Neuropsychic development and autism: Potential effect of casomorphins derived from goat milk

The concept of autism has evolved from being viewed as psychopathological symptom to being recognized as a separate spectrum of neurodevelopmental disorders. One of the potential mechanisms discussed is blood–brain barrier (BBB) dysfunction: an increase in its permeability can promote peripheral cytokine and immune cell trafficking into the central nervous system (CNS), amplifying neuroinflammation and vulnerability of neural networks. In cascade models of autism spectrum disorders (ASD), these changes are attributed to intestinal dysbiosis, increased permeability of epithelial barriers and systemic effects of dietary opioid-like peptides, including β-casomorphin-7. The aim of this review is to summarize 2020–2025 data on the possible impact of casomorphins formed from proteolytic digestion of β-casein in goat milk (including β-casomorphin-7) on neuropsychic development and ASD manifestations. The search was performed in PubMed databases using key terms related to ASD, the gut – brain axis, β-casein A1, β-casomorphin-7, goat milk, microbiome and barrier function; experimental, clinical and survey studies were included. The literature data suggest the biologically plausible mechanisms underlying the associations between dietary opioid peptides and CNS functions via the gut – brain axis, including modulation of the microbiome, inflammatory responses and the gut barrier function. However, clinical evidence for the specific effects of goat milk-associated casomorphins on ASD remains limited and inconsistent.

1. Evans B. How autism became autism: The radical transformation of a central concept of child development in Britain. Hist Human Sci. 2013;26(3):3–31. https://doi.org/10.1177/0952695113484320.

2. Шипицына ЛМ (ред.). Детский аутизм. СПб.: Международный университет семьи и ребенка им. Р. Валленберга; 1997. 254 с.

3. Vivanti G, Nuske HJ. Autism, attachment, and social learning: Three challenges and a way forward. Behav Brain Res. 2017;325(Pt. B):251–259. https://doi.org/10.1016/j.bbr.2016.10.025.

4. Maltinskaya NA. History of exercise about autism. Koncept. 2017;(11):53–61. (In Russ.) Available at: https://e-koncept.ru/2017/470137.htm?ysclid=mkckc71dgc603162169.

5. Iovchuk NM, Severniy AA. On the Book by Kagan V.E. “Autism in Children”. 2nd edition, supplemented. Autism and Developmental Disorders. 2019;17(4):57–61. (In Russ.) https://doi.org/10.17759/autdd.2019170408.

6. Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet. 2014;383(9920):896–910. https://doi.org/10.1016/S0140-6736(13)61539-1.

7. Shaw KA, Williams S, Patrick ME, Valencia-Prado M, Durkin MS, Howerton EM et al. Prevalence and Early Identification of Autism Spectrum Disorder Among Children Aged 4 and 8 Years – Autism and Developmental Disabilities Monitoring Network, 16 Sites, United States, 2022. MMWR Surveill Summ. 2025;74(2):1–22. http://doi.org/10.15585/mmwr.ss7402a1.

8. Eyal G. The Autism Matrix: The Social Origins of the Autism Epidemic. Br J Sociol. 2011;62(4):60–65. Available at: https://www.gla.ac.uk/media/Media_230789_smxx.pdf.

9. Rosen NE, Lord C, Volkmar FR. The Diagnosis of Autism: From Kanner to DSM-III to DSM-5 and Beyond. J Autism Dev Disord. 2021;51(12):4253–4270. http://doi.org/10.1007/s10803-021-04904-1.

10. Баландина ОВ, Бондарь ЕА, Власов ВВ, Григоренко ЕЛ, Кузнецова ЮЕ, Кузюкова АА и др. Расстройство аутистического спектра: клиничeскиe рeкомeндации. 2024. Режим доступа: https://cr.minzdrav.gov.ru/view-cr/594_3.

11. Al-Beltagi M. Autism medical comorbidities. World J Clin Pediatr. 2021;10(3):15–28. https://doi.org/10.5409/wjcp.v10.i3.15.

12. Leisman G, Melillo R. Autism Spectrum Disorder: What Do We Know and Where Do We Go? Brain Sciences. 2025;15(9):1010. https://doi.org/10.3390/brainsci15091010.

13. Grove J, Ripke S, Als TD, Mattheisen M, Walters RK, Won H et al. Identification of common genetic risk variants for autism spectrum disorder. Nat Genet. 2019;51(3):431–444. https://doi.org/10.1038/s41588-019-0344-8.

