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Abstract BackgroundSepsis and trauma are known to disrupt gut bacterial microbiome communities, but the impacts and perturbations in the fungal (mycobiome) community after severe infection or injury, particularly in patients experiencing chronic critical illness (CCI), remain unstudied. MethodsWe assess persistence of the gut mycobiome perturbation (dysbiosis) in patients experiencing CCI following sepsis or trauma for up to two-to-three weeks after intensive care unit hospitalization. ResultsWe show that the dysbiotic mycobiome arrays shift toward a pathobiome state, which is more susceptible to infection, in CCI patients compared to age-matched healthy subjects. The fungal community in CCI patients is largely dominated byCandidaspp; while, the commensal fungal species are depleted. Additionally, these myco-pathobiome arrays correlate with alterations in micro-ecological niche involving specific gut bacteria and gut-blood metabolites. ConclusionsThe findings reveal the persistence of mycobiome dysbiosis in both sepsis and trauma settings, even up to two weeks post-sepsis and trauma, highlighting the need to assess and address the increased risk of fungal infections in CCI patients. Graphical Abstract 

IntroductionCognitive decline is a common consequence of aging. Dietary patterns that lack fibers and are high in saturated fats worsen cognitive impairment by triggering pro-inflammatory pathways and metabolic dysfunctions. Emerging evidence highlights the neurocognitive benefits of fiber-rich diets and the crucial role of gut-microbiome-brain signaling. However, the mechanisms of this diet-microbiome-brain regulation remain largely unclear. MethodsAccordingly, we herein investigated the unexplored neuroprotective mechanisms of dietary pulses-derived resistant starch (RS) in improving aging-associated neurocognitive function in an aged (60-weeks old) murine model carrying a human microbiome. Results and discussionFollowing 20-weeks dietary regimen which included a western-style diet without (control; CTL) or with 5% w/w fortification with RS from pinto beans (PTB), black-eyed-peas (BEP), lentils (LEN), chickpeas (CKP), or inulin fiber (INU), we find that RS, particularly from LEN, ameliorate the cognitive impairments induced by western diet. Mechanistically, RS-mediated improvements in neurocognitive assessments are attributed to positive remodeling of the gut microbiome-metabolome arrays, which include increased short-chain fatty acids and reduced branched-chain amino acids levels. This microbiome-metabolite-brain signaling cascade represses neuroinflammation, cellular senescence, and serum leptin/insulin levels, while enhancing lipid metabolism through improved hepatic function. Altogether, the data demonstrate the prebiotic effects of RS in improving neurocognitive function via modulating the gut-brain axis. 

Emerging evidence reveals the fundamental role of the gut microbiome in human health. Among various factors regulating our gut microbiome, diet is one of the most indispensable and prominent one. Inulin is one of the most widely-studied dietary fiber for its beneficial prebiotic effects by positively modulating the gut microbiome and microbial metabolites. Recent research underscores sexual dimorphism and sex-specific disparities in microbiome and also diet-microbiome interactions. However, whether and how the prebiotic effects of dietary fiber differ among sexes remain underexplored. To this end, we herein examine sex-specific differences in the prebiotic effects of inulin on gut microbiome and metabolome in a humanized murine model of aging i.e., aged mice carrying human fecal microbiota. The findings demonstrate that inulin exerts prebiotic effects, but in a sex-dependent manner. Overall, inulin increases the proportion ofBacteroides,Blautia,and glycine, while decreasingEggerthella,Lactococcus,Streptococcus, trimethylamine, 3-hydroxyisobutyrate, leucine and methionine in both sexes. However, we note sex-specific effects of inulin including suppression off_Enteroccaceae:_,Odoribacter, bile acids, malonate, thymine, valine, acetoin, and ethanol while promotion ofDubosiella, pyruvate, and glycine in males. Whereas, suppression ofFaecalibaculum, Lachnoclostridium, Schaedlerella,phenylalanine and enhancement ofParasutterella, Phocaeicola, f_Lachnospiraceae;_, Barnesiella, Butyricimonas, glycine, propionate, acetate and glutamate are observed in females. Altogether, the study reveals that prebiotic mechanisms of dietary fiber vary in a sex-dependent manner, underscoring the importance of including both sexes in preclinical/clinical studies to comprehend the mechanisms and functional aspects of dietary interventions for effective extrapolation and translation in precision nutrition milieus.