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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 per 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. Error bars indicate xxxxxxxxxxxxxxxx. (B) Average T SEM (error bars) PC1 coordinate obtained from the weighted UniFrac distances shown in fig. S9, A and B, for fecal microbiota sampled from mice over time. Same color key as in (A). (C) Heatmap of phylotypes assigned to species-level taxa whose representation in the fecal microbiota of gnotobiotic mice changed significantly (P < 0.05, Students t test with Bonferroni correction) as a function of donor microbiota and Malawian versus RUTF diets. Asterisks indicate taxa that changed significantly in both healthy and kwashiorkor microbiota transplant recipients. Species level taxa are colored by phylum: red, Firmicutes; blue, Actinobacteria; black, Bacteroidetes; and green, Proteobacteria. 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, the increase of Bifidobacterium is sustained into the early phases of 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: Bacteroidales decrease with the administration of 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 is 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, is 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 tables S7A and S8A).
Source publication
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...
Contexts in source publication
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... nutrient-deficient diet and fig. S6 for ex- perimental design) (10). In two of the three discordant twin pairs (families 196 and 57), trans- plantation of the kwashiorkor co-twin's microbiota resulted in significantly greater weight loss in recipient mice over the ensuing 3 weeks than in those harboring the healthy sibling's microbiota ( F2 Fig. 2A). This discordant weight loss phenotype was dependent on the combination of Malawian diet and kwashiorkor microbiota; when separate groups of animals were placed on a standard mouse chow, there were no significant differences between the weights of mice with kwashiorkor compared to healthy co-twin microbiota (93.6 T 4% versus 93 T 11% ...
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... Whereas all recipients of microbiota trans- plants lost weight, this re-exposure did not produce the profound weight loss that mice col- onized with the kwashiorkor microbiota had experienced during their first exposure ( Fig. 2A). These results indicate that the gut micro- biota from two of the three discordant pairs are able to transmit a discordant malnutrition pheno- type, manifested by weight loss, to recipient gnotobiotic mice. Given that the most discordant weight loss phenotype was produced by micro- biota from twin pair 196, we initiated a detailed ...
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... type, manifested by weight loss, to recipient gnotobiotic mice. Given that the most discordant weight loss phenotype was produced by micro- biota from twin pair 196, we initiated a detailed time-series analyses of the organismal, gene, and metabolite content of the transplanted microbial communities as a function of co-twin donor and diet ( fig. S6 and table S2, B and ...
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... from a Malawian diet to RUTF produced a rapid change in configuration of the fecal microbiota that was most pronounced in recipients of the kwashiorkor co-twin's commu- nity (Fig. 2B and fig. S9, A and B). Thirty species-level taxa exhibited significant changes in their representation in kwashiorkor microbiota transplant recipients (Fig. 2C and tables S7B and S8A), with prominent increases in Bifidobacteria (B. longum, B. bifidum, plus another unclassified taxon), two Lactobacilli [L. reuteri and L. gasseri, which can produce ...
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... from a Malawian diet to RUTF produced a rapid change in configuration of the fecal microbiota that was most pronounced in recipients of the kwashiorkor co-twin's commu- nity (Fig. 2B and fig. S9, A and B). Thirty species-level taxa exhibited significant changes in their representation in kwashiorkor microbiota transplant recipients (Fig. 2C and tables S7B and S8A), with prominent increases in Bifidobacteria (B. longum, B. bifidum, plus another unclassified taxon), two Lactobacilli [L. reuteri and L. gasseri, which can produce bacteriocins and stimulate the innate immune system to inhibit the growth and eliminate various enteropathogens ( 21-23)], and two members of ...
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... activity in a mouse model of colitis and whose decreased representa- tion is associated with increased risk of ileal Crohn's disease (25)]. We observed statistically significant decreases in the representation of members of the Bacteroidales (B. uniformis, Parabacteroides distasonis, plus an unclassified Parabacteroides taxon) (see Fig. 2C and legend for time courses). Twenty-eight bacterial species- level taxa also exhibited significant changes in their representation in gnotobiotic mice harboring the healthy co-twin's microbiota in response to RUTF. The pattern of change of 13 different taxa- including the two Ruminococcus spp., B. uniformis, P. distasonis, B. longum, ...
