Current Understanding of Giardia lamblia and Pathogenesis of Stunting and Cognitive Deficits in Children from Low- and Middle-Income Countries

Abstract

Purpose of Review

Giardia lamblia is a common intestinal parasite worldwide, mainly in children from low- and middle-income countries (LMIC). Also, it has been associated with increased intestinal permeability, stunting, and cognitive impairment. Nonetheless, the pathogenesis of long-term consequences is difficult to elucidate.

Recent Findings

Recent studies try to understand the long-term consequences of Giardia infections. First, well-characterized studies associate Giardia with intestinal damage and child growth. Second, infections appear not to be associated with inflammation, but “lack of inflammation” may not, however, entirely exclude a pro-inflammatory pathway. Finally, some important amino acids are lower and could contribute to prolongate stunting and cognitive deficit.

Summary

Giardia infections in LMIC used to be associated with child growth shortfalls, gut permeability, and cognitive deficits. Multifactorial effects could be associated with Giardia, including nutritional, altered microbiota, and generation of potentially toxic microbial metabolic byproducts, all together increasing risk of long-term outcomes.

Introduction

Giardia lamblia is a globally distributed enteric flagellated protozoan associated with gastrointestinal infections in both children and adults. There are an estimated 280 million infections in humans annually [1–3]. The highest burden occurs in children living in low- and middle-income countries (LMIC) and Giardia exposure is commonly associated with poor socioeconomic conditions [4, 5]. G. lamblia (aka G. duodenalis and G. intestinalis) is one of the most common intestinal parasitic infections, and it is transmitted through the fecal-oral route by waterborne and food sources. Due to disproportionate exposures in children in limited resource settings and the potential for long-term developmental sequelae after infection, G. lamblia is recognized as a neglected tropical disease by the World Health Organization (WHO) [6, 7].

Historically, the first description of G. lamblia during a diarrhea episode was in 1681 by Anton van Leeuwenhoek who identified G. lamblia in his diarrheal stool. Nowadays, giardiasis (diarrhea disease caused by G. lamblia) is clinically characterized by abdominal cramping and bloating, malabsorptive diarrhea (steatorrhea), and weight loss [8]. Although giardiasis is a well-defined disease and reproducible by Koch’s postulates [9], the pathogenesis and diarrhea attributable to G. lamblia are still debated. It is well-known that G. lamblia can produce different clinical infections, which can vary from diarrhea (acute which may progress to chronic episodes) to asymptomatic infections [10]. In LMIC where G. lamblia is highly endemic, children are exposed early in life and usually develop an asymptomatic infection [1]. The presence/absence of clinical manifestations can also vary during prolonged G. lamblia colonization, a phenomenon that could be multifactorial due to fluctuation in the gut micro-environment, host responses, and parasite traits that remain incompletely defined [11]. Infection is considered to spontaneously resolve, but recent birth cohort studies have identified a significant proportion of young children (>50%) develop chronic intestinal carriage for >3 months and some may never clear the parasite [3, 12••]. Independent of typical giardiasis symptoms, the presence of G. lamblia in stool samples has been associated with increased intestinal permeability and decreased weight-for-age and length-for-age in children in the first 2 years of life with effects measurable at least to 5 years of life [3]. Furthermore, other chronic sequelae including post-infectious irritable bowel syndrome, chronic fatigue[13], stunting [14], and cognitive impairment [15] have been reported, but the pathogenesis of those sequelae is unclear yet.

To understand the pathological mechanisms, different hypotheses have been proposed regarding possible pathways, including pro-inflammatory response, intestinal permeability, gut microbiome composition, and disruption of nutrient metabolism. Here, we present a review of the current understanding of long-term sequelae associated with G. lamblia infection.

