This review provides a comprehensive synthesis of contemporary literature examining the molecular and metabolic mechanisms underlying childhood stunting, with particular emphasis on systems biology–derived insights. The scope of the review encompasses key biological pathways implicated in growth faltering, including nutrient-sensing signaling (e.g., mTOR), amino acid metabolism, the tryptophan–kynurenine pathway, one-carbon metabolism, inflammation, and their interactions with maternal, environmental, and nutritional factors influencing linear growth and long-term health outcomes.

To ensure consistency and transparency, a structured literature search approach was applied across multiple databases, including PubMed, Scopus, Web of Science, and Google Scholar. For PubMed, Scopus, and Web of Science, search strategies employed combinations of keywords and Boolean operators such as “childhood stunting,” “linear growth faltering,” “systems biology,” “metabolomics,” “mTOR signaling,” “tryptophan-kynurenine pathway,” “one-carbon metabolism,” “amino acid deficiency,” “inflammation,” and “environmental enteric dysfunction.” Titles, abstracts, and keywords were initially screened for relevance, followed by full-text review of articles deemed pertinent to the objectives of this review.

For Google Scholar, the same search terms were used; however, due to limited filtering capabilities, search results were manually screened based on relevance, study quality, and publication date. Priority was given to peer-reviewed human studies, including observational studies, cohort studies, clinical trials, and relevant narrative or systematic reviews, with particular focus on children under 5 years of age and maternal–child dyads.

The literature included in this review primarily spans publications from 2000 to 2025, with earlier seminal studies incorporated where necessary to provide historical or mechanistic context. Collectively, this approach enabled a balanced and integrative evaluation of current evidence linking molecular dysregulation to childhood stunting, while acknowledging the predominantly associative nature of much of the existing data.

The mTOR pathway is a central regulator of cell growth and metabolism, integrating signals from nutrients, energy status, and growth factors. It comprises two complexes: mTORC1 and mTORC2. mTORC1 is sensitive to nutrient levels, especially amino acids, and regulates protein and lipid synthesis, while mTORC2 governs cytoskeletal organization and survival (55, 56).

Amino acids, particularly leucine, are key activators of mTORC1, promoting protein synthesis by phosphorylating downstream targets such as S6K1 and 4E-BP1 (57, 58). Other amino acids like glutamine, arginine, and tryptophan also modulate mTORC1 signaling (59, 60). Disruptions in this signaling cascade have been linked to stunting. Studies in Malawi, Indonesia, and Bangladesh have consistently shown that stunted children have lower circulating levels of essential (e.g., leucine, histidine, methionine) and conditionally essential amino acids (e.g., arginine, glutamine), along with altered lipid metabolites (61–63). This amino acid deficiency likely impairs mTORC1 activity, thereby limiting protein synthesis and growth. In low nutrient conditions, mTORC1 becomes inactive, triggering autophagy to recycle cellular components for survival (64, 65). However, even with sufficient energy and growth factors, mTORC1 cannot function effectively without adequate amino acids (66).

Growth factors such as insulin growth factor 1 (IGF-1) and leptin further modulate mTORC1 through the PI3K/Akt pathway. IGF-1 deficiency has been correlated with stunting in several studies from Bangladesh, Malawi, and Burkina Faso, suggesting long-term endocrine alterations due to early malnutrition (67–69). Another critical hormone, fibroblast growth factor 21 (FGF21), modulates the AMPK-sirtuin-mTOR axis and responds to protein restriction. High baseline FGF21 levels in Bangladeshi children were predictive of better growth outcomes following nutritional supplementation, highlighting its potential as a biomarker for intervention responsiveness (70).

Energy status also plays a critical role in mTORC1 regulation. AMP-activated protein kinase (AMPK), a key energy sensor, inhibits mTORC1 during energy scarcity to conserve resources. Dietary studies in Egypt, Indonesia, and the Philippines reveal that stunted children often consume insufficient energy and protein, which may contribute to mTORC1 suppression (71–73).

mTORC2, while less well-characterized, also contributes to growth regulation. It is activated by insulin, IGF-1, and leptin via PI3K signaling and plays a role in cytoskeletal dynamics and lipid metabolism (74, 75). mTORC2 indirectly enhances mTORC1 activity via Akt-mediated phosphorylation of tuberous sclerosis complex 2 (TSC2) and other downstream targets like PI3KC2-β (76, 77). Thus, inhibition of mTORC2 can secondarily impair mTORC1, compounding growth deficits (78). These mechanisms are depicted in Figure 1.

