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Review: Lactobacillus plantarum strain maintains growth of infant mice during chronic undernutrition

Figure S1. The somatotropic axis and associated molecular markers.

Opinion

Overall, I thought this paper is easy to follow and relatively compelling based on the results presented. This experiment demonstrates another important function of gut microbes, which have been studied by many to be essential in maintaining life on earth. The paper has a logical flow: I understand why each experiment was conducted and each experiment addresses a specific question that explains the effect of microbiota in juvenile growth. The data clearly shows the relationship between gut microbiota and the somatotropic axis and how they affect postnatal systemic growth in infant mice. Most importantly, this paper has great implication for public health because malnutrition still affects many children in developing countries, and malnutrition is not always remedied by improvement in nutrition. This study provides insights into how the introduction of gut microbiota can potentially mediate some of the pathology. Therefore, I would like to see what species of microbiota are in the WT mice since they outperformed the two Lactobacillus strains monocolonized mice in growth as measured by both body weight and length.

However, there can be improvements in data visualization in this paper. I found the order of the figures in this paper rather confusing. For example, figure 4 was referenced in the paper before figure 3 so it might be easier for the readers to follow if they rearrange the order. Also, while panel A to C in Figure 4 addresses how the somatotropic axis activity was reduced in GF mice during chronic undernutrition, panel D to G discusses that the somatotropic axis is required for juvenile growth; the two are not closely related, so it might be better to have them as two separate figures. Furthermore, in Figure 4 panel A, they switch the position of GF and WT as opposed to Figure 1 where WT is on the left and GF is on the right; it will be nicer if they can be consistent throughout the paper.

Gut microbiota helps juvenile growth in mice, as measured in both weight and body length. Both WT and GF infant male mice were fed a standard diet and both weight and body length of GF mice increased at a slower rate over time than WT mice (Figure 1A and 1C). Moreover, WT mice have significantly higher weight and body height than GF mice even when they consumed similar amounts of food relative to body weight (Figure 1B and 1D). Bone growth parameters such as femur length, cortical thickness, and cortical bone fraction were also measured using caliper and a high-resolution nanotom device. Both photograph of representative femur bones (Figure 1E) and three-dimensional reconstructions of representative distal parts of femur bones (Figure 1F) at day 56 show reduction of growth in GF animals. In conclusion, gut microbiota sustains postnatal somatic tissue growth.

Gut microbiota helps juvenile growth through systemic somatotropic axis activity. By using the enzyme-linked immunosorbent assay (ELISA) kit, circulating levels of GH, IGF-1, and IGFBP-3, major components of the axis, were measured. Both WT and GF mice have similar levels of GH over time, with GH levels peaking around birth and gradually declining (Figure 2A). IGF-1 and IGFBP-3 are both significantly higher in WT mice (Figure 2B and 2C). Igf1 and Igfbp3 expressions in liver, measured by quantitative RT-PCR, also showed significance decrease in GF mice (figure 2D and 2E). The group further studied phosphorylation of Akt at Ser 473, a marker of IGF-1 receptor signaling activity, and three western blot results showed that phosphorylation event was significantly reduced in the liver of GF animals at day 28 after birth (Figure 2F).

Gut microbiota helps maintain juvenile growth under the condition of chronicundernutrition. After feeding WT mice, GF mice and mice with Lactobacillus plantarum strain, either Lp^WJL or Lp^NIZO2877, with either a standard diet or a nutritionally depleted diet, the group compared body weights and body lengths and determined that they all lost weight and reduced longitudinal growth; nonetheless, GF mice suffered a greater reduction in both body weights and body lengths (Figure 3A, 3B, 3C, and 3D). Furthermore, Lp^WJLhas a greater potential than Lp^NIZO2877in rescuing the somatotropic axis activity, showing strain-dependent promotion of juvenile growth. In summary, specific Lactobacillus strains can help reduce the negative effects of stunting during chronic undernourishment.

Gut microbiota promotes juvenile growth through systemic somatotropic axis activity during chronic undernutrition. GH, IGF-1, and IGFBP-3 levels were measured using ELISA kit at day 28 and day 56. Even though GH levels peaked in GF mice at day28, there is no significant difference in GH levels at day 56 (Figure 4A). WT mice have the highest concentrations of both IGF-1 and IGFBP-3, followed by Lp^WJL then Lp^NIZO2877 (Figure 4B). In summary, the somatotropic axis activity was reduced in GF mice under the condition of chronic undernutrition. The group also injected WT mice with the noncompetitive inhibitor of IGF-1R, PPP, and observed that both body weight and body length reduced significantly when compared to WT mice treated with DMSO (control) when they were fed the standard diet; femur length decreased significantly with both the standard diet and the nutritionally depleted diet (Figure 4D, 4E, 4F and 4G). Thus, the result demonstrates that the somatotropic axis activity is required for postnatal systemic growth.

Schwarzer M, Makki K, Storelli G, Machuca-Gayet I, Srutkova D, Hermanova P, Martino ME, Balmand S, Hudcovic T, Heddi A, Rieusset J, Kozakova H, Vidal H, Leulier F. 2016. Lactobacillus plantarum strain maintains growth of infant mice during chronic undernutrition. Science [Internet]. [cited 17 Jan 2016]; 351(6275):854-857. Available from: http://science.sciencemag.org/content/351/6275/854.long