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Comparative Study
. 2013 Feb 1;339(6119):548-54.
doi: 10.1126/science.1229000. Epub 2013 Jan 30.

Gut Microbiomes of Malawian Twin Pairs Discordant for Kwashiorkor

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Free PMC article
Comparative Study

Gut Microbiomes of Malawian Twin Pairs Discordant for Kwashiorkor

Michelle I Smith et al. Science. .
Free PMC article

Abstract

Kwashiorkor, an enigmatic form of severe acute malnutrition, is the consequence of inadequate nutrient intake plus additional environmental insults. To investigate the role of the gut microbiome, we studied 317 Malawian twin pairs during the first 3 years of life. During this time, half of the twin pairs remained well nourished, whereas 43% became discordant, and 7% manifested concordance for acute malnutrition. Both children in twin pairs discordant for kwashiorkor were treated with a peanut-based, ready-to-use therapeutic food (RUTF). Time-series metagenomic studies revealed that RUTF produced a transient maturation of metabolic functions in kwashiorkor gut microbiomes that regressed when administration of RUTF was stopped. Previously frozen fecal communities from several discordant pairs were each transplanted into gnotobiotic mice. The combination of Malawian diet and kwashiorkor microbiome produced marked weight loss in recipient mice, accompanied by perturbations in amino acid, carbohydrate, and intermediary metabolism that were only transiently ameliorated with RUTF. These findings implicate the gut microbiome as a causal factor in kwashiorkor.

Figures

Fig 1
Fig 1. Functional development of the gut microbiomes of Malawian twin pairs concordant for healthy status, and twin pairs who became discordant for kwashiorkor
(A) PCoA of Hellinger distances between KEGG EC profiles. The position of each fecal microbiome along principal coordinate 1 (PC1), which describes the largest amount of variation (17%) in this dataset of 308 sequenced twin fecal microbiomes, is plotted against age. Each sphere represents a microbiome colored by the age of the human donor. PC1 is strongly associated with age (and with family membership) (linear mixed-effects model, table S4). We did not find significant associations between the positions of samples along other principal coordinates and the other host parameters presented in table S2A). On average the degree of intrapersonal variation in a co-twin was not smaller than the variation between co-twins (fig. S2). Similar to twins who remained healthy, the temporal variation within a co-twin member of a discordant twin pair was equal to the variation between co-twins, but still smaller compared to unrelated children (fig. S2). (B) Average ± SEM PC1 coordinate obtained from the data shown in panel A for microbiomes sampled at three consecutive time points from nine twin pairs who remained well-nourished (healthy) during the study (subjects surveyed between three weeks and 24.5 months of age). (C) Average ± SEM PC1 coordinate obtained from panel A for microbiomes sampled before, during and after RUTF treatment from co-twins discordant for kwashiorkor. *p<0.05, Friedman test with Dunn’s post-hoc test applied to data shown in panels B and C. Similar results were obtained using other distance metrics [Bray Curtis, Euclidian, and Kulzyncki (fig. S3)]. (See fig. S4 which shows how changes in the relative proportion of Actinobacteria parallel the patterns observed with the changes along PC1; children with kwashiorkor manifested a statistically significant decrease in Actinobacteria with introduction of RUTF, unlike their healthy co-twins).
Fig 2
Fig 2. Transplantation of fecal microbiota from kwashiorkor and healthy co-twins from family 196 into gnotobiotic mice fed Malawian and RUTF diets
(A) Discordant weight loss in recipient mice, n=10 mice/group, *p<0.05, Student’s t-test. Data points are colored by recipient group; blue, kwashiorkor co-twin fecal microbiota recipients; red, healthy co-twin fecal microbiota recipients. (B) Average ± SEM PC1 coordinate obtained from the weighted UniFrac distances shown in fig. S9A, B for fecal microbiota sampled from mice over time. Same color key as in panel A. (C) Heatmap of phylotypes assigned to species-level taxa whose representation in the fecal microbiota of gnotobiotic mice change significantly (p<0.05, Students t-test with Bonferroni correction) as a function of donor microbiota and Malawian versus RUTF diets. An asterisk indicates taxa that changed significantly in both healthy and kwashiorkor microbiota transplant recipients. Species level taxa are colored by phylum: Firmicutes (red), Actinobacteria (blue), Bacteroidetes (black) and Proteobacteria (green). Switching from a Malawian diet to RUTF produces a rapid change in the configuration of the transplanted kwashiorkor microbiota. A bloom in Lactobacilli occurs early during treatment with RUTF but regresses by the end of this diet period and remains unchanged when animals are returned to the Malawian diet. Bifidobacterium spp also bloom early during administration of RUTF. Unlike the Lactobacilli, their increase is sustained into the early phases of the second Malawian diet period (M2) after which they diminish. Like the members of Bifidobacterium, R. torques increases its representation during RUTF and then rapidly diminishes when mice returned to a Malawian diet. The increase in F. prausnitzii is sustained into and through M2. The responses of the Bacteroidales were opposite to that of the other three groups: they decrease with RUTF and re-emerge with M2. The response of the Lactobacilli observed in the kwashiorkor transplant recipients is not seen in gnotobiotic mice containing the healthy co-twin’s microbiota. The pattern of change of the two Ruminococcus spp., B. uniformis, P. distasonis, B. longum and an unclassified Bifidobacterium taxon are shared by both recipient groups (healthy and kwashiorkor), although the Bifidobacterium response is more diminutive in the healthy microbiota treatment group. Parabacteroides merdae, an unclassified taxon from the genus Faecalibacterium, as well as a member of the Coriobacteriaceae are specifically elevated in the healthy co-twin’s microbiota when mice switch to a RUTF diet. Of these, only P. merdae does not persist when animals are returned to the Malawian diet (also see table S7A and table S8A).
Fig. 3
Fig. 3. Metabolites with significant differences in their fecal levels in gnotobiotic mice colonized with microbiota from discordant twin pair 196 as a function of diet
Data are from fecal samples collected three days before the end of (A) the first period of consumption of the Malawian diet (M1, day 16; abbreviated M1.D16), (B) RUTF treatment (RUTF.D10), and (C) the second period of Malawian diet consumption (M2.D26). Significant differences are defined as p<0.05 according to Student’s t-test. Procrustes analysis of data obtained from the transplanted microbiota from discordant co-twins in family 196 (fig. S13) revealed significant correlation between metabolic and taxonomical profiles on each diet with an overall goodness of fit (M2 value) of 0.380 (p<0.0001; 1,000 Monte Carlo label permutations) for all diets and microbiota.

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