Overall, disruptions in the mTOR pathway whether due to amino acid deficiency, energy deprivation, or hormonal imbalance contribute significantly to the pathophysiology of stunting (Figure 1). Targeting these molecular mechanisms may enhance the efficacy of nutritional and clinical interventions aimed at improving growth outcomes in undernourished children.

Studies supporting the mTOR pathway disruption are summarized in Table 1.

The relationship between the tryptophan-kynurenine pathway (TKP) and childhood stunting is complex and influenced by chronic inflammation, nutritional deficiencies, and metabolic alterations. Tryptophan is an essential amino acid which plays a significant role in protein synthesis and serves as a precursor of two main pathways: the serotonin pathway and the kynurenine pathway. Under normal physiological conditions, most dietary tryptophan (over 90%) is metabolized via the kynurenine pathway, while only about 1% is used for serotonin synthesis, which serves a critical role in cellular function. The rest of the unmetabolized tryptophan is used for protein synthesis in tissues like muscles. This metabolic balance is generally maintained unless disrupted by inflammation or stress, which can shift tryptophan metabolism away from serotonin and protein production, leading to physiological and neurological consequences (79–81).

In the serotonin pathway, tryptophan is first hydroxylated by tryptophan hydroxylase-1 (TPH-1), the rate-limiting enzyme in serotonin biosynthesis, producing 5-hydroxytryptophan (5-HTP), which is then converted into serotonin (79, 82). Additionally, the availability of amino acids, including tryptophan, activates the mTORC1 pathway, a growth regulator that promotes protein synthesis which is essential for child growth (83). However, chronic inflammation can significantly alter this process by upregulating the kynurenine pathway, diverting tryptophan metabolism toward kynurenine synthesis. This shift is driven by increased activity of indoleamine 2,3-dioxygenase 1 (IDO1), the key enzyme in the kynurenine pathway, whose expression is elevated in inflammatory conditions (79, 84, 85). In addition, tryptophan 2,3-dioxygenase (TDO), a liver-specific enzyme, also catalyzes the first step of tryptophan degradation under homeostatic conditions and in response to glucocorticoids and tryptophan levels, further regulating systemic tryptophan availability and influencing the balance between serotonin and kynurenine pathway metabolism (86).

In the context of childhood stunting, chronic inflammation commonly associated with environmental enteric dysfunction, elevates pro-inflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α), Interferon-γ (IFN-γ), and Nuclear Factor kappa-B (NF-κB). These inflammatory signals activate IDO1, increasing the conversion of tryptophan to kynurenine and its downstream metabolites, thereby reducing tryptophan availability for serotonin synthesis and protein production (86–88). This metabolic shift contributes to abnormally low serotonin and protein levels, impairing both linear growth and cognitive development (Figure 2) (85, 87). Gazi et al. (83) reported that elevated kynurenine-to-tryptophan (K/T) ratios indicating increased tryptophan catabolism, are negatively associated with linear growth. Chronic inflammation not only accelerates catabolism in kynurenine pathway but divert tryptophan away from serotonin and protein production leading to a metabolic imbalance which contributes to muscle wasting and weight loss and far-reaching consequences on cognitive development and growth (87, 89, 90).

Metabolomics studies demonstrated a relationship between altered tryptophan metabolism and childhood stunting. Guerrant et al. (91) found that lower plasma tryptophan levels correlate with biomarkers of systemic and intestinal inflammation in Brazilian children, reinforcing the association between tryptophan depletion and growth impairment. Similarly, Kosek et al. (90) reported that low plasma tryptophan levels are linked to growth deficits in impoverished children. Their analysis of child cohorts in Peru and Tanzania revealed a direct correlation between plasma tryptophan concentrations and linear growth up to 8 months after biomarker assessment. Conversely, increased kynurenine production due to increased IDO1 activity is associated with intestinal injury and inflammation, ultimately leading to poorer growth outcomes.