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... to RUTF. The pattern of change of 13 different taxa- including the two Ruminococcus spp., B. uniformis, P. distasonis, B. longum, and an unclassified Bifidobacterium taxon-was shared by both re- cipient groups (healthy and kwashiorkor), al- though the Bifidobacterium response was less pronounced in the healthy microbiota treatment group ( Fig. 2C and tables S7A, S7B, and S8A). These changes were representative of those that occurred in the human donors; the change in Bifidobacterium was unique to the kwashiorkor co-twin (table ...
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... For example, children with kwashiorkor disease suffer from protein malabsorption (Williams, 2003). Their gut microbiomes appear to play a role in the disease because feces from children with kwashiorkor can cause similar symptoms when introduced into germ-free mice (Smith et al., 2013). Perhaps the gut bacteria of kwashiorkor patients inhibit protein uptake similarly to V. cholerae in zebrafish. ...
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... The gut microbiome is crucial in regulating digestive function, immune response, and metabolic processes, and there is growing evidence that dysbiosis of the gut microbiome may contribute to malnutrition and frailty [7]. For instance, the research conducted in East Africa has demonstrated a link between gut bacteria and malnutritionrelated conditions such as kwashiorkor [8], suggesting that the gut microbiome may also play a role in the onset of malnutrition among other populations. ...
... Malnutrition is prevalent among older adults and often challenging to treat, even with nutritional therapy. Recent studies indicate that alterations in the gut microbiome contribute to persistent malnutrition by affecting intestinal permeability and nutrient absorption [8]. Similar changes have been observed in children with kwashiorkor, where gut microbiome differences persisted despite dietary improvements [8]. ...
... Recent studies indicate that alterations in the gut microbiome contribute to persistent malnutrition by affecting intestinal permeability and nutrient absorption [8]. Similar changes have been observed in children with kwashiorkor, where gut microbiome differences persisted despite dietary improvements [8]. Furthermore, imbalances in gut microbiota have been linked to reduced production of short-chain fatty acids (SCFAs) and other metabolites essential for maintaining intestinal health, exacerbating nutritional deficiencies [29]. ...
Background: Frailty increases the risk of needing nursing care and significantly affects the life and functional prognosis of older individuals. Early detection and tailored interventions are crucial for maintaining and enhancing their life functions. Recognizing distinct clinical phenotypes is essential for devising appropriate interventions. This study aimed to explore diverse frailty phenotypes, focusing on poor nutrition in older Japanese individuals through observational research. Methods: Twenty-one nursing home residents underwent a comprehensive survey covering physical, blood, dietary, cardiac, cognitive, nutritional, nursing care, frailty, agitated behavior, and gut microbiome assessments (high-throughput 16S rRNA gene sequencing). Using clustering analysis with 239 survey items (excluding gut microbiome), participants were classified into subgroups based on clinical phenotypes, and group characteristics were compared through analysis. Results: Individuals with moderate or severe frailty and suspected dementia formed subgroups with distinct clinical phenotypes based on nutritional, defecation, and nursing care statuses. The gut microbiome significantly varied among these groups (p = 0.007), indicating its correlation with changes in clinical phenotype. Nutritional status differences suggested poor nutrition as a differentiating factor in the core clinical phenotype. Conclusions: This study proposes that the gut microbiome differs based on the clinical phenotype of Japanese older individuals with frailty, and targeted interventions addressing the gut microbiome may contribute to preventing frailty in this population.
... Although non-industrialized populations show lower prevalence and incidence of chronic and non-communicable diseases, their life expectancy is notably lower while child mortality rates are considerably higher compared with industrialized populations, often due to infectious diseases mediated by other types of microorganisms 84 . These findings emphasize the importance of understanding variability within and between countries in establishing baseline health-associated data, as well as geography-relevant confounders and crucial differences in health and disease priorities in non-industrialized and industrialized populations 85,86 . ...