G. lamblia and Host Interactions

G. lamblia is a non-invasive intestinal protozoan, which is able to establish chronic colonization in the host. The transmission stage is cysts that are resistant to harsh environmental conditions. After ingestion, the excystation process generates four trophozoites following two rounds of division via asexual binary fission. The trophozoites are the replicating and infectious stage that colonize in the host’s intestinal tract, mainly the duodenum [1]. To sustain colonization, the protozoan must be able to avoid the effects of mucus barrier in the intestinal mucosa, which is composed mainly of water and MUC-2 mucin [16]. To cross the mucus barrier, G. lamblia trophozoites use flagellar movement and likely other specialized cellular processes [17]. Secreted proteins, like cysteine proteases, can also cleave MUC-2 to help the protozoan directly interface with intestinal epithelial cells [18]. G. lamblia is non-invasive; rather, trophozoites attach to enterocytes via a combination of surface lectins and parasite proteins such as giardin, variant-specific surface proteins (VSPs), tenascins, and secreted cysteine proteases located in its ventral disk [19, 20]. Whether trophozoite adhesion is required for these effects on intestinal epithelial cells is a subject of ongoing research, since some studies have shown that excreted/secreted products of G. lamblia can also cause damage to intestinal epithelial cells. Those products of G. lamblia are involved in parasite pathogenesis which have been associated with the shortening of brush-border microvilli [21, 22], disruption of epithelial junction complexes mediated by the parasite [23, 24], and recently associated with activation of signaling pathways to regulate cell cycle arrest and apoptosis [25]. This harm to the epithelial cells in children might lead to different alterations at intestinal levels and could be associated with impaired growth and diarrhea.

The Epidemiological Link Between G. lamblia and Impaired Child Growth

Although G. lamblia was recognized as a pathogen by WHO in 1981, the prevalence and pathogenesis of long-term sequelae remain unclear. One of the challenges in establishing a link between G. lamblia and long-term sequelae is that the majority of G. lamblia detections are present in children without symptoms, and when G. lamblia is present in a diarrheal episode, there are usually other co-pathogens that are more likely driving symptomatology [26]. Only recently have longitudinal studies accounted for the presence and persistence of intestinal pathogens independent of episodic diarrhea [27]. While these studies rank G. lamblia as a major pathogen associated with childhood linear growth impairment [28, 29]. A recent systematic review focused on intestinal parasites and impaired growth in children ≤ 5 years old included in 15 different studies from 12 countries found that G. lamblia is associated with stunting (OR 2.34 [1.07–5.10]), wasting (OR 2.90 [1.12–7.49]), and underweight (OR 1.53 [1.02–2.29]) [30]. Similar negative associations between G. lamblia and poor children’s linear growth have also been reported in different studies in children for endemic areas like Ecuador [31], Brazil [32], and Nepal [33].

Estimating the differential effects between symptomatic and asymptomatic G. lamblia infections is also challenging, given the frequency of co-intestinal infections that may be attributable to symptoms and that in some studies, Giardia is negatively associated with diarrhea. From these studies, previous reports have found that the presence of diarrhea during G. lamblia infection is more frequently associated with weight decreases, but not with linear growth impairment [34, 35•], although, in persistent giardiasis, a decrease of weight and linear growth has been described in Brazilian children [36]. Conversely, asymptomatic G. lamblia infections have been more associated with linear growth impairment [29, 35•]. A recent study from Global Enteric Multicenter Study (GEMS) in children from South Asian and sub-Saharan Africa found that children with asymptomatic G. lamblia infection had lower height-for-age and weight-for-age comparing to the G. lamblia–negative children; interestingly, G. lamblia–positive children with moderate-to-severe diarrhea did not have any significant associations with wasting and linear growth [27].

While the association between Giardia and impaired linear growth is getting clarified in large prospective child cohorts, there remain wide variations in the strength of the association and estimate of that G. lamblia and impairments in child growth between studies, sites, and populations. These variations are even observed in multi-site studies following the same enrollment criteria, protocol, measurements, and analyses, suggesting that study design is not the primary driver of the observed outcome variability. The potential host, environmental, and parasite-specific variables that account for these variations at an individual level are a topic of ongoing research.