Dietary intake also plays a crucial role in tryptophan metabolism. In Tanzania, for instance, a maize-based diet has been linked to low tryptophan intake. Even as low as 25% below the required tryptophan intake can reduce the synthesis of proteins leading to symptoms such as anorexia and impaired growth (83, 90). This further stresses the importance of tryptophan as a critical biomarker for growth and nutritional status.

In stunted children, the combination of low tryptophan availability and heightened kynurenine production exacerbates the effects of malnutrition and inflammation, creating a detrimental cycle that impairs growth and development (Figure 2) (61).

Additionally, kynurenine and its derivatives exhibit complex immunomodulatory effects, influencing immune responses by promoting T-cell apoptosis and inhibiting T-cell proliferation. These immunosuppressive effects can exacerbate the impact of infections prevalent in stunted populations, creating a vicious cycle where chronic inflammation increases tryptophan catabolism, further compromising immune function and nutrient absorption, ultimately resulting in stunted growth (83, 92, 93).

It should be noted, however, that in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial conducted in Zimbabwe, the K/T ratio was significantly associated with stunting only at 12 months of age, introducing some inconsistency across studies (94). Nevertheless, the majority of evidence supports a strong association between dysregulation of the TKP and childhood stunting, with elevated kynurenine levels proposed as potential biomarkers of growth impairment. A summary of the relevant studies and their key findings is presented in Table 2.

One-carbon metabolism (OCM) plays a vital role in early development by providing one-carbon units necessary for the synthesis of deoxyribonucleic acid (DNA), proteins, and lipids, as well as for epigenetic modifications that regulate gene expression (95). This interconnected network, which includes the folate and methionine cycles, acts as an integrator of nutrient status and relies on essential nutrients such as B vitamins, amino acids, choline, betaine, and methionine for proper function (96, 97). These nutrients drive critical biochemical reactions that support DNA replication, repair, and methylation (98, 99). Functional biomarkers like S-adenosylmethionine (S-AM) and homocysteine further reflect OCM’s role in maintaining cellular health and epigenetic regulation (100). Given its significance during pregnancy and childhood, impairments in OCM have been closely linked to stunting and malnutrition (Figure 3) (101).

The role of OCM in childhood malnutrition and growth impairment is increasingly evident, as deficiencies in key nutrients disrupt methylation processes critical for gene regulation and cellular function (102). Studies have shown that children with edematous severe acute malnutrition, such as kwashiorkor, exhibit widespread DNA hypomethylation compared to those with non-edematous Severe Acute Malnutrition (SAM), likely due to low methionine levels and reduced methylation capacity—changes that are reversible with nutritional rehabilitation (103). In Malawian children with kwashiorkor, significantly lower serum levels of methionine, homocysteine, and related metabolites further support the link between OCM dysfunction and redox (101).

Epigenetic alterations such as elevated histone H3 lysine 9 trimethylation have also been observed in stunted children and are associated with suppressed immune gene expression and impaired linear growth from birth to 1 year (104). Notably, these molecular changes were detected prior to the clinical manifestation of stunting, highlighting their potential as early biomarkers of growth faltering.

Maternal deficiencies in one-carbon nutrients such as folate, vitamin B6, and B12 are linked to elevated homocysteine levels and adverse pregnancy outcomes, including fetal growth restriction, low birth weight, and preterm birth (105, 106). Adequate intake of these nutrients is crucial for regulating homocysteine metabolism and supporting healthy fetal development. A study among Chinese pregnant women revealed significant imbalances in OCM biomarkers during mid-to-late pregnancy, including low levels of folate and B vitamins and elevated total homocysteine. Elevated homocysteine was inversely associated with red blood cell folate and vitamin B6 levels, while plasma S-AM showed a positive relationship with serum betaine and a negative one with vitamin B6 (97). These findings emphasize the critical need to ensure sufficient one-carbon nutrient levels during pregnancy for optimal maternal and fetal health.