14. De Rubeis S, Buxbaum JD. Genetics and genomics of autism spectrum disorder: embracing complexity. Hum Mol Genet. 2015;24(R1):R24–R31. https://doi.org/10.1093/hmg/ddv273.

15. Chaste P, Leboyer M. Autism risk factors: genes, environment, and geneenvironment interactions. Dialogues Clin Neurosci. 2012;14(3):281–292. https://doi.org/10.31887/DCNS.2012.14.3/pchaste.

16. Yenkoyan K, Mkhitaryan M, Bjørklund G. Environmental Risk Factors in Autism Spectrum Disorder: A Narrative Review. Curr Med Chem. 2024;31(17):2345–2360. https://doi.org/10.2174/0109298673252471231121045529.

17. Schwarzenberg SJ, Georgieff MK; COMMITTEE ON NUTRITION. Advocacy for Improving Nutrition in the First 1000 Days to Support Childhood Development and Adult Health. Pediatrics. 2018;141(2):e20173716. https://doi.org/10.1542/peds.2017-3716.

18. Gilmore JH, Knickmeyer RC, Gao W. Imaging structural and functional brain development in early childhood. Nat Rev Neurosci. 2018;19(3):123–137. https://doi.org/10.1038/nrn.2018.1.

19. Bhardwaj RD, Curtis MA, Spalding KL, Buchholz BA, Fink D, Björk-Eriksson T et al. Neocortical neurogenesis in humans is restricted to development. Proc Natl Acad Sci USA. 2006;103(33):12564–12568. https://doi.org/10.1073/pnas.0605177103.

20. Nascimento MA, Biagiotti S, Herranz-Pérez V, Santiago S, Bueno R, Ye CJ et al. Protracted neuronal recruitment in the temporal lobes of young children. Nature. 2024;626(8001):1056–1065. https://doi.org/10.1038/s41586-023-06981-x.

21. Gilmore JH, Shi F, Woolson SL, Knickmeyer RC, Short SJ, Lin W et al. Longitudinal development of cortical and subcortical gray matter from birth to 2 years. Cereb Cortex. 2012;22(11):2478–2485. https://doi.org/10.1093/cercor/bhr327.

22. Zhao T, Xu Y, He Y. Graph theoretical modeling of baby brain networks. Neuroimage. 2019;185:711–727. https://doi.org/10.1016/j.neuroimage.2018.06.038.

23. Salinas RD, Connolly DR, Song H. Invited Review: Epigenetics in neurodevelopment. Neuropathol Appl Neurobiol. 2020;46(1):6–27. https://doi.org/10.1111/nan.12608.

24. Suleiman KY, Akorede GJ, Afisu B, Onimajesin AO, Saadudeen A, Lawal MO. The epigenetic influence of diet-induced gut microbiome changes in precision nutrition – a systematic review. Gastroenterol Hepatol Bed Bench. 2025;18(3):270–285. https://doi.org/10.22037/ghfbb.v18i3.3136.

25. Yuan C, He Y, Xie K, Feng L, Gao S, Cai L. Review of microbiota gut brain axis and innate immunity in inflammatory and infective diseases. Front Cell Infect Microbiol. 2023;13:1282431. https://doi.org/10.3389/fcimb.2023.1282431.

26. Beopoulos A, Gea M, Fasano A, Iris F. Autonomic Nervous System Neuroanatomical Alterations Could Provoke and Maintain Gastrointestinal Dysbiosis in Autism Spectrum Disorder (ASD): A Novel Microbiome-Host Interaction Mechanistic Hypothesis. Nutrients. 2021;14(1):65. https://doi.org/10.3390/nu14010065.

27. Müller L, Di Benedetto S. Bridging the brain and gut: neuroimmune mechanisms of neuroinflammation and therapeutic insights. Front Cell Neurosci. 2025;19:1590002. https://doi.org/10.3389/fncel.2025.1590002.

28. Biagioli V, Matera M, Cavecchia I, Di Pierro F, Zerbinati N, Striano P. Gut Microbiota and Autism: Unlocking Connections. Nutrients. 2025;17(23):3706. https://doi.org/10.3390/nu17233706.

