Gut–brain Axis: Impact of Intestinal Inflammation and Micronutrient Deficiency on Psychomotor Development and Cognitive Functions in Egyptian Children with Undernutrition

Maged A. El Wakeel; Ghada El-Kassas; Eman Elsheikh; Alshaimaa Adel ElKhatib; Shaimaa Hashem; Salwa Refat Elzayat; Hiba Sibaii; Nevein Fadl; Thanaa Rabah

doi:10.3889/oamjms.2022.9059

Authors

Maged A. El Wakeel Department of Child Health, National Research Centre, Dokki, Giza, Egypt https://orcid.org/0000-0003-2634-8577
Ghada El-Kassas Department of Child Health, National Research Centre, Dokki, Giza, Egypt https://orcid.org/0000-0002-5258-8446
Eman Elsheikh Department of Child Health, National Research Centre, Dokki, Giza, Egypt https://orcid.org/0000-0001-5991-6476
Alshaimaa Adel ElKhatib Department of Child Health, National Research Centre, Dokki, Giza, Egypt https://orcid.org/0000-0001-7362-7216
Shaimaa Hashem Department of Child Health, National Research Centre, Dokki, Giza, Egypt https://orcid.org/0000-0002-7210-4250
Salwa Refat Elzayat Department of Medical Physiology, National Research Centre, Dokki, Giza, Egypt https://orcid.org/0000-0001-7940-6051
Hiba Sibaii Department of Medical Physiology, National Research Centre, Dokki, Giza, Egypt https://orcid.org/0000-0002-0414-0567
Nevein Fadl Department of Medical Physiology, National Research Centre, Dokki, Giza, Egypt
Thanaa Rabah Department of Community Medicine Research, National Research Centre, Dokki, Giza, Egypt

DOI:

https://doi.org/10.3889/oamjms.2022.9059

Keywords:

EED, Serum markers, Micronutrients, Psychomotor, Cognitive functions

Abstract

BACKGROUND: Cognitive impairment, growth faltering, and stunting are pervasive in many countries. Many times, cause is unknown. Suspecting the role of intestinal inflammation in such cases should be minded, especially in countries with low and middle income.

AIM: The study objective is to assess the impact of malnutrition and macronutrient deficiency that might occur secondary to gut inflammation on cognitive functions in children.

METHODS: We investigated serum markers of inflammation, fecal markers of intestinal inflammation, and serum micronutrients in cases with an age range from 1 to 10 years who suffer from moderate or severe malnutrition “having weight-for-age z-score and height-for-age z-score (WAZ or HAZ) less than −2 SD”. Cognitive abilities were assessed using the Wechsler Intelligence Scale for Preschool and School Children and Bayley Scale III. 55.6% of preschool cases were below average or had mild or moderate intelligence retardation, while 24.5% of school cases and 5% of children below 2 years were below average regarding cognitive functions.

RESULTS: Cases showed a statistically significant reduction of Vitamin D, zinc, and iron as compared to controls. Endo Cab Serum markers of inflammation such as alpha-1-acid glycoprotein (α1-AGP) and endotoxin-core antibody (EndoCAB) and fecal markers of intestinal inflammation such as alpha-1 antitrypsin (α1-AT) and neopterin (NEOP) showed a statistically significant increase in cases than in controls. Schoolchildren showed a negative correlation between processing functions and α1-AGP and a positive correlation between perceptual reasoning and serum Vitamin A. Children below 2 years showed negative correlations between motor function and α1-AT, α1-AGP, tumor necrosis factor-alpha (TNF-α), and Endo Cab and a positive correlation between language and serum zinc.

CONCLUSION: The study showed impaired neurocognitive and psychomotor functions in malnourished stunted children. Furthermore, vitamin and mineral deficiency and increased markers of intestinal inflammation were observed in cases compared to healthy controls indicating the role of intestinal inflammation in psychomotor development and cognitive functions in children with undernutrition.

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References

Elzaree FA, Shehata MA, El Wakeel MA, El-Alameey IR, AbuShady MM, Helal SI. Adaptive functioning and psychosocial problems in children with beta thalassemia major. Open Access Maced J Med Sci. 2018;6(12):2337-41. https://doi.org/10.3889/oamjms.2018.367 PMid:30607187

Agustí A, García-Pardo MP, López-Almela I, Campillo I, Maes M, Romaní-Pérez M, et al. Interplay between the gut-brain axis, obesity and cognitive function. Front Neurosci. 2018;12:155. https://doi.org/10.3389/fnins.2018.00155 PMid:29615850

Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: Interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol. 2015;28(2):203. PMid:25830558

El Wakeel MA, El-Kassas GM, Ahmed GF, Ali WH, Elsheikh EM, El-Zayat SR, et al. Fecal markers of environmental enteric dysfunction and their relation to faltering growth in a sample of Egyptian children. Open Access Maced J Med Sci. 2021;9:1117-22.