Potential Mechanistic Pathways of Giardia-Mediated Child Growth Impairment

The impairments in child growth associate with asymptomatic G. lamblia carriage [29], indicating that simply the presence of the parasite, independent of the conventional giardiasis malabsorptive diarrhea syndrome, can have a negative impact on childhood linear growth velocity [37•, 38] [39, 40]. These studies have also shown that G. lamblia can restrict linear growth without an apparent association with diminished weight or wasting [41]. In the MAL-ED study, G. lamblia detection associates with increased intestinal permeability measured by the lactulose-to-mannitol ratio, a marker of epithelial cell dysfunction [3]. However, the specific mechanisms leading to growth impairment are not yet known, though several different hypotheses are under investigation (Figure 1).

Fig. 1.

Proposed pathways for Giardia-mediated growth and cognitive impairment. Recent findings in children in low- and middle-income countries (LMICs) and animal models designed to recapitulate dietary conditions in these children have described an absence of typical environmental enteric dysfunction (EED)-like inflammation. However, this “lack of inflammation” during G. lamblia infection may be due to parasite-driven immune modulation of some responses without entirely excluding all potential pro-inflammatory pathways evidence by the presence of upstream inflammatory signaling markers. Another potential pathway for developmental sequelae is through direct disruptions in epithelial cells by action of secreted proteins, like proteases, or other processes like the unique metabolic properties of the protozoan, and/or an interaction with resident intestinal microbes or other gut pathogens. These factors may result in inadequate nutrient absorption due to epithelial cell dysfunction. Increased intestinal permeability, diminished nutrient transport, and/or pre-absorption factors may result in sequestration or shunting of important nutrients into the luminal compartment during G. lamblia infections. The nutrient-metabolic disruption is hypothesized to result in growth impairment with or without cognitive deficit that may be long-lasting. IEC, intestinal epithelial cell; MPO, myeloperoxidase; NEO, neopterin; LPC, lipocalin; AGP, alpha(1)-acid glycoprotein; Anti-FliC, anti-flagellin; Reg-1β, regenerating gene 1β; AA, amino acid; up arrow, increase/high levels; down arrow, decrease/low levels. ⟘Cognitive deficit includes the following: receptive language, gross and fine motor, and social (SQ) and intelligence quotients (IQ)

One potential mechanism is the inflammation pathway, in which enteric infections induce epithelial cell damage and promote pro-inflammatory mucosal responses that drive chronic intestinal and systemic inflammation, known as environmental enteric dysfunction (EED). Although conventional murine models of experimental giardiasis supported host lymphocyte-mediated intestinal pathology [42, 43], several studies in LMICs have reported a lack of conventional inflammatory signals in children with G. lamblia detections. A lack of markers of prototypic T cell–mediated EED-like inflammation (neopterin) was first reported in 2003 [44]. Similar findings were validated in a multi-pathogen analysis in MAL-ED, where the reduced growth associated with G. lamblia was not mediated by any of fecal EED-biomarkers (myeloperoxidase, neopterin, and α-1-antitrypsin) evaluated [45]. More recently, G. lamblia intestinal quantity was reported to have an inverse relationship with concentrations of two primary EED fecal biomarkers, myeloperoxidase and neopterin [3], and the presence of G. lamblia on intestinal biopsy associated with diminished markers of lymphocyte gene activation in a population of children with nutrition supplement-refractory undernutrition [46].

These data, emerging from different cohorts and through different approaches of measuring immune response, collectively indicate that the negative impact of G. lamblia on child growth is not carried out through the conventional EED chronic inflammation pathway. If inflammation during G. lamblia infection contributes to gut dysfunction, it would be due to an alternative inflammatory milieu that may in part be driven by unique immunomodula-tory properties of the parasite. Some findings suggest that G. lamblia can alter both myeloid cell and lymphocyte function by action of arginine deiminases, which in vitro can deplete enough arginine to alter immunophenotypic responses to TLR agonists in vitro and with consistent profiles described in experimental mouse models [42, 43]. These finding could indicate that an apparent “lack of inflammation” during G. lamblia infection (by intestinal biopsy or fecal biomarkers) may be due to parasite-driven immune modulation of some responses without entirely excluding all potential pro-inflammatory pathways. G. lamblia does for example associate with low-grade intestinal inflammation through other pathways: increases in fecal lipocalin and α1-acid glycoprotein [40, 43] in fecal samples in one study and increases in anti-fliC IgA and fecal regenerating gene 1β (Reg 1β) in serum samples in another [28]. Though Giardia was shown to increase fecal lipocalin-2 in murine malnutrition models [43], studies linking these pathways with Giardia in specific human cohorts are lacking. More studies are needed to determine the role and impact of these fecal and systemic biomarkers on the development of long-sequelae in children.

