Early-life gastrointestinal inflammation and the developing brain: Unravelling the pathways to long-term cognitive dysfunction

Table 1 Co-development in of gut microbiome, immune system and brain and cognitive functions in early life (the critical window)

Time frame	Gut microbiome development	Immune system development	Brain/cognitive development
Prenatal (in utero)	Microbiome density increases rapidly leading up to birth	Immature: Components are developing but not fully functional	Foundation laid: Neurulation, neural proliferation, neuronal migration, and initial axon growth are active
Birth – 3 months	Rapid colonization: Window of opportunity for microbial assembly. Diversity is fluctuating	Education/expansion: Immune system begins learning to repel new bacterial strains. IgG/IgM are developing	High activity: Synapse formation (synaptogenesis) is highly active. Myelination begins
Birth – 2 years	Assembling/fluctuating: Gut microbiota is actively assembling. Microbial density is high but composition is unstable	Developing: Natural killer cells are above adult levels. Key immunoglobulin levels (IgG, IgA) are developing but not yet mature. T cell independent antibody response is immature	Peak proliferation (first 1000 days): Synapses intensely proliferate. Brain metabolism increases. Sensory pathways (vision, hearing) peak, and language develops rapidly
Year 2-3	Stabilization phase: Composition begins to settle toward an adult-like state	Transition: Continues developing toward adult levels, including Th1 mediated immunity	Pruning begins: Synapses are pruned (eliminated). Metabolism decreases, and higher cognitive function development approaches its peak

It effectively highlights the synchronization of these three major biological systems during the first 1000 days of life, illustrating why early-life gastrointestinal inflammation is such a significant neurodevelopmental risk factor. Ig: Immunoglobulin.

Table 2 Strengths and limitations of animal models

Strengths	Limitations
Allow direct control of diet, microbes, and inflammatory triggers	Rodent neurodevelopmental timelines differ from humans
Enable mechanistic dissection of the gut-immune-brain axis	Necrotizing enterocolitis and colitis models do not perfectly replicate human disease complexity
Permit invasive measurements: Cytokine profiling, neural imaging, electrophysiology	Microbiome composition differs significantly between species
Facilitate genetic manipulation (e.g., knockout mice)	Behavioral tests may not fully translate to human cognition or socio-emotional behavior
Allow testing of causal relationships via fecal microbiota transplantation, antibiotics, germ-free models	Artificial induction of inflammation may exaggerate severity relative to human infants

Table 3 Summary of findings: Preterm Infants and necrotizing enterocolitis survivors

Ref.	Study type/follow-up age	Primary finding on NDI	Key associated deficits/brain pathology
Wang et al[133], 2024	Systematic review and meta-analysis (corrected age > 12 months)	Significant association between NEC and increased odds of NDI (adjusted odds ratio: 1.89).	Increased risk of severe brain injury: IVH and PVL. Severity matters: Surgical NEC carries a higher NDI risk than medical NEC
Matei et al[132], 2020	Systematic review and meta-analysis (n = 2403 NEC infants)	High NDI incidence: 40% (median interquartile range 28%-64%). Severity correlates: NDI incidence is higher in surgical NEC (43%) vs medical NEC (27%)	Most common NDI: Cerebral palsy (18%). NEC is associated with increased incidence of IVH and PVL compared to preterm controls
Mondal et al[134], 2021	Retrospective cohort (average follow-up: 11.2 years)	High burden: 61% of survivors had neurological impairment	Cognitive impairment was the most common deficit (56%), followed by motor (33%). High rates of special education needs and learning difficulties
Roze et al[136], 2011	Case-control cohort (mean age 9 years)	Borderline or abnormal functional scores: Mean total intelligence quotient was lower (86 vs 97 in controls)	Specific deficits in attention and visual perception. Children requiring surgery were at the highest risk for adverse outcomes
Shin et al[137], 2021	Retrospective cohort (preterm infants with surgical NEC vs SIP)	NEC group had more prevalent abnormal findings at 36 months in motor (gross and fine), cognitive, and social domains compared to SIP survivors	Slower head growth in surgical NEC group compared to SIP group
Arnold et al[135], 2010	Retrospective cohort (long-term follow-up: 39 months)	49% of long-term survivors had significant neurodevelopmental delay	The 20% had severe neurological deficits, including auditory and visual impairment. Highlights the ongoing morbidity risk
Hansen et al[138], 2019	Historic cohort study (school age)	Increased rates of abnormal behavioral scores and cerebral palsy observed, but differences were statistically insignificant after adjustment for confounders	Provides a counterpoint to the consensus, suggesting the long-term effects on behavioral and NDI scores may be moderate and of limited clinical importance