... Due to its capacity to regulate nutritional harvest, the gut microbiota is an important nexus between diet and health outcomes (30). This is evidenced by a longitudinal study of Malawian twins, which found that poorly matured gut microbiota was associated with malnutrition and the causal relationship between microbiota and malnutrition is supported by multiple independent mouse studies (78)(79)(80). Malnutrition is associated with reduced obligate anaerobic species and an increase in potentially pathogenic microbes in the infant gut microbiome (78,(81)(82)(83)(84). Furthermore, this phenomenon is widespread, as multiple studies in low-SES countries have consistently demonstrated decreased bacterial diversity in malnourished children, reduced beneficial microbes and increased pathogen enrichment (82,84,85). Recent randomized clinical trials have established that microbiota-directed foods, but not caloric intake alone, successfully support growth recovery in malnourished children (86, 87). ...
... This is evidenced by a longitudinal study of Malawian twins, which found that poorly matured gut microbiota was associated with malnutrition and the causal relationship between microbiota and malnutrition is supported by multiple independent mouse studies (78)(79)(80). Malnutrition is associated with reduced obligate anaerobic species and an increase in potentially pathogenic microbes in the infant gut microbiome (78,(81)(82)(83)(84). Furthermore, this phenomenon is widespread, as multiple studies in low-SES countries have consistently demonstrated decreased bacterial diversity in malnourished children, reduced beneficial microbes and increased pathogen enrichment (82,84,85). ...
Socioeconomic (SE) disparity and health inequity are closely intertwined and associated with cross-generational increases in the rates of multiple chronic non-communicable diseases (NCDs) in North America and beyond. Coinciding with this social trend is an observed loss of biodiversity within the community of colonizing microbes that live in and on our bodies. Researchers have rightfully pointed to the microbiota as a key modifiable factor with the potential to ease existing health inequities. Although a number of studies have connected the adult microbiome to socioeconomic determinants and health outcomes, few studies have investigated the role of the infant microbiome in perpetuating these outcomes across generations. It is an essential and important question as the infant microbiota is highly sensitive to external forces, and observed shifts during this critical window often portend long-term outcomes of health and disease. While this is often studied in the context of direct modulators, such as delivery mode, family size, antibiotic exposure, and breastfeeding, many of these factors are tied to underlying socioeconomic and/or cross-generational factors. Exploring cross-generational socioeconomic and health inequities through the lens of the infant microbiome may provide valuable avenues to break these intergenerational cycles. In this review, we will focus on the impact of social inequality in infant microbiome development and discuss the benefits of prioritizing and restoring early-life microbiota maturation for reducing intergenerational health disparities.
... Understanding this transition and the impacts on the host requires longitudinal sampling of gut microbiota of large populations together with observations of changes in host physiology. Previously, several studies have investigated gut microbial taxa and compositional adaptations in early life and childhood [4][5][6][7][8] . Although gut microbiome longitudinal studies have revealed changes in the metagenome taxa over time and associated functional shifts 9 , the ecological destabilization of the core gut microbiota, notably the underlying species and their functions, has been far less investigated. ...
Species composition of the healthy adult gut microbiota tends to be stable over time. Destabilization of the gut microbiome under the influence of different factors is the main driver of the microbial dysbiosis and subsequent impacts on host physiology. Here, we used metagenomics data from a Swedish longitudinal cohort, to determine the stability of the gut microbiome and uncovered two distinct microbial species groups; persistent colonizing species (PCS) and transient colonizing species (TCS). We validated the continuation of this grouping, generating gut metagenomics data for additional time points from the same Swedish cohort. We evaluated the existence of PCS/TCS across different geographical regions and observed they are globally conserved features. To characterize PCS/TCS phenotypes, we performed bioreactor fermentation with faecal samples and metabolic modeling. Finally, using chronic disease gut metagenome and other multi-omics data, we identified roles of TCS in microbial dysbiosis and link with abnormal changes to host physiology.
... In undernourished children, the 'microbiota-for-age zscore' is lower because maturation is severely impaired [120]. Children with undernutrition may also have a functionally immature gut microbiome with disrupted pathways of carbohydrate and amino acid metabolism, vitamin B production, and nucleotide biosynthesis [121], [122]. Notably, studies have shown that changes associated with undernutrition can be transferred to animal models through fecal microbial transplantation, ...
