Traumatic brain injury (TBI) is a complex condition where heterogeneity impedes the advancement of care. Understanding the diverse presentations of TBI is crucial for personalized medicine. Our study aimed to identify clinically relevant patient endotypes in TBI using latent class analysis based on comorbidity data. We used the Medical Information Mart for Intensive Care III database, which includes 2,629 adult TBI patients. We identified five stable endotypes characterized by specific comorbidity profiles: Heart Failure and Arrhythmia, Healthy, Renal Failure with Hypertension, Alcohol Abuse, and Hypertension. Each endotype had distinct clinical characteristics and outcomes: The Heart Failure and Arrhythmia endotype had lower survival rates than the Renal Failure with Hypertension despite featuring less comorbidities overall. Patients in the Hypertension endotype had higher rates of neurosurgical intervention but shorter stays in contrast to the Alcohol Abuse endotype which had lower rates of neurosurgical intervention but significantly longer hospital stays. Both endotypes had high overall survival rates comparable to the Healthy endotype. Logistic regression models showed that endotypes improved the predictability of survival compared to individual comorbidities alone. This study validates clinical endotypes as an approach to addressing heterogeneity in TBI, and demonstrates the potential of this methodology in other complex conditions.

Neonatal antibiotics administered to human infants initiate gut microbiota dysbiosis that may have long-term effects on body weight (BW) and metabolism. We examined antibiotic-induced adaptations in pancreatic islets of the piglet, a well-accepted model of human infant microbiota and pancreas development. Neonatal piglets randomized to amoxicillin (30mg/kg BW/day; n=7, ANTI) or placebo (vehicle control; n=7, CON) from postnatal day (PND)0-13 were euthanized at PND7, 14 and 49. The metabolic phenotype along with functional, immunohistological and transcriptional phenotypes of the pancreatic islets were studied. The gut microbiome was characterized by 16S sequencing and microbial metabolites and microbiome-sensitive host molecules were measured. Compared with CON, ANTI PND7 piglets had elevated transcripts of genes involved in GLP-1 synthesis or signaling in islets (p<0.05) coinciding with higher plasma GLP-1 (p=0.11), along with increased Tnf (p<0.05) and Npg1 (p<0.05). Antibiotic-induced relative increases in Escherichia, Coprococcus, Ruminoccocus, Dehalobacterium and Oscillospira of the ileal microbiome at PND7 normalized after antibiotic withdrawal. In ANTI islets at PND14, the expression of key regulators Pdx1, Igf2 and Tcf7l2 was down-regulated, preceding a 40% reduction of b-cell area (p<0.01) and islet insulin content at PND49 (p<0.05). At PND49, a 2-fold elevated plasma insulin concentration (p=0.07) was observed in ANTI compared with CON. We conclude that antibiotic treatment of neonatal piglets elicits gut microbial changes accompanied by phasic alterations in key regulatory genes in pancreatic islets at PND7 and 14. By PND49, reduced b-cell area and islet insulin content were accompanied by elevated non-fasted insulin despite normoglycemia, indicative of islet stress.