Reduced infant rhesus macaque growth rates due to environmental enteric dysfunction and association with histopathology in the large intestine

Hendrickson, Sara M; Thomas, Arthur W.; Prongay, Kamm; Haertel, Andrew J; Garzel, Laura; Gill, Leanne; Barr, Tasha; Rhoades, Nicholas S; Reader, Rachel; Galan, Mark; Carroll, Julie M.; Roberts, Charles T.; Gao, Lina; Amanna, Ian J.; Messaoudi, Ilhem

doi:10.1038/s41467-021-27925-x

Cited by 9 publications

(21 citation statements)

References 60 publications

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“…Geographical differences in biopsy features related to the degree of villous atrophy and lymphocytic infiltration have also been noted previously [1]. Furthermore, recent evidence in a primate model of environmental enteropathy points towards the involvement of the large intestine in association with growth faltering [4], which has barely been explored in humans…”

Section: Introductionmentioning

confidence: 71%

Protein status in relation to linear growth faltering and environmental enteropathy

Shivakumar,

Kelly

2023

Current Opinion in Clinical Nutrition &Amp; Metabolic Care

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Purpose of review Children with linear growth faltering refractory to nutritional management show evidence of environmental enteropathy, which may compromise nutrient availability. Protein could be particularly affected, due to the possibility of sub-optimal digestibility and/or increase in requirement for immune response. This increase in protein requirement along with poor intake could potentially lead to increased breakdown of body protein sources and in turn a depleted protein state. The present review focuses on protein status in children at risk of linear growth faltering and environmental enteropathy. One pig study is also presented. Recent findings There is consistent evidence of low circulating essential and conditionally essential amino acids, in children. One study showed no difference in protein synthesis/breakdown, and fat free mass (FFM) in children at risk of linear growth faltering and environmental enteropathy. Weanling pigs exposed to nutrient deprivation showed a decrease in plasma albumin, with a slower rate of weight and length accretion, and a lower FFM. Summary These findings emphasize the need for improving intake of high-quality protein in children living in regions with a high prevalence of environmental enteropathy, with careful studies of the effect on growth rate and protein status.

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Section: Introductionmentioning

confidence: 71%

Protein status in relation to linear growth faltering and environmental enteropathy

Shivakumar,

Kelly

2023

Current Opinion in Clinical Nutrition &Amp; Metabolic Care

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“… 44 An animal model of moderate acute malnutrition in mice revealed increased intestinal permeability in the cecum and colon, 40 and an animal model of EED in primates revealed increased permeability in the colon, which was associated with growth faltering. 45 These findings highlight the importance of additional studies conducted to examine the colon in children with SAM and the importance of animal models in helping to understanding the pathophysiology.…”

Section: Inflammation and The Pathophysiological Changes In Severe Ac...mentioning

confidence: 98%

Inflammation: the driver of poor outcomes among children with severe acute malnutrition?

et al. 2023

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Severe acute malnutrition (SAM) is the most life-threatening form of undernutrition and underlies at least 10% of all deaths among children younger than 5 years in low-income countries. SAM is a complex, multisystem disease, with physiological perturbations observed in conjunction with the loss of lean mass, including structural and functional changes in many organ systems. Despite the high mortality burden, predominantly due to infections, the underlying pathogenic pathways remain poorly understood. Intestinal and systemic inflammation is heightened in children with SAM. Chronic inflammation and its consequent immunomodulation may explain the increased morbidity and mortality from infections in children with SAM, both during hospitalization and in the longer term after discharge. Recognition of the role of inflammation in SAM is critical in considering new therapeutic targets in this disease, which has not seen a transformational approach to treatment for several decades. This review highlights the central role of inflammation in the wide-ranging pathophysiology of SAM, as well as identifying potential interventions that have biological plausibility based on evidence from other inflammatory syndromes.

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“…11 Various conditions, such as bacterial and viral infections, can lead to an oedematous caecal mucosa and increased lamina propria (LP) cell numbers, 12 although such observations are rarely made in practice. It is notable that environmental enteric dysfunction in rhesus macaques is associated with histopathological changes along the large intestine (including the caecum) and reduced infant growth rates, 13 and that adenocarcinoma of the ileocecocolic junction, caecum or colon is the most common spontaneous neoplasm in captive animals. 14 In humans, 'caecal patch lesions' are manifestations of ulcerative colitis (UC) that can aid diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Maintenance of caecal homeostasis by diverse adaptive immune cells in the rhesus macaque

Castro Dopico,

Guryleva,

Mandolesi

et al. 2024

Clin & Trans Imm

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ObjectivesThe caecum bridges the small and large intestine and plays a front‐line role in discriminating gastrointestinal antigens. Although dysregulated in acute and chronic conditions, the tissue is often overlooked immunologically.MethodsTo address this issue, we applied single‐cell transcriptomic‐V(D)J sequencing to FACS‐isolated CD45+ caecal patch/lamina propria leukocytes from a healthy (5‐year‐old) female rhesus macaque ex vivo and coupled these data to VDJ deep sequencing reads from haematopoietic tissues.ResultsWe found caecal NK cells and ILC3s to co‐exist with a spectrum of effector T cells partially derived from SOX4+ recent thymic emigrants. Tolerogenic Vγ8Vδ1‐T cells, plastic CD4+ T helper cells and GZMK+EOMES+ and TMIGD2+ tissue‐resident memory CD8+ T cells were present and differed metabolically. An IL13+GATA3+ Th2 subset expressing eicosanoid pathway enzymes was accompanied by IL1RL1+GATA3+ regulatory T cells and a minor proportion of IgE+ plasma cells (PCs), illustrating tightly regulated type 2 immunity devoid of ILC2s. In terms of B lymphocyte lineages, caecal patch antigen‐presenting memory B cells sat alongside germinal centre cells undergoing somatic hypermutation and differentiation into IGF1+ PCs. Prototypic gene expression signatures decreased across PC clusters, and notably, expanded IgA clonotypes could be traced in VDJ deep sequencing reads from additional compartments, including the bone marrow, supporting that these cells contribute a steady stream of systemic antibodies.ConclusionsThe data advance our understanding of caecal immunological function, revealing processes involved in barrier maintenance and molecular networks relevant to disease.

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Reduced infant rhesus macaque growth rates due to environmental enteric dysfunction and association with histopathology in the large intestine

Cited by 9 publications

References 60 publications

Protein status in relation to linear growth faltering and environmental enteropathy

Protein status in relation to linear growth faltering and environmental enteropathy

Inflammation: the driver of poor outcomes among children with severe acute malnutrition?

Maintenance of caecal homeostasis by diverse adaptive immune cells in the rhesus macaque

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