... Finally, nutrition plays an important role in the overall development of organisms, as malnutrition leads to severe weight loss and disruption of the gut microbiota [124]. Thus, ensuring adequately balanced, nutritional diet may help prevent gut microbiome dysbiosis or health imbalance, ensure bone health, and possibly prevent alterations of bone architecture ( Figure 2). ...
Background
Breast cancer is the most predominant and heterogeneous cancer in women. Moreover, breast cancer has a high prevalence to metastasize to distant organs, such as the brain, lungs, and bones. Patients with breast cancer metastasis to the bones have poor overall and relapse‐free survival. Moreover, treatment using chemotherapy and immunotherapy is ineffective in preventing or reducing cancer metastasis.
Recent Findings
Microorganisms residing in the gut and breast, termed as the resident microbiome, have a significant influence on the formation and progression of breast cancer. Recent studies have identified some microorganisms that induce breast cancer metastasis to the bone. These organisms utilize multiple mechanisms, including induction of epithelial–mesenchymal transition, steroid hormone metabolism, immune modification, bone remodeling, and secretion of microbial products that alter tumor microenvironment, and enhance propensity of breast cancer cells to metastasize. However, their involvement makes these microorganisms suitable as novel therapeutic targets. Thus, studies are underway to prevent and reduce breast cancer metastasis to distant organs, including the bone, using chemotherapeutic or immunotherapeutic drugs, along with probiotics, antibiotics or fecal microbiota transplantation.
Conclusions
The present review describes association of gut and breast microbiomes with bone metastases. We have elaborated on the mechanisms utilized by breast and gut microbiomes that induce breast cancer metastasis, especially to the bone. The review also highlights the current treatment options that may target both the microbiomes for preventing or reducing breast cancer metastases. Finally, we have specified the necessity of maintaining a diverse gut microbiome to prevent dysbiosis, which otherwise may induce breast carcinogenesis and metastasis especially to the bone. The review may facilitate more detailed investigations of the causal associations between these microbiomes and bone metastases. Moreover, the potential treatment options described in the review may promote discussions and research on the modes to improve survival of patients with breast cancer by targeting the gut and breast microbiomes.
... The bacteriome of childhood malnutrition is associated with low alpha diversity and disproportionate expansion of Pseudomonadota [106]. Furthermore, the microbiome maintains an "immature" state as postnatal maturation of the gut microbiota is perturbed [106,107]. Dysbiosis of malnutrition also influences the phageome and is transferrable to gnotobiotic mice through fecal viral transfer causing weight loss, barrier disruption, and metabolic phenotypes [107][108][109]. Treatment with antibiotics concurrent with the provision of nutritious food has shown better outcomes and faster recovery of a healthy microbiome [110][111][112]. ...
... Furthermore, the microbiome maintains an "immature" state as postnatal maturation of the gut microbiota is perturbed [106,107]. Dysbiosis of malnutrition also influences the phageome and is transferrable to gnotobiotic mice through fecal viral transfer causing weight loss, barrier disruption, and metabolic phenotypes [107][108][109]. Treatment with antibiotics concurrent with the provision of nutritious food has shown better outcomes and faster recovery of a healthy microbiome [110][111][112]. ...
... Treatment with antibiotics concurrent with the provision of nutritious food has shown better outcomes and faster recovery of a healthy microbiome [110][111][112]. However, the ready-to-use therapeutic food interventions alone in child populations suffering from severe acute malnutrition are transient [106,107]. While gut bacteria have been shown to be causally related to malnutrition [107,109], the role of the virome is less well understood. ...