Growth Reductions by Processes Other than Inflammation

Given that impaired linear growth associated with G. lamblia infections appears to be a process independent of conventional EED-inflammatory pathways, the field has hypothesized other possible mechanisms. In this context, sequelae could be due to the direct disruptions in epithelial cells by action of secreted proteins, like proteases, or other processes [24] like the unique metabolic properties of the protozoan, and/or an interaction with resident intestinal microbes or other gut pathogens (Figure 1).

Interactions with intestinal microbiota have had a recent resurgence of interest. Historical observations in small patient cohorts described greater severity of symptoms in patients with Giardia with concurrent overgrowth of small intestinal communities and an increase in Enterobacteriaceae [47, 48]. However, casual findings in human populations have not been definitely seen. An analysis of the MAL-ED multisite birth cohort identified the presence of a bacterial-derived metabolite of tyrosine metabolism, 4-hydroxyphenylacetate (4-HPA), in urine as a mediator of Giardia-associated gut permeability and growth impairment. However, intestinal microbial profiling was not performed to identify the source of 4-HPA. Furthermore, a lack of a consistent finding across all study sites suggested other environmental co-factors may be involved [12••]. Indeed, there are an increasing number of observations identifying differences in gut microbial community 16S gene profiles that discriminate by G. lamblia status, but the findings at times are within only a restricted number of taxa, and investigators have yet to hone in on consistent or specific intestinal bacterial shifts (Table 1). In addition, distinctive microbial diversity profiles between individuals with asymptomatic and symptomatic G. lamblia infections have been reported [49] complicating the determination of the impact of G. lamblia on gut microbiome changes.

Table 1.

Examples of 16S community profiles during G. lamblia colonization in humans and in experimental models

Host	Author [ref.]	Country	Population	Increased with Giardia detection	Increased without Giardia detection
Human	Toro-Londono et al. [54]	Colombia	Children <5 years old from different day-care centers	Prevotella€,§ spp. Ruminococcaceae (unclassified) Alloprevotella§, Roseburia§, Veillonella€,§	Bacteroides§, Alistipes
	Mejia et al. [55]	Argentina	Children 3–8 years old	Prevotella€ spp.
	Berry et al. [56••]	Multicenter case-control studyα1	Children 0–59 months old	Prevotella€,§ spp. Ruminococcus§, Clostridiales, Lachnospiraceae, Coriobacteriales	Gammaproteobacteria, Natronobacillus, Lactobacillus, Leuconostoc
		Multicenter longitudinal studyβ	Children 17 days to 60 months	Prevotella€,§ spp. Ruminococcus§, Faecalibacterium§, Blautia§, Roseburia§, Lachnospiraceae, Lactobacillus, Coprococcus	Bifidobacterium§, Escherichia§, Streptococcus§, Bacteroides§
	Rouhani et al. [57]	Peru	Children 17 days to 24 months	At 18 months of age: Clostridium colinum At 24 months of age: Prevotella€,§ spp.	At 18 months of age: Clostridiaceae At 24 months of age: Clostridium
	von Huth et al. [58]	Guinea-Bissau	Children-adolescents 2–15 years old	Prevotella€,§ spp.	Collinsella
	Caudet et al. [60]	Spain	Adults with obesity£ 38 to 58 years old	Bacteroides §	Prevotella€,§ spp., Faecalibacterium§, Lactobacillus
	Muhsin-Sharafaldine et al.¥ [59]	New Zealand	Children and adults with acute gastrointestinal symptoms 0 to 60 years old	Prevotellaceae, Ruminococcaceae, Marinifilaceae, Campylobacteriaceae	Streptococcaceae, Pseudomonadaceae, Enterobacteriaceae, Peptostreptococcaceae, Moraxellaceae, Eggerthellaceae, Cellulomonadaceae
	McGregor et al. [49]	Iran	Children and adults with and without gastrointestinal symptoms 5–73 years old	With gastrointestinal symptoms: Parolsenella catena, Mitsuokella jalaludinii Without gastrointestinal symptoms: Enterococcus§ faecium, Bifidobacterium dentium	With gastrointestinal symptoms: Bacteroidetes, Alistipes shahii, Gordonibacter pamelaeae Without gastrointestinal symptoms: Bacteroidetes, Alistipes shahii, Gordonibacter pamelaeae
Mice	Bartelt et al. [43]	-	-	C57Bl/6 with PD diet (Abx): Enterobacteriaceae C57Bl/6 with PD diet (No-Abx) Firmicutes	C57Bl/6 with PD diet (Abx): Firmicutes, Bacteroidetes C57Bl/6 with PD diet (No-Abx): Bacteroidetes
	Barash et al.[65]	-	-	C5Bl/6J Comamonadaceae, Lachnospiraceae, Lactobacillaceae	C5Bl/6J Ruminococcaceae, Enterobacteriaceae, Erysipelotrichaceae, Melainabacteria, Clostridiaceae
	Yordanova et al. [66]	-	-	BALB/c: Coriobacteriales, Candidatus Arthromitus, Erysipelotrichaceae, C57Bl/6J: Blautia, Akkermansiaceae	BALB/c: Candidatus Saccharimonas, Lachnospiraceae UCG006, Blautia, Intestinimonas, Ruminiclostridium 5 C57BL/6J: Candidatus Saccharimonas, Gastranaerophilales
	Riba et al. [67•]	-	-	Coriobacteriaceae Enterorhabdus	Staphylococcus
	Allain et al. [68]	-	-	C57BL/6 with high-fat diet: Firmicutes	C57BL/6 with high-fat diet: Bacteroidetes