Stunted children have shown reduced levels of choline-derived metabolites such as betaine and dimethylglycine (DMG), which are vital for growth-related processes like cell proliferation and gene regulation (107–110). Studies in Malawian children found significantly lower serum choline and phosphatidylcholine levels among those who were stunted, alongside higher betaine-to-choline and trimethylamine N-oxide (TMAO)-to-choline ratios—patterns associated with impaired growth (61, 111). In Brazilian children, urinary excretion of choline and DMG was positively linked to better growth outcomes (112). Furthermore, a longitudinal lipidomics study of a birth cohort in Gambia identified serum polyunsaturated fatty acids (PUFAs) and phosphatidylcholines as reliable predictors of future growth, highlighting their importance in early-life dietary interventions (113).

Interventions targeting PUFAs and choline, particularly through egg consumption, have shown mixed results in reducing childhood stunting. The 2014 Lulun Project demonstrated that consuming one egg daily for 6 months during early complementary feeding reduced stunting by 47% and increased linear growth by 0.63 length-for-age Z-score (LAZ). This intervention significantly elevated plasma levels of choline, betaine, methionine, TMAO, dimethylamine (DMA), and docosahexaenoic acid (DHA), which are key components in metabolic and growth-related processes (114).

However, a follow-up study, Lulun Project II, tracking over 90% of the original cohort, found that the growth benefits were not sustained beyond 2 to 3 years of age. HAZ declined more in the egg group than in the control group, indicating greater growth faltering over time. These findings suggest that while egg consumption provides crucial early benefits, longer intervention periods and a more comprehensive approach to stunting prevention are needed (115).

Other studies report varying results. In Ethiopia, Omer et al. (116) found that a child-owned poultry intervention significantly reduced stunting rates and improved nutritional status in children aged 6–18 months. However, Stewart et al. (117) reported that a six-month egg intervention did not improve linear growth among Malawian children. Similarly, Ricci et al. (118) found no significant improvement in linear growth or other health parameters in South African children following a six-month egg intervention.

Despite these inconsistencies, a meta-analysis of seven egg intervention trials concluded that overall, egg consumption was associated with improved height outcomes in children (119). These findings highlight the potential role of eggs in child growth but also suggest the need to consider additional dietary and environmental factors for long-term effectiveness (Table 3).

Inflammation is a normal immune response to harmful stimuli. However, chronic inflammation disrupts the balance of immune signaling, leading to oxidative stress, tissue damage, and metabolic disturbances that can negatively affect child growth (120). Elevated pro-inflammatory cytokines like TNF-α and interleukin 6 (IL-6) have been linked to impaired nutrient absorption, hormonal dysregulation, and reduced energy availability. However, findings on TNF-α levels in stunted children vary: Zambruni et al. (121) observed elevated TNF-α among stunted Peruvian infants, whereas Nuryandari et al. (122) and Hossain et al. (67) reported lower levels among older stunted children with chronic infections. These discrepancies may reflect differences in age, health status or immune suppression due to severe malnutrition and wasting (123). Supporting this, other studies show that TNF-α levels correlate with body mass index (BMI), suggesting that lower TNF-α may be a marker of severe malnutrition and immune dysfunction (124–126).

One potential driver of chronic inflammation and growth impairment is EED, a subclinical condition prevalent in low and middle-income countries. EED arises from repeated exposure to enteric pathogens due to poor sanitation and hygiene and is characterized by chronic intestinal inflammation, villous blunting, crypt hyperplasia, increased intestinal permeability, and impaired nutrient absorption (29).

EED contributes to growth faltering through multiple, interrelated mechanisms. Recurrent pathogen exposure (e.g., Escherichia coli and Shigella) induces sustained production of inflammatory cytokines such as TNFα and IL6, which interfere with growth hormone signaling, suppress IGF-1, and divert energy toward immune responses. TNF α–mediated activation of the NF κB pathway further amplifies inflammation and inhibits anabolic processes required for linear growth (127). Intestinal damage in EED, such as villous atrophy and crypt hyperplasia, impairs nutrient absorption and increases gut permeability, allowing bacterial products to enter the bloodstream and sustain systemic inflammation. Humphrey (128) highlighted how this “leaky gut” phenomenon triggers an immune response that diverts nutrients and energy away from growth processes, exacerbating stunting. Prendergast et al. (129) further demonstrated that chronic inflammation suppresses the IGF-1 axis, leading to hormonal disruptions that impair linear growth. Harper et al. (130) observed that children with EED exhibited poor HAZ due to persistent intestinal damage. A recent systematic review demonstrated that all EED domains including intestinal damage and repair, absorption and permeability, microbial translocation, intestinal inflammation, and systemic inflammation are consistently associated with impaired linear growth in children (131).