It summarizes the clinical evidence from systematic reviews and longitudinal cohort studies quantifying the enduring neurodevelopmental burden in survivors of necrotizing enterocolitis (NEC). The findings consistently demonstrate that NEC, particularly severe (surgically managed) NEC, significantly increases the risk for long-term neurodevelopmental impairment, cognitive deficits, and major structural brain lesions (intraventricular hemorrhage, periventricular leukomalacia), indicating that severe gut inflammation in the neonatal period critically compromises central nervous system development. IVH: Intraventricular hemorrhage; NDI: Neurodevelopmental impairment; NEC: Necrotizing enterocolitis; PVL: Periventricular leukomalacia; SIP: Spontaneous intestinal perforation.

Table 4 The longitudinal human cohort studies linking the burden of early childhood enteric infections to long-term cognitive and neurodevelopmental deficits

Ref.	Population/cohort	Exposure	Key findings on learning, memory, and intelligence quotient
Niehaus et al[141], 2002 and Pinkerton et al[142], 2016	Cohort of children from a Brazilian shantytown (followed to 5.6-12.7 years)	ECD in the first 2 years of life	ECD is a significant inverse predictor of later childhood cognitive function (lower test of nonverbal intelligence and Wechsler Intelligence Scale for Children-Third Edition Coding scores). This effect was independent of malnutrition (stunting/wasting) and maternal education
MAL-ED Network Investigators[139], 2014	Multi-site longitudinal birth cohort	Enteropathogen infection causing intestinal inflammation	Established the core study hypothesis: Enteropathogen infection leads to intestinal inflammation, which causes growth faltering and deficits in cognitive development
MAL-ED Network Investigators[140], 2018	Longitudinal birth cohort in 6 low/middle-income countries (birth to 24 months)	Higher rates of enteropathogen detection and days with illness	Negatively associated with lower cognitive scores at 24 months. Higher illness rates were linked to lower hemoglobin concentrations, which in turn predicted lower cognitive scores
Upadhyay et al[143], 2021	low birth weight infants (North India)	Increased number of diarrheal episodes in the first year	Negatively influenced composite scores in all three domains assessed: Cognitive, motor, and language at 12 months. Linear growth and diarrheal prevention are crucial factors
El Wakeel et al[144], 2022	Malnourished, stunted children (Egypt, age 1-10 years)	Intestinal inflammation (high fecal markers) and micronutrient deficiency (zinc, iron, vitamin D)	Showed impaired neurocognitive and psychomotor functions. Cognitive performance was negatively correlated with both fecal and serum inflammatory markers
Streit et al[145], 2021	Children (n = 380, age 45 months)	Fecal microbiome profile (relative abundance of specific taxa)	Microbiome profile was significantly associated with cognitive functioning (Wechsler Preschool and Primary Scale of Intelligence-Third Edition scores). Found a strong inverse correlation between cognitive scores and a genus related to Enterobacter asburiae

It aggregates evidence from large-scale human cohort studies (like MAL-ED) that track the long-term relationship between early childhood gut health (measured by diarrheal frequency, pathogen detection, and intestinal inflammation markers) and neurodevelopmental outcomes in later childhood (measured by intelligence quotient, cognitive, motor, and language scores). Findings highlight that the negative impact of early enteric disease on cognitive function is often independent of malnutrition, suggesting a direct gut-brain axis mechanism. ECD: Early childhood diarrhea.

