Published September 1, 2025
| Version v3
Preprint
Open
Cascading Pathways in Autism: A New Clinical Lens on Early Pediatric Intervention
Description
Version 3 Update (September 2025):
This version includes refined language and clarity improvements using Paperpal. No changes were made to figures, data, or core content. The manuscript remains a preprint and has not yet undergone peer review.
This preprint presents the Cascading Pathways in Autism hypothesis, offering a new clinical framework for understanding early neurodevelopmental trajectories and their implications for pediatric intervention. Drawing on recent findings in neuroinflammation, gut–brain axis research, and early-life environmental exposures, the manuscript synthesizes evidence from neuroscience, immunology, and clinical practice to propose an integrated model of autism onset and progression.
The work emphasizes the importance of early detection and intervention strategies, with a focus on modifiable biological and environmental factors. This version has been deposited on Zenodo prior to submission to Pediatrics (AAP) in accordance with the journal’s preprint policy.
Files
Diagram PNG.png
Files
(4.8 MB)
| Name | Size | Download all |
|---|---|---|
|
md5:2eafc633e47f794f389fb6075315f346
|
38.1 kB | Download |
|
md5:177c82aa669345ee09c5685c009d24a1
|
4.8 MB | Preview Download |
Additional details
Dates
- Updated
-
2025-09-01Version 3 release date (language edits only)
References
- 1. Bolat R, Mach N, Vasic V, et al. BCM 7: Opioid like peptide with potential role in disease mechanisms. Molecules. 2024;29(9):2161. doi:10.3390/molecules29092161 2. Brownell JN, Bokulich NA, Parmar A, et al. Exclusive formula feeding is associated with greater gut permeability compared to breastfeeding. J Pediatr Gastroenterol Nutr. 2020;71(2):238 245. 3. Cano ACS, Santos D, Beltrão Braga PCB. The interplay of astrocytes and neurons in autism spectrum disorder. In: Advances in Neurobiology. Vol 39. Springer; 2024:269 284. doi:10.1007/978-3-031-64839-7_11 4. Çatlı NE, Özyurt G. The relationship between autism spectrum disorders and vaccination: Review of current literature. Trends Pediatr. 2025;6(2):76 81. doi:10.59213/TP.2025.222 5. Children's Hospital of Philadelphia Vaccine Education Center. Vaccines and the Blood–Brain Barrier. Philadelphia, PA: Children's Hospital of Philadelphia; 2024. 6. Clemente JC, Ursell LK, Parfrey LW, Knight R. The impact of gut microbiota on human health: An integrative view. Cell. 2012;148(6):1258 1271. 7. Dogra S, Sakwinska O, Soh SE, et al. Dynamics of the gut microbiome in early life: Longitudinal associations with breastfeeding and formula feeding. Microbiome. 2015; 3:3. 8. European Food Safety Authority (EFSA). Review of the potential health impact of β casomorphins and related peptides. EFSA Sci Rep. 2009; 231:1 107. doi: 10.2903/j.efsa.2009.231r 9. Fiorentino M, Camhi SM, Cascella N, et al. Changes in blood–brain barrier and intestinal permeability in people with autism. Neuroscience News. January 21, 2017. Accessed August 29, 2025. https://neurosciencenews.com/autism-blood-brain-barrier-5979/ 10. Fiorentino M, Sapone A, Senger S, et al. Blood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders. Mol Autism. 2016; 7:49. doi:10.1186/s13229-016-0110-z 11. Fortunato G, Proietti I, Tanassi J, et al. Elevated serum β casomorphin 7 levels in children with autism spectrum disorder. J Pediatr Gastroenterol Nutr. 2021;72(3): e86 e90. doi:10.1097/MPG.0000000000003074 12. Grimaldi R, Gibson GR, Vulevic J, et al. Oligofructose and Bifidobacterium improve intestinal barrier integrity in infants: A randomized crossover study. J Pediatr Gastroenterol Nutr. 2021;72(6): e89 e95. 13. Jarmołowska B, Bukało M, Fiedorowicz E, et al. Role of milk derived opioid peptides and proline dipeptidyl peptidase 4 in autism spectrum disorders. Nutrients. 2019;11(1):87. doi:10.3390/nu11010087 14. Kwon HJ, Park JH, Lee JY, et al. Aluminum adjuvants disrupt blood–brain barrier integrity and induce microglial activation in neonatal mice. J Neuroinflammation. 2023; 20:85. doi:10.1186/s12974-023-02845-0 15. Mawson AR, Jacob B. Vaccination and neurodevelopmental disorders: A study of nine year old children enrolled in Medicaid. Sci Public Health Policy Law. 2025; 6:55 61. 16. Nguyen TL, Vieira Silva S, Liston A, Raes J. Skin to skin contact promotes microbial colonization: A metagenomic analysis. PLoS One. 2021;16(5): e0251299. 17. Petrelli F, Pucci L, Bezzi P. Astrocytes, microglia and their potential link with autism spectrum disorders. Front Cell Neurosci. 2016; 10:21. doi:10.3389/fncel.2016.00021 18. Smith M, Wood L, Nichols M. Claudin and occludin expression in the blood–brain barrier: Role of probiotics. Brain Res. 2019; 1721:146312. 19. Stewart CJ, Ajami NJ, O'Brien JL, et al. Temporal development of the gut microbiome in early childhood from the TEDDY study. Cell. 2018;173(4):963 974.e13. 20. Van den Elsen LWJ, Vivanco Calvo F, Nylund G, et al. Impact of early life antibiotics on the gut microbiota and behavioral outcomes in rodents. Gut Microbes. 2020;11(5):1184 1194. 21. Vasconcelos ML, Oliveira LMFS, Hill JP, Vidal AMC. Difficulties in establishing the adverse effects of β casomorphin 7 released from β casein variants: A review. Foods. 2023;12(17):3151. doi:10.3390/foods12173151 22. Zhao Y, Huang Y, Cao Y, Yang J. Astrocyte mediated neuroinflammation in neurological conditions. Biomolecules. 2024;14(10):1204. doi:10.3390/biom14101204 23. Zhu L, Baker RD, Baker SS. Opioid peptides influence intestinal motility and permeability in adults: Implications for infants. J Pediatr Gastroenterol Nutr. 2018;66(3):477 484.