PD protein deficient, Abx antibiotics

^¥16S community profiles were reported only to the Family taxonomic level

^£Obesity was defined: body mass index (BMI), >40 kg/m², or >35 kg/m² in coexistence with significant comorbidity

^α1Microbiome database belonging to “The Global Enteric Multicenter Study (GEMS): GEMS diarrheal case/control study Targeted Locus (Loci).” Accession: PRJNA234437. ID: 234437

^βMicrobiome database belonging to “Malnutrition and Enteric Disease Study (MAL-ED): Diarrhea as a cause and consequence of reduced gut microbial diversity among undernourished children in Peru.” Accession: PRJEB28159. ID:557862

^€Associated with stunted child (>2SD LAZ)

^§Taxa identified in the small intestine of undernourished children according to references[52, 55]

Previous studies have described the role of the gut microbiota in the pathogenesis of stunting [50–53], and this gut microbiota imbalance can be caused by chronic exposure to a myriad enteric pathogens. Although there is no consensus on the microbial changes during G. lamblia infections in either nourished or undernourished individuals, recent studies in different geographic populations have observed an increase in relative abundance of Prevotella during the infection [54, 55, 56••, 57–59], though an opposite result was reported in obese adults in a non-endemic population [60]. Interestingly, separate studies have also described increased relative abundance of Prevotella as being associated with stunted children [61] and enhanced differentiation of Th-17 cells [62], which has been described to be significantly elevated in G. lamblia–exposed individuals [63]. More studies are needed to elucidate the joint interaction of microbiome, parasite, and immune response in childhood development.

In experimental models, microbiome changes during G. lamblia infections have also been described, but like human studies, with different microbial shifts between studies [64–66, 67•, 68]. In mice, dietary intake appears to influence the G. lamblia–microbiota interaction. Feeding mice a protein deficient diet (PD) has been found to recapitulate features of endemic pediatric G. lamblia outcomes: permitting persistent infection, impairing growth attainment, and enhancing intestinal permeability defects. These features were seen only in mice with intact intestinal microbiota, but not in mice that were either mono-associated with G. lamblia absent resident intestinal bacteria or exposed to continuous antibiotics to deplete intestinal microbiota [12••, 43]. In contrast, mice fed an isocaloric conventional diet (CD) with intact microbiota cleared G. lamblia within 2 weeks of challenge and showed no growth impairment or permeability defects [43]. Beyond protein malnutrition, in another recent study, mice fed a westernized high fat diet (HF) had increased G. lamblia trophozoite proliferation, enhanced gut, and increased stool water, and the HF diet–induced microbiota shifts were more pronounced in G. lamblia–challenged mice resulting in increased richness and evenness with high levels of Firmicutes and reducing levels of Bacteroidetes in infected mice [68].