Tickell KD, Atlas HE, Walson JL. Environmental enteric dysfunction: A review of potential mechanisms, consequences and management strategies. BMC Med. 2019;17(1):1-9. https://doi.org/10.1186/s12916-019-1417-3

Hadjina IT, Zivkovic PM, Matetic A, Rusic D, Vilovic M, Bajo D, et al. Impaired neurocognitive and psychomotor performance in patients with inflammatory bowel disease. Sci Rep. 2019;9(1):13740. https://doi.org/10.1038/s41598-019-50192-2 PMid:31551482

World Health Organization. Dissemination of WHO Guidelines and Recommendations on Micronutrients: Policy, Practice and Service Delivery Issues (No. SEA-NUT-195). Geneva: World Health Organization; 2015.

Goswami U. Cognitive Development: The Learning Brain. American Psychological Association: Psychology Press; 2008.

Gilbride J. Anthropometric standardization reference manual. J Am Dietetic Assoc. 1989;89(6):872-4.

Wechsler D. Wechsler Intelligence Scale for Children–Fourth Edition (WISC-IV). San Antonio, TX: The Psychological Corporation; 2003.

Wechsler D. WISC-3: Wechsler Intelligence Scale for Children: Manual. San Antonio, TX: Psychological Corporation; 1991.

Bayley N, Reuner G. Bayley Scales of Infant Development. New York: Psychological Corporation; 1969.

Lin A, Arnold BF, Afreen S, Goto R, Huda T, Haque R, et al. Household environmental conditions are associated with enteropathy and impaired growth in rural Bangladesh. Am J Trop Med Hyg. 2013;89(1):130-7. https://doi.org/10.4269/ajtmh.12-0629 PMid:23629931

Guerrant RL, Leite AM, Pinkerton R, Medeiros PH, Cavalcante PA, DeBoer M, et al. Biomarkers of environmental enteropathy, inflammation, stunting, and impaired growth in children in northeast Brazil. PloS One. 2016;11(9):e0158772. https://doi.org/10.1371/journal.pone.0158772 PMid:27690129

Thurstans S, Sessions N, Dolan C, Sadler K, Cichon B, Isanaka S, et al. The relationship between wasting and stunting in young children: A systematic review. Matern Child Nutr. 2022;18(1):e13246. https://doi.org/10.1111/mcn.13246 PMid:34486229

Li N, Yolton K, Lanphear BP, Chen A, Kalkwarf HJ, Braun JM. Impact of early-life weight status on cognitive abilities in children. Obesity (Silver Spring). 2018;26(6):1088-95. https://doi.org/10.1002/oby.22192 PMid:29797555

Kroupina MG, Eckerle JK, Fuglestad AJ, Toemen L, Moberg S, Himes JH, et al. Associations between physical growth and general cognitive functioning in international adoptees from Eastern Europe at 30 months post-arrival. J Neurodev Disord. 2015;7(1):36. https://doi.org/10.1186/s11689-015-9132-7 PMid:26568773

Poh BK, Rojroonwasinkul N, Le Nyugen BK, Budiman B, Ng LO, Soonthorndhada K, et al. Relationship between anthropometric indicators and cognitive performance in Southeast Asian school-aged children. Br J Nutr. 2013;110 Suppl 3: S57-64. https://doi.org/10.1017/S0007114513002079 PMid:24016767

Gu H, Wang L, Liu L, Luo X, Wang J, Hou F, et al. A gradient relationship between low birth weight and IQ: A meta-analysis. Sci Rep. 2017;7(1):18035. https://doi.org/10.1038/s41598-017-18234-9 PMid:29269836

Kirkegaard H, Möller S, Wu C, Häggström J, Olsen SF, Olsen J, et al. Associations of birth size, infancy, and childhood growth with intelligence quotient at 5 years of age: A Danish cohort study. Am J Clin Nutr. 2020;112(1):96-105. https://doi.org/10.1093/ajcn/nqaa051 PMid:32232408

Broekman BF, Chan YH, Chong YS, Quek SC, Fung D, Low YL, et al. The influence of birth size on intelligence in healthy children. Pediatrics. 2009;123(6):e1011-6. https://doi.org/10.1542/peds.2008-3344 PMid:19482733

Rahman A, Al-Taiar A, Shaban L, Al-Sabah R, Al-Harbi A, Mojiminiyi O. Plasma 25-hydroxy vitamin D is not associated with either cognitive function or academic performance in adolescents. Nutrients. 2018;10(9):1197. https://doi.org/10.3390/nu10091197 PMid:30200421

Tofail F, Islam MM, Mahfuz M, Ashraful Alam M, Aktar S, Haque R, et al. Association of vitamin D nutrition with neuro-developmental outcome of infants of slums in Bangladesh. PLoS One. 2019;14(9):e0221805. https://doi.org/10.1371/journal.pone.0221805 PMid:31557172

Aspell N, Lawlor B, O’Sullivan M. Is there a role for vitamin D in supporting cognitive function as we age? Proc Nutr Soc. 2018;77(2):124-34. https://doi.org/10.1017/S0029665117004153 PMid:29233204

Olson CR, Mello CV. Significance of vitamin A to brain function, behavior and learning. Mol Nutr Food Res. 2010;54(4):489-95. https://doi.org/10.1002/mnfr.200900246 PMid:20077419

Annelies V, Harry R, Ines W, Annelies B, Tess DB, Nina H. Evaluation of biomarkers of oxidative stress in attention-deficit/hyperactivity disorder (ADHD). J Mol Biomark Diagn. 2018;9(390):10-4172.