As knowledge of the gut microbiome has expanded our understanding of the symbiotic and dysbiotic relationships between the human host and its microbial constituents, the influence of gastrointestinal (GI) microbes both locally and beyond the intestine has become evident. Shifts in bacterial populations have now been associated with several conditions including Crohn’s disease (CD), Ulcerative Colitis (UC), irritable bowel syndrome (IBS), Alzheimer’s disease, Parkinson’s Disease, liver diseases, obesity, metabolic syndrome, anxiety, depression, and cancers. As the bacteria in our gut thrive on the food we eat, diet plays a critical role in the functional aspects of our gut microbiome, influencing not only health but also the development of disease. While the bacterial microbiome in the context of disease is well studied, the associated gut phageome—bacteriophages living amongst and within our bacterial microbiome—is less well understood. With growing evidence that fluctuations in the phageome also correlate with dysbiosis, how diet influences this population needs to be better understood. This review surveys the current understanding of the effects of diet on the gut phageome.
... The gut microbiota of children with malnutrition or undernourished has significantly lower microbiota diversity and a lower number of Bacteroidetes and pathogenic Proteobacteria and Firmicutes than normal or healthy children [4,[6][7][8]. In addition, based on a research in Malawi, the abundances of Prevotella, Bacteroidetes, Eubacterium, and Blautia species were lower in malnourished children than in undernourished children [9]. ...
The present study investigated the ingestion effect of chocolate probiotic containing Lactobacillus plantarum Dad-13 in undernourished children. A 100-day observation was conducted on undernourished children in Lombok, who were divided into probiotic (n=28) and placebo (n=28) groups. Fecal sampling was performed on the 10th and 100th days and further analyzed for gut microbiota composition, short-chain fatty acid (SCFA), and fecal pH. A significant difference was found in the diversity index, fecal pH, and several microbiotas at the phylum and genus levels. At the phylum level, Bacteroidetes was significantly higher in the probiotic group, and a higher relative abundance (RA) of Firmicutes was found in the placebo group. At the genus level, significant differences were observed in some bacteria, such as Bifidobacterium and Prevotella. Therefore, it can be concluded that the probiotic intervention in this study resulted in changes of gut microbiota diversity and fecal pH.
Trial Registration: Thai Clinical Trials Registry identifier: TCTR20220425001
... In the last decade, the gut microbiota has become a key target for strategies aiming at controlling energy metabolism and weight gain. Many studies have revealed that specific gut microbes can both promote obesity [4] and play a causal role in severe acute underweight individuals [2,5]. In addition, recent evidence has been accumulating on the importance of gut microbiota for juvenile linear growth [2,[6][7][8][9]. ...
Background
Colostrum is the first milk for a newborn. Its high content in microbiota shaping compounds and its intake at the time of gut microbiota seeding suggests colostrum may be critical in the establishment of a healthy microbiota. There is also accumulating evidence on the importance of the gut microbiota for healthy growth. Here, we aimed to investigate the contribution of colostrum, and colostrum-induced microbiota to growth promotion. Addressing this question is highly significant because (1) globally, less than half of the newborns are fully colostrum fed (2) the evidence for the importance of the microbiota for the prevention of undernutrition has only been demonstrated in juvenile or adult pre-clinical models while stunting already starts before weaning.
Results
To address the importance of diet at birth in growth failure, we developed a unique mouse model in which neonates are breastfed by mothers at an advanced stage of lactation who no longer provide colostrum. Feeding newborn mice with mature milk instead of colostrum resulted in significant growth retardation associated with the biological features of chronic undernutrition, such as low leptin levels, dyslipidemia, systemic inflammation, and growth hormone resistance. We next investigated the role of colostrum in microbiota shaping. At the end of the lactation period, we found a major difference in gut microbiota alpha diversity, beta diversity, and taxa distribution in control and colostrum-deprived mice. To determine the causal relationship between changes in microbiota and growth trajectories, we repeated our experiment in germ-free mice. The beneficial effect of colostrum on growth remained in the absence of microbiota.
Conclusion
Our data suggest that colostrum may play an important role in the prevention of growth failure. They highlight that the interplay between neonatal gut microbiome assembly and diet may not be as crucial for growth control in the developing newborn as described in young adults. This opens a paradigm shift that will foster research for colostrum’s bioactives that may exert a similar effect to microbiota-derived ligands in promoting growth and lead to new avenues of translational research for newborn-tailored prevention of stunting.
98mWSFedBqCALfgBr5hPfAVideo Abstract