In addition to alterations in the composition of intestinal microbial communities, experimental models in mice also show a wide range of potential functional impacts of G. lamblia on resident intestinal microbiota [12••, 43, 64, 65, 68]. Findings from these studies indicate that G. lamblia exposure results in alterations in microbiota-mediated metabolic function. Theoretical consequences of these changes may be a sequestration of important nutrients at intestinal levels, a conversion of microbial-derived metabolites from those that support intestinal epithelial cell function to those that may be toxic. Preliminary findings do suggest a resulting nutrient-metabolic disruption in the host, a modulation of host immune responses to microbial ligands after G. lamblia exposure in these model systems [67•, 69, 70], and changes in growth factors that are mediated by microbiota-dependent bile acid metabolism [67•].

More studies are needed to understand the role of microbiome composition during G. lamblia infections and how these microbiome changes impact child growth and development, taking account differences in host (human and mice), dietary intake, and clinical and sub-clinical infections variables. These variations at an individual/host levels are a topic of ongoing research.

Impaired Growth by Inadequate Nutrient Absorption

Another potential pathway to growth impairment in children is inadequate nutrient absorption due to epithelial cell dysfunction. Increased intestinal permeability, diminished nutrient transport, and/or pre-absorption factors may result in sequestration or shunting of important nutrients into the luminal compartment during G. lamblia infections [43] (Fig. 1).

Healthy child development depends on adequate nutrient absorption. For example, stunted children in Malawi have significantly lower serum concentrations of both essential amino-acids (AA) (arginine, glycine, glutamine) and non-essential AA (asparagine, glutamate, serine) [71]. Similar, MAL-ED investigators have previously published that lower dietary protein intake was associated with linear growth restriction and may worsen pathogen-mediated effects [72]. In this context, the limitation of AA acquisition could be a possible pathway for stunting independent to EED-inflammation route.

In G. lamblia infections, some different pathological changes have been observed, such as diffuse shortening of the intestinal brush-border microvilli, which could lead to lose the intestinal absorptive function [21, 22], and that could also affect the natural absorption of sugars, peptides, and vitamins in the small intestine [12••, 73, 74]. In humans, different studies have tried to evaluate the nutritional status during G. lamblia infections, which have been associated decreasing vitamin B12 (cobalamin) biosynthesis in Argentinian children [55], fructose malabsorption accompanied with a deficit of fat-soluble vitamins (mainly vitamin A) in adults from Spain [73], and decreasing the level several amino acids (AAs) in children from Peru [12••]. The latter study analyzed circulating AAs in 15-month-old children using cohorts from Peru (where G. lamblia associated with linear growth impairment and increased intestinal permeability) and Bangladesh (where G. lamblia was associated with neither linear growth impairment nor intestinal permeability changes) belonging to the MAL-ED study. This study found that concurrent G. lamblia detection among children from Peru associated with lower levels of multipole free serum AA, including reductions of essential AAs (histidine, lysine, methionine, threonine, and tryptophan), and the branched-chain AAs (isoleucine, leucine, and valine). Also, the presence of G. lamblia was associated decreasing arginine and AAs involved in arginine metabolism (ornithine and citrulline), tyrosine, and taurine. However, this finding was not seen in the Bangladesh cohort [12••]. Investigators posited that differences between sites might be explained by feeding practices, such as longer duration exclusive breast-feeding and complementary diets with higher proportion of proteins and fat in Bangladesh cohort compared with Peru, suggesting that the effects of G. lamblia are contextual and mediated by other factors.