Huang X, Zhang H, Zhen J, Dong S, Guo Y, Van Halm- Lutterodt N, et al. Diminished circulating retinol and elevated α-TOH/retinol ratio predict an increased risk of cognitive decline in aging Chinese adults, especially in subjects with ApoE2 or ApoE4 genotype. Aging (Albany NY). 2018;10(12):4066-83. https://doi.org/10.18632/aging.101694 PMid:30573705

El-Meshad G, Abd El-Nabi S, Moharam N, Abou El-Khair M. The plasma zinc/serum copper ratio as a biomarker in dwith autism spectrum disorders. Menoufia Med J. 2017;30(3):727.

Russo AJ, Bazin AP, Bigega R, Carlson RS 3rd, Cole MG, Contreras DC, et al. Plasma copper and zinc concentration in individuals with autism correlate with selected symptom severity. Nutr Metab Insights. 2012;5:41-7. https://doi.org/10.4137/NMI.S8761 PMid:23882147

Brion LP, Heyne R, Lair CS. Role of zinc in neonatal growth and brain growth: Review and scoping review. Pediatr Res. 2021;89:1627-40. https://doi.org/10.1038/s41390-020-01181-z PMid:33010794

Hochepied T, Berger FG, Baumann H, Libert C. α1-Acid glycoprotein: An acute phase protein with inflammatory and immunomodulating properties. Cytokine Growth Factor Rev. 2003;14(1):25-34. https://doi.org/10.1016/s1359-6101(02)00054-0 PMid:12485617

Mancuso E, Spiga R, Rubino M, Averta C, Rotundo S, Segura- Garcìa C, et al. Effects of alpha-2-HS-glycoprotein on cognitive and emotional assessment in prediabetic and diabetic subjects. J Affect Disord. 2021;282:700-6. https://doi.org/10.1016/j.jad.2020.12.135 PMid:33445096

Brown G. Exploring the Relationship between Intestinal Permeability and Growth in Children Under 2 Years of Age in Rural Nicaragua (Master’s Thesis, Graduate Studies); 2017

Zareen Z, Strickland T, Eneaney VM, Kelly LA, McDonald D, Sweetman D, et al. Cytokine dysregulation persists in childhood post Neonatal Encephalopathy. BMC Neurol. 2020;20(1):115. https://doi.org/10.1186/s12883-020-01656-w PMid:32228505

Hori H, Kim Y. Inflammation and post-traumatic stress disorder. Psychiatry Clin Neurosci. 2019;73(4):143-53. https://doi.org/10.1111/pcn.12820 PMid:30653780

Quinones MM, Gallegos AM, Lin FV, Heffner K. Dysregulation of inflammation, neurobiology, and cognitive function in PTSD: An integrative review. Cogn Affect Behav Neurosci. 2020;20(3):455-80. https://doi.org/10.3758/s13415-020-00782-9 PMid:32170605

Oriá RB, Murray-Kolb LE, Scharf RJ, Pendergast LL, Lang DR, Kolling GL, et al. Early-life enteric infections: Relation between chronic systemic inflammation and poor cognition in children. Nutr Rev. 2016;74(6):374-86. https://doi.org/10.1093/nutrit/nuw008 PMid:27142301

Thomas DW, Sinatra FR, Merritt RJ. Random fecal alpha- 1-antitrypsin concentration in children with gastrointestinal disease. Gastroenterology. 1981;80(4):776-82. PMid:6970702

Kosek M, Haque R, Lima A, Babji S, Shrestha S, Qureshi S, et al. Fecal markers of intestinal inflammation and permeability associated with the subsequent acquisition of linear growth deficits in infants. Am J Trop Med Hyg. 2013;88(2):390-6. https://doi.org/10.4269/ajtmh.2012.12-0549 PMid:23185075

Levitt DG, Levitt MD. Protein losing enteropathy: Comprehensive review of the mechanistic association with clinical and subclinical disease states. Clin Exp Gastroenterol. 2017;10:147-68. https://doi.org/10.2147/CEG.S136803 PMid:28761367

Pearl GS, Mullins RE. α1-Antitrypsin in cerebrospinal fluid of patients with neurologic diseases. Arch Neurol. 1985;42(8):775-7.