Table 5 Summary of studies: Celiac disease and cognitive/neurological outcomes

Ref.	Study type/population	Key cognitive/symptomatic findings	Key structural/mechanistic findings	Effect of GFD
Edwards George et al[148], 2022	Nationwide online survey (CD and NCGS patients)	89% of CD and 95% of NCGS reported GINI (brain fog). Most common symptoms: Difficulty concentrating, forgetfulness, and grogginess	High prevalence suggests GINI is a genuine and common symptom complex	N/A (focus on symptoms after exposure)
Croall et al[149], 2020	United Kingdom biobank (population-based cohort)	Significant deficits in reaction time. Increased rates of self-reported anxiety and depression	Widespread white matter changes (increased axial diffusivity) observed via diffusion tensor imaging	N/A (cross-sectional comparison)
Croall et al[153], 2020	Pilot study (newly diagnosed vs established CD vs controls)	Underperformed relative to controls in visual and verbal memory (established at diagnosis)	Dysfunction appears established at the point of diagnosis	Cognitive deficit stabilizes but does not necessarily fully reverse, implying a benefit against further decline
Lichtwark et al[152], 2014	Longitudinal pilot study (newly diagnosed CD, 12-month follow-up)	Cognitive tests (verbal fluency, attention, motoric function) showed significant improvement over 12 months	Cognitive improvement strongly correlated with mucosal healing (Marsh score) and decreased tissue transglutaminase antibodies	Improved cognitive performance in parallel with resolution of intestinal inflammation
Casella et al[150], 2012	Case-control study (elderly CD patients on GFD vs controls)	Worse cognitive performance in CD patients despite long-term GFD, including lower scores on Mini Mental Test Examination, Semantic Fluency, and Digit Symbol Test	Emphasizes the risk of irreversible effects from diagnostic delay and prolonged gluten exposure	Suggests long-term GFD may not fully restore function if diagnosis is late
Hu et al[154], 2006	Case series (patients with cognitive decline associated with CD)	Presentation included amnesia, acalculia, and confusion. Average impairment was in the moderately impaired range. Ataxia common (10/13 patients)	Frequent deficiencies in folate, vitamin B12, or vitamin E. Brain magnetic resonance imaging often showed non-specific white matter hyperintensities	Three patients improved or stabilized cognitively with gluten withdrawal
Lanza et al[146], 2018 and Pennisi et al[147], 2017	Review of neurophysiological studies (TMS, electroencephalography)	Adult CD patients often report “brain fog” to overt dementia	Evidence suggests a profile of “hyperexcitable celiac brain” (measured by TMS) which is a feature also reported in degenerative/vascular dementia	Hyperexcitability partially reverts back after long-term gluten restriction
Lebwohl et al[155], 2016	Population-based cohort study (age $\geq$ 50 years)	No increased overall risk for dementia in CD patients over the long term	Subgroup analysis showed a non-significant trend for increased risk of vascular dementia (hazard ratio = 1.28) but not Alzheimer’s	N/A (population risk analysis)
Beas et al[151], 2024	Systematic review and meta-analysis	Confirmed a significant association between CD and insomnia. Provided valuable insight into studies on cognitive impairment	N/A (meta-analysis of existing literature)	N/A (meta-analysis)

It summarizes key findings from clinical studies investigating the neurological and cognitive manifestations of celiac disease. The evidence consistently demonstrates objective cognitive deficits (memory, reaction time, attention), subjective symptoms (brain fog/gluten-induced neurocognitive impairment), and associated brain pathology (white matter changes, cerebral hyperexcitability). Findings highlight the critical importance of a timely diagnosis, as the effectiveness of the gluten-free diet may vary between reversing new symptoms and stabilizing or failing to fully resolve deficits established during chronic, untreated inflammation. CD: Celiac disease; GINI: Gluten-induced neurocognitive impairment; GFD: Gluten-free diet; NCGS: Non-celiac gluten sensitivity; N/A: Not applicable; TMS: Transcranial magnetic stimulation.

Table 6 Summary of studies: Pediatric inflammatory bowel disease and neurocognitive outcomes

Ref.	Population/condition	Key cognitive/functional findings	Key mechanistic/psychosocial findings	Implication/conclusion
Tadin Hadjina et al[157], 2019	Adult IBD patients (n = 60) vs controls	Impaired neurocognitive and psychomotor function: Significantly longer total test-solving time in tests for convergent thinking, perceptive abilities, and complex operative thinking	Deficits in mental processing speed and mental endurance	IBD patients show objective impairment in cognitive and psychomotor speed, even in adulthood
Clarke et al[159], 2020	Adult Crohn’s disease and UC patients in clinical remission (prospective)	Impaired attentional performance was a stable feature of Crohn’s disease patients over a 6-month period (UC patients were unaffected)	Consistently elevated plasma IL-6 and kynurenine-to-tryptophan ratio; blunted cortisol awakening response. No correlation between biochemical markers and cognitive impairment was found, but the markers indicated ongoing, subclinical inflammation	Impaired cognitive function is a stable feature of Crohn’s disease, likely driven by persistent inflammatory/metabolic changes
Castaneda et al[158], 2013	Adolescents with IBD (n = 34) vs peers with JIA	IBD group, especially those in the acute phase, made more perseverative errors in the California Verbal Learning Test (verbal memory), suggesting executive function deficits	IBD group had more depressive symptoms than JIA group (especially with acute illness). Depressive symptoms were not related to the cognitive difference	Acute IBD may cause mild verbal memory/executive function problems; psychosocial burden (depression) is significant
Herzer et al[160], 2011	Adolescents with IBD (n = 62) and their caregivers	Poorer HRQOL across multiple dimensions (emotional, social, total HRQOL)	Adolescent depressive symptoms fully mediated the relation between parent distress (illness-related stress) and the youth’s poorer HRQOL	Psychosocial factors (parental distress-adolescent depression) are crucial targets for intervention to improve HRQOL
Friedman et al[161], 2020	Children exposed to maternal IBD in utero (followed to 7 years)	Children exposed to IBD in utero scored similarly to unexposed children on survey-based tools assessing motor and cognitive development	No obvious differences in language, motor, or cognitive/behavioral scores at 7 years	Reassuring data suggesting that maternal IBD exposure alone does not increase the risk of long-term neurodevelopmental delay