The gut microbiome plays a central role in mediating these effects. Metagenomic studies consistently show that stunted children exhibit an immature and dysbiotic gut microbiome, which compromises nutrient utilization, immune regulation, and metabolic signaling (132). This dysbiotic state alters endocrine pathways critical for growth, including the IGF-1 axis (133).

Microbiome-derived metabolites further link gut dysfunction to stunting. Short-chain fatty acids (SCFAs), particularly butyrate, support epithelial integrity, modulate immune responses, and provide energy to colonocytes (134). Stunted children show reduced abundance of butyrate-producing taxa such as Faecalibacterium, Megasphaera, and Blautia, alongside increased Ruminococcus, a pattern associated with intestinal inflammation and barrier dysfunction (135). Data from the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort indicate that subclinical, non-diarrheal infections with Shigella, enteroaggregative Escherichia coli, Campylobacter, and Giardia are associated with larger declines in length-for-age Z-scores than infections caused by other microbes (136). Giardia infection has additionally been linked to amino acid deficiencies and elevated phenolic acids, reflecting altered microbial amino acid metabolism (137).

Disruption of tryptophan metabolism represents another microbiome-mediated pathway. Gut dysbiosis can shift tryptophan metabolism toward the kynurenine pathway, promoting inflammation and impairing gut barrier function (138). Reduced levels of indole-3-propionic acid, a microbiota-derived tryptophan metabolite, have been associated with epithelial damage and intestinal inflammation in EED (139).

Bile acid metabolism is also markedly altered in stunted children. Dysbiosis disrupts bile acid composition and enterohepatic circulation, impairing lipid absorption and immune regulation. Reduced duodenal concentrations of secondary bile acids such as deoxycholic and lithocholic acid (140–142), alongside elevated plasma glycine-conjugated bile acids, suggest bile acid malabsorption and contribute to diarrhea, systemic inflammation, and growth impairment (143). In addition, microbial fermentation of undigested substrates generates inflammatory products such as lipopolysaccharides, which are elevated in stunted children and further activate immune pathways (91, 144). A summary of these studies is provided in Table 4.

Environmental and nutritional factors strongly modulate EED risk. Poor sanitation, inadequate hygiene, and close contact with livestock increase exposure to enteric pathogens, while nutrient-poor diets limit intestinal repair and immune competence (145). Observational studies consistently show that children living in unhygienic environments or households practicing open defecation exhibit higher EED biomarker levels and poorer growth outcomes (146) found that children exposed to unsanitary environments exhibited elevated markers of gut inflammation and stunted growth. Although improvements in environmental hygiene are associated with reduced intestinal inflammation (147), evidence from randomized trials indicates that conventional household-level water, sanitation, and hygiene (WASH) interventions alone have limited effects on EED biomarkers and stunting (148, 149). Large trials in Bangladesh, Kenya, and Zimbabwe demonstrated that while improved infant and young child feeding (IYCF) enhanced linear growth, household-level WASH interventions did not consistently reduce stunting or enteropathogen exposure (150). Recent systematic reviews confirm that poor WASH conditions are strongly associated with elevated EED biomarkers, yet WASH interventions show inconsistent effects, highlighting the need for transformative, community-level and nutrition-integrated approaches (131, 151, 152).

Dietary inadequacies further exacerbate EED and growth failure. Deficiencies in key micronutrients, particularly zinc (153–155) and iron (156, 157), impair epithelial repair, weaken immune defenses, and intensify chronic inflammation, compounding the effects of environmental exposures.

Collectively, current evidence indicates that stunting associated with chronic inflammation and EED arises from complex interactions among enteric infections, gut dysbiosis, metabolic dysfunction, and nutritional deficiencies. Effective prevention and mitigation will require integrated, multisectoral strategies that combine improved sanitation and hygiene, nutrient-dense diets, and interventions to reduce zoonotic and environmental pathogen exposure through improved household and livestock management practices.