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Review of "Lactobacillus plantarum strain maintains growth of infant mice during chronic undernutrition"
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Summary: Juvenile growth largely depends on external nutrition input and intrinsic hormone levels. This paper aimed to uncover the previously unknown role of microbiota in juvenile growth during chronic undernutrition. Schwarzer et al. found that the gut microbiota support normal juvenile growth rate in mice fed a normal diet or a depleted diet. Gut microbiota support normal growth by sustaining hormone activity of somatotropic axis. Additionally, certain lactobacilli strain may help alleviate the effects of chronic undernutrition on juvenile growth. These finding may help treat chronic undernutrition in humans in the future.
Opinion: I found this paper very well written, its objectives clearly stated, results and conclusions reasonably drawn, and figures clearly labeled. I particularly appreciate the hypothesis and conclusion statements. The authors facilitated reading using brief but clear explanation of specific topics such as somatotropic axis pathway and cyclolignan compound picropodophyllin (PPP). Overall, the presentation of the research felt like a story, and I was well-guided in terms of scientific questions, purpose of experiments, and conclusions. However, some conclusions jumped from figure to figure, and the organization of the paper could be improved. It is a compelling paper, although I am not entirely convinced because the lack of mechanisms.
Although gut microbiome has a huge impact on mammal well-being, I have doubts about this particular phenomenon because the author did not provide enough detailed biological mechanisms. How can microbe have an effect on gene expression and cell-hormone activity if microbes only stay in gut? What are the biological difference between LpWJL and LpNIZO2877? Does microbiota alleviate weight loss during chronic undernutrition in adult? At the end of the paper, authors proposed using microbial interventions of selected strains to treat chronic undernutrition postnatal growth in human. I think there must be a lot of intermediate activities between bacteria and hormone levels, and we must be cautious about making such a big leap. In the future, researchers may focus on understanding the detailed biological mechanisms involved. This paper brought more questions than answers (which I think is a good thing).
Figure 1: Researchers started exploring the role of microbiota in postnatal growth. Researchers compared body weight (panel A), body length (panel C), femur bone length (panel E) and femur bone trabecular fraction (panel F) of wide type mice (with normal gut microbiota) and germ-free mice (without normal microbiota) fed a breeding diet for 8 weeks (time of reaching young adulthood). Panel B and D compares weight gaining rates and length growth rates. Despite similar food consumption, in almost all cases, GF mice had significantly lower measurements than WT mice. Researchers concluded that gut microbiota sustains normal postnatal growth.
Figure 2: Researchers continued to explore the biological mechanisms by focusing on levels of three hormones in the somatotropic axis: growth hormone (GH), insulin-like growth factor 1 (IGF-1) and IGF binding protein 3 (IGFBP-3). Researchers hypothesized microbiota maintains somatotropic axis activity. Mice were fed breeding diet after weaning (day 21). Sera hormone levels were measured by ELISA (Enzyme-Linked Immunosorbent Assay). Panel A shows GH levels were not significantly different between WT and GF mice. Panel B shows IGF-1 levels were significantly greater in WT mice in most part of the juvenile stage, and IGF-1 level peaked around 28th day. Similarly, panel C shows IGFBP-3 levels were higher in WT mice. Researchers performed quantitative RT-PCR on Igf1 and Igfbp3 transcripts in liver, and found gene expression of the two hormones are higher in WT as well (panel D and E). Note that gene expression level was measured in relation to Tbp, which served as an internal control to normalize gene expression. It is interesting that expression of Igf1 were ~150 times of Igfbp3 (compare D and E), but hormone level of IGF-1 were a third of IGFBP-3 at most (compare B and C). This may suggest transcriptome does not correlate with proteome abundance, or IGF-1 are rapidly consumed. Researchers quantified phospho-S4730-Akt, a marker of IGF-1 receptor activity, in liver by Western blots at 28th day. Panel F shows phospho-S4730-Akt level were much lower in GF mice, indicating low IGF-1 receptor signaling activity in GF mice.
Figure 3: Researchers studied the effects of chronic undernutrition and gut microbiota on postnatal growth. One more variable was introduced: breeding or depleted diet. Again, weight (panel A) and length (panel B, C) were measured for 8 weeks, and bone measurements (panel D) at the end of the experiment. Researchers found both WT and GF mice lost weight after receiving nutritionally depleted diet after weaning. However, under depleted diet, WT mice were able to recover from weight loss and continued growing, whereas GF mice virtually stopped gaining weight and stopped growing in length. By young adulthood (56th day), WT mice were significantly heavier and bigger in both breeding diet and depleted diet. Therefore, researchers concluded that gut microbiota was crucial in maintaining healthy juvenile growth rate during chronic undernutrition.
Figure 4: Similar to experiments performed in Figure 2, researchers investigated the biological mechanisms of the somatotropic axis during undernutrition. GH and IGFBP-3 levels were higher in GF mice on the 28th day, and IGF-1 and IGFBP-3 levels were lower in GF mice on the 56th day (panel A-C). These results indicate a reduced activity of the somatotropic axis in GF mice during undernutrition, possibly due to GH resistance. To investigate the specific mechanism, researchers targeted IGF-1:IGF-1R interaction by repeated injection of picropodophyllin (PPP) compound, a IGF-1R inhibitor, in GF mice fed a depleted diet. DMSO was used as a negative control. Not surprisingly, PPP-treated mice exhibited lower weight gain, length gain and shorter femur bones. These results indicate depressed somatotropic axis activity in GF mice contributed to slower postnatal growth during undernutrition.
Finally, researchers were interested in how different bacteria strains effect juvenile growth. Previous works have studied two Lactobacillus plantarum strains in Drosophila: LpWJL promoted growth, and LpNIZO2877 did not promote growth. Researchers hypothesized similar effects of these bacteria on murine juvenile growth. Two strains of monocolonized mice were generated. Not surprisingly, both LpWJL and LpNIZO2877 mice gained more weight and length than GF mice under breeding diet and depeleted diet, and LpWJL mice grew faster than LpNIZO2877 mice (Figure 3A, 3C). Surprisingly, GH, IGF-1, IGFBP-3 levels in LpNIZO2877 were comparable to those of GF mice (Figure 4D - 4G), implying similarly reduced somatotropic activity, possibly due to GH resistance.
Schwarzer, M., Makki, K., Storelli, G., et al. Lactobacillus plantarum strain maintains growth of infant mice during chronic undernutrition. Science. 351(6275):854-857. DOI: 10.1126/science.aad8588.
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