29. Ullah H, Arbab S, Tian Y, Chen Y, Liu CQ, Li Q, Li K. Crosstalk between gut microbiota and host immune system and its response to traumatic injury. Front Immunol. 2024;15:1413485. https://doi.org/10.3389/fimmu.2024.1413485.

30. Fang Z, Zhou Y, Chen K, Wang J, Liu X, Jia P. Gut microbiota and autism spectrum disorder: advances in dietary intervention strategies based on the microbiota-gut-brain axis mechanism. Front Neurosci. 2025;19:1587818. https://doi.org/10.3389/fnins.2025.1587818.

31. Lewandowska-Pietruszka Z, Figlerowicz M, Mazur-Melewska K. Microbiota in Autism Spectrum Disorder: A Systematic Review. Int J Mol Sci. 2023;24(23):16660. https://doi.org/10.3390/ijms242316660.

32. Volpedo G, Riva A, Nobili L, Zara F, Ravizza T, Striano P. Gut-immune-brain interactions during neurodevelopment: from a brain-centric to a multisystem perspective. BMC Med. 2025;23(1):263. https://doi.org/10.1186/s12916-025-04093-z.

33. Hughes HK, Moreno RJ, Ashwood P. Innate immune dysfunction and neuroinflammation in autism spectrum disorder (ASD). Brain Behav Immun. 2023;108:245–254. https://doi.org/10.1016/j.bbi.2022.12.001.

34. Bryn V, Aass HC, Skjeldal OH, Isaksen J, Saugstad OD, Ormstad H. Cytokine Profile in Autism Spectrum Disorders in Children. J Mol Neurosci. 2017;61(1):1–7. https://doi.org/10.1007/s12031-016-0847-z.

35. Ninkov A, Frank JR, Maggio LA. Bibliometrics: Methods for studying academic publishing. Perspect Med Educ. 2022;11(3):173–176. https://doi.org/10.1007/s40037-021-00695-4.

36. Benarroch E. What Is the Role of Cytokines in Synaptic Transmission? Neurology. 2024;103(8):e209928. https://doi.org/10.1212/WNL.0000000000209928.

37. Lampiasi N, Bonaventura R, Deidda I, Zito F, Russo R. Inflammation and the Potential Implication of Macrophage-Microglia Polarization in Human ASD: An Overview. Int J Mol Sci. 2023;24(3):2703. https://doi.org/10.3390/ijms24032703.

38. Candelario-Jalil E, Dijkhuizen RM, Magnus T. Neuroinflammation, Stroke, Blood-Brain Barrier Dysfunction, and Imaging Modalities. Stroke. 2022;53(5):1473–1486. https://doi.org/10.1161/STROKEAHA.122.036946.

39. Berthier N. Cascading Pathways in Autism: A New Clinical Lens on Early Diagnosis and Pediatric Intervention. Open J Ped. 2025;15:1048–1063. https://doi.org/10.4236/ojped.2025.156099.

40. Bragg MG, Rando J, Carroll KN, Eick SM, Karagas MR, Lin PI et al. The Association of Prenatal Dietary Factors with Child Autism Diagnosis and Autism-Related Traits Using a Mixtures Approach: Results from the Environmental Influences on Child Health Outcomes Cohort. J Nutr. 2025;155(6):1938–1951. https://doi.org/10.1016/j.tjnut.2025.02.025.

41. Schmidt RJ, Iosif AM, Guerrero Angel E, Ozonoff S. Association of Maternal Prenatal Vitamin Use With Risk for Autism Spectrum Disorder Recurrence in Young Siblings. JAMA Psychiatry. 2019;76(4):391–398. https://doi.org/10.1001/jamapsychiatry.2018.3901.

42. Barón-Mendoza I, González-Arenas A. Relationship between the effect of polyunsaturated fatty acids (PUFAs) on brain plasticity and the improvement on cognition and behavior in individuals with autism spectrum disorder. Nutr Neurosci. 2022;25(2):387–410. https://doi.org/10.1080/1028415X.2020.1755793.

43. Doaei S, Bourbour F, Teymoori Z, Jafari F, Kalantari N, Abbas Torki S et al. The effect of omega-3 fatty acids supplementation on social and behavioral disorders of children with autism: a randomized clinical trial. Pediatr Endocrinol Diabetes Metab. 2021;27(1):12–18. https://doi.org/10.5114/pedm.2020.101806.

