropic axis, they measured levels of GH, IGF-1, and IGFBP-3 in mice and found that reduced activity of the somatotropic axis in GF mice. Finally, they incorporated two different strains of L. plantarum into their tests to identify effects of Lactobacillus strain on growth recovery, and found that mice monocolonized with LpWJL experienced recovery of large amounts of lost weight while mice monocolonized with LpNIZO2877 experienced nominal recapitulating effects.
Altogether, Shwarzer et al. show that GF mice, when exposed to undernutriton, experience stunted growth, and that microbiota native to WT mice can recover growth by making mice more sensitive to GH. Specifically, they identified a strain of Lactobacillus that accounts for many of the growth enhancing effects of the WT microbiota. Clinically, the authors predict that microbial interventions can counteract undernutrition in humans and promote growth.
I found this paper to be well written, with clearly stated objectives, hypotheses, and results. Their methods were logical and easy to follow, as each experiment brought up a question that was then addressed in the following experiment, and their figures were typically presented in an understandable way. I was compelled to believe their claims because they looked at differing growth responses in GF and WT mice as well as circulating growth hormone and IGF-1 levels and gene expression levels.
Most of my complaints with this paper are related to small aspects of their figure presentation. First, I found their figures showing femur length (Fig. 1E and 3B) to be uninformative. While there was perhaps a noticeable difference in femur length, I would have preferred that they show a quantitative difference (bar graph) with standard deviation. By picking one bone from each treatment, they may have selected a pair that have the greatest size difference, rather than offering a measure of variance across the two treatment groups.
I would have liked for them to include a figure showing variation in organ size, because they mention organ growth in the introduction but do not mention it anywhere else in the paper. Additionally, they introduced Fig. 4 before they wrote about their investigation with two strains of L. bacillus and without any discussion of DSMO, which was confusing at first.
Finally, the authors state that this research gives evidence for bacterial intervention to be able to counteract the negative growth effects of chronic undernutrition in children. Iím curious, because lack of growth when undernourished may be adaptive and forcing the body to grow without ample nutrients could have detrimental effects. Also, Iím skeptical of spending money to treat children with bacteria when money could also go to providing nutrition more conventionally, which would address many of the other problems that come with undernutrition, besides poor growth.
Figure 1 compares growth of GF and WT mice in the first two months after birth. Growth is measured by weight, weight gain per day, body length, body length gain per day, and femur length. In each instance, GF mice exhibit less growth than WT mice. Thus, it appears that microbiota have an influence on juvenile mouse growth.
Figure 2 shows the effects of the somatotropic axis on juvenile mouse growth in GF and WT mice. Circulating levels of GH, IGF-1, and IGFBP-3 are lower in sera of GF mice than they are in WT mice across the board.. Additionally expression levels of Igf1 and Igfbp3 in the livers of GF mice are lower, and Akt phosphorylation is lower. Overall, the data in Figure 2 suggest that somatotropic axis activity is lower in GF mice and thus, systemic growth is limited.
Figure 3 shows the growth, weight, and femur length of GF and WT mice, along with mice monocolonized with two different strains of L. plantarum, when fed standard breeding diets or nutritionally depleted diets. Altogether, mice fed the standard diet weighed more and were longer than mice fed nutritionally depleted diets, and WT mice of a treatment exhibited more growth than their GF counterparts. Additionally, LpWJL had similar growth to WT mice of the same diet, while LpNIZO2877 mice were more similar to GF mice of the same diet. This figure shows that mice monocolonized with particular bacterial strains can replicate the growth effects of WT micorbiota.
Figure 4 shows activity of the somatotropic axis in WT mice, GF mice, and mice monocolonized with either of the two L. plantarum strains when raised on nutrient depeleted diets. Like figure 2, figure 4 shows circulating levels of GH, IGF-1, and IGFBP-3 in mouse sera at different stages of growth (A-C). GH levels in WT and LpWJL was significantly decreased compared to GF and LpNIZO2877 at 28 days after birth. Levels of IGF-1 and IGFBP-3 at 56 days were increased in WJ and LpWJL mice and to a lesser extent, in LpNIZO2877 mice. This data is consistent with Figure 2 in suggesting that the somatotropic axis is less active in GF mice. Finally, WT mice injected with a PPP compound (IGF-1 inhibitor, and therefore inhibitor of the somatotropic axis) experienced less growth when compared to a DSMO control, and treated and untreated mice raised on depleted diets experienced less growth than mice raised on breeding diets. In summary, this figure shows that somatotropic activity is lower in GF mice and that microbiota are essential for growth.
*Permission pending from Shwarzer et al. for all figures
Schwarzer, M., Makki K., et al. 2016. Lactobacillus plantarum strain maintains growth of infant mice during chronic undernutrition. Science 351(6275):854-857. Web.
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