It summarizes human-based findings concerning the cognitive, functional, and psychosocial impacts of inflammatory bowel disease on children and adolescents. Studies demonstrate that inflammatory bowel disease, particularly Crohn’s disease, is associated with persistent deficits in executive functions and mental processing speed, often linked to systemic inflammation (interleukin-6, kynurenine-to-tryptophan ratio). Critically, the psychosocial burden is high, with adolescent depressive symptoms serving as a key mediator between parental distress and poor health-related quality of life. IBD: Inflammatory bowel disease; HRQOL: Health-related quality of life; JIA: Juvenile idiopathic arthritis; UC: Ulcerative colitis.

Table 7 Red flags for neurocognitive risk in gut disorder

Patient group	Gut-related red flag (trigger)	Actionable neurocognitive risk
Infancy/neonatal	Necrotizing enterocolitis, especially requiring surgical intervention	High risk (40% of global neurodevelopmental impairment, intraventricular hemorrhage, periventricular leukomalacia, and attention/executive function deficits
Infancy/early childhood	High burden of early severe enteric infections or chronic diarrheal illness (especially coupled with stunting/low growth)	Long-term risk of Lower intelligence quotient/cognitive scores and poor school performance (independent of malnutrition)
Children/adolescents	Active or newly diagnosed inflammatory bowel disease (especially Crohn’s disease), even with mild symptoms	Deficits in mental processing speed, executive function (attention, memory), and high comorbidity of depression/anxiety
All ages	Unexplained chronic symptoms: Brain fog, memory lapse, severe fatigue, or new-onset psychiatric symptoms (e.g., anxiety, depression)	Possible underlying celiac disease, requiring assessment for cognitive stabilization and screening for white matter changes

Table 8 Clinical Recommendations for screening and monitoring in gut-brain axis-related disorders

Domain of assessment	Rationale for screening	Relevant population	Key clinical outcome measures
Cognitive function	To identify deficits in processing speed, memory, and attention linked to systemic inflammation and micronutrient deficiencies (e.g., in IBD, CD)	NEC survivors, chronic IBD (adolescents/adults), CD	intelligence quotient tests (Wechsler Preschool and Primary Scale of Intelligence/Wechsler Intelligence Scale for Children), Reaction Time tests, Verbal/Visual Memory tests
Executive function	To detect impairments in planning, attention, and cognitive flexibility, commonly seen in active IBD and linked to frontal lobe dysfunction	Pediatric IBD (active disease), NEC survivors (attention deficits)	Trail Making Test, Stroop Color-Word Test, tests for perseverative errors (California Verbal Learning Test)
Mood/affective status	To address the high comorbidity of anxiety and depression in IBD and CD, which often mediates poor health-related quality of life	All chronic gastrointestinal patients (pediatric and adult)	Beck depression inventory, state-trait anxiety inventory, generalized anxiety disorder scale
Inflammatory markers	To correlate inflammation with cognitive status and assess the therapeutic target (i.e., deep healing)	IBD and CD patients	Plasma interleukin-6, fecal calprotectin, kynurenine-to-tryptophan ratio

It outlines specific neurocognitive, behavioral, and biological assessments required for high-risk patient populations with a history of severe early gastrointestinal disease (e.g., necrotizing enterocolitis, severe enteric infections) or chronic inflammatory conditions (e.g., inflammatory bowel disease, celiac disease). The recommendations emphasize a shift toward multidisciplinary, longitudinal monitoring to proactively identify and manage the subtle, yet persistent, cognitive and emotional deficits driven by chronic inflammation and malabsorption. CD: Celiac disease, IBD: Inflammatory bowel disease; NEC: Necrotizing enterocolitis.