44. Wang Z, Ding R, Wang J. The Association between Vitamin D Status and Autism Spectrum Disorder (ASD): A Systematic Review and Meta-Analysis. Nutrients. 2020;13(1):86. https://doi.org/10.3390/nu13010086.

45. Song L, Luo X, Jiang Q, Chen Z, Zhou L, Wang D, Chen A. Vitamin D Supplementation is Beneficial for Children with Autism Spectrum Disorder: A Meta-analysis. Clin Psychopharmacol Neurosci. 2020;18(2):203–213. https://doi.org/10.9758/cpn.2020.18.2.203.

46. Henschen A, Lottspeich F, Brantl V, Teschemacher H. Novel opioid peptides derived from casein (beta-casomorphins). II. Structure of active components from bovine casein peptone. Hoppe Seylers Z Physiol Chem. 1979;360(9):1217–1224. Available at: https://pubmed.ncbi.nlm.nih.gov/511111/.

47. Pal S, Woodford K, Kukuljan S, Ho S. Milk Intolerance, Beta-Casein and Lactose. Nutrients. 2015;7(9):7285–7297. https://doi.org/10.3390/nu7095339.

48. Jinsmaa Y, Yoshikawa M. Enzymatic release of neocasomorphin and betacasomorphin from bovine beta-casein. Peptides. 1999;20(8):957–962. https://doi.org/10.1016/s0196-9781(99)00088-1.

49. Bolat E, Eker F, Yılmaz S, Karav S, Oz E, Brennan C et al. BCM-7: Opioid-like Peptide with Potential Role in Disease Mechanisms. Molecules. 2024;29(9):2161. https://doi.org/10.3390/molecules29092161.

50. Deth R, Clarke A, Ni J, Trivedi M. Clinical evaluation of glutathione concentrations after consumption of milk containing different subtypes of β-casein: results from a randomized, cross-over clinical trial. Nutr J. 2016;15(1):82. https://doi.org/10.1186/s12937-016-0201-x.

51. Farrell HM Jr, Jimenez-Flores R, Bleck GT, Brown EM, Butler JE, Creamer LK et al. Nomenclature of the proteins of cows’ milk – sixth revision. J Dairy Sci. 2004;87(6):1641–1674. https://doi.org/10.3168/jds.S0022-0302(04)73319-6.

52. Woodford KB. Devil in the Milk; Chelsea Green: White River Junction. VT, USA; 2009. Available at: http://www.r-5.org/files/books/ethology/inequality/v-style/deep-nutrition/Keith_Woodford-Devil_in_the_Milk-EN.pdf.

53. Jeong H, Park YS, Yoon SS. A2 milk consumption and its health benefits: an update. Food Sci Biotechnol. 2023;33(3):491–503. https://doi.org/10.1007/s10068-023-01428-5.

54. Ashwood P, Anthony A, Torrente F, Wakefield AJ. Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10. J Clin Immunol. 2004;24(6):664–673. https://doi.org/10.1007/s10875-004-6241-6.

55. Sokolov O, Kost N, Andreeva O, Korneeva E, Meshavkin V, Tarakanova Y et al. Autistic children display elevated urine levels of bovine casomorphin-7 immunoreactivity. Peptides. 2014;56:68–71. https://doi.org/10.1016/j.peptides.2014.03.007.

56. Duarte-Vázquez MÁ, García-Ugalde C, Villegas-Gutiérrez LM, García-Almendárez BE, Rosado JL. Production of Cow’s Milk Free from Beta-Casein A1 and Its Application in the Manufacturing of Specialized Foods for Early Infant Nutrition. Foods. 2017;6(7):50. https://doi.org/10.3390/foods6070050.

57. ALKaisy QH, Al-Saadi JS, Al-Rikabi AKJ, Altemimi AB, Hesarinejad MA, Abedelmaksoud TG. Exploring the health benefits and functional properties of goat milk proteins. Food Sci Nutr. 2023;11(10):5641–5656. https://doi.org/10.1002/fsn3.3531.

58. Ul Haq MR, Kapila R, Kapila S. Release of β-casomorphin-7/5 during simulated gastrointestinal digestion of milk β-casein variants from Indian crossbred cattle (Karan Fries). Food Chem. 2015;168:70–79. https://doi.org/10.1016/j.foodchem.2014.07.024.