In experimental mouse models infected with G. lamblia, bacteria-derived metabolites of tryptophan, phenylalanine, and tyrosine are increased, suggesting increased microbial mediated proteolysis even despite little measurable perturbation in the intestinal microbial 16S composition [43]. Metabolites of AAs generated by resident intestinal bacteria could alter the natural host metabolism through tricarboxylic acid cycle [43] and enhance malnutrition. Recently, a G. lamblia mono-association study in immunodeficient mice fed a protein deficient diet (PD) reported a decrease of intestinal free essential AAs (isoleucine, leucine, methionine, phenylalanine, threonine, and valine) and non-essential AA (tyrosine) during G. lamblia infections [12••]. Those data together suggest that one of the important mechanisms of G. lamblia is the disruption of nutrient homeostasis by noinflammatory pathways. Collectively, these findings indicate a possible “triple-hit” model [12••], in which G. lamblia converges with nutritional and dietary factors to modify resident microbial functions and ultimately dysregulate nutrient absorption, stimulate the generation of potentially toxic microbial metabolic byproducts, and restrict child growth.

Does G. lamblia Associate with Cognitive Deficits?

The bases of language and socioemotional behavior, part of sensory and perceptual systems, are formed in the first 2 years of life, suggesting this moment as a critical window for an adequate cognitive development [75]. The role of enteropathogens on child cognitive development is an area of active research. Recently, a negative association between enteropathogen detection and child cognitive development was described in both diarrheal and non-diarrheal stools [76]. Complex interactions may underlie how enteropathogens converge with other factors that can affect cognitive development, including biological components (childbirth weight, nutrition) [77], environmental and socio-economic factors [78], and psychosocial stimulation [79, 80]. The relationship between pathogens and cognitive development is linked with poor lineal growth and stunting [81–85], mainly in persistent stage of stunting [86, 87]. In a study from Bangladesh, both stunting and underweight during early childhood (6–24 months of age) were associated with poor cognitive, motor, language, and social-emotional skills [77]. Also, a meta-analysis of 29 LMICs established a positive association between linear growth and cognitive development in the first 2 years of life [88]. Similarity, lower cognitive scores have been detected in early-onset persistent stunting in children [89].

In G. lamblia infections, studies over last 25 years have documented a negative impact in cognitive impairment in children infected. Different observational studies conducted in Peru [15], India [34], and Turkey [90] reported that the presence of G. lamblia is not only associated with growth impairment, but also that Giardia detection in early life independently associated with poor cognitive function, with trend toward lower social quotients (SQ) and significantly lower intelligence quotients (IQ) [34]. However, casual pathways in human populations have not been definitely understood. Nutrient deficiencies arising from Giardia-mediated gut dysfunction could alter neurodevelopment given that AAs act as neuromodulators, neurotransmitters, and regulators of energy metabolism in the central nervous system [91] [92]. Indeed, some neurological diseases, including mild cognitive impairment (MCI), correspond with low cerebrospinal fluid amino acid precursors (AAPs) of neurotransmitter synthesis, such as tyrosine (precursor of dopamine and catecholamines), tryptophan (precursor of serotonin), and methionine (precursor of acetylcholine) [93]. These serum AAs are lower in children with G. lamblia detection [12••]. Moreover, other nutritional deficiencies or consequences of altered intestinal microbiota metabolism could also be involved. Alternatively, increased barrier permeability may allow for passage of harmful or neurotoxic chemicals that impair cognitive development [94].

Conclusion

G. lamblia is a frequent infection in children from LMICs, and it is associated with impaired linear growth in the first 2 years of life. Giardia-mediated growth impairment is likely multifactorial and operates through other environmental triggers. G. lamblia is likely modulated by nutritional and microbial factors and likewise results in alterations in the nutrient and metabolic functions of resident intestinal microbiota. The result is dysregulated nutrient absorption, metabolism, and gut-derived growth signals together with potential generation of toxic microbial metabolic byproducts. Future investigations are necessary to determine the mechanisms underlying growth failure and possible cognitive deficits resulting from the deranged microbial-host co-metabolism. More studies are needed to identify predictor factors to growth and cognitive impairment during G. lamblia infections and also determinate the G. lamblia–attributable fraction contributions to arrested childhood development.

Data Availability

No datasets were generated or analyzed during the current study.