An Enteric Bacterial Infection Triggers Neuroinflammation and Neurobehavioral Impairment in 3xTg-AD Transgenic Mice.

BACKGROUND: Klebsiella pneumoniae is infamous for hospital-acquired infections and sepsis, which have also been linked to Alzheimer disease (AD)-related neuroinflammatory and neurodegenerative impairment. However, its causative and mechanistic role in AD pathology remains unstudied. METHODS: A preclinical model of K. pneumoniae enteric infection and colonization is developed in an AD model (3xTg-AD mice) to investigate whether and how K. pneumoniae pathogenesis exacerbates neuropathogenesis via the gut-blood-brain axis. RESULTS: K. pneumoniae, particularly under antibiotic-induced dysbiosis, was able to translocate from the gut to the bloodstream by penetrating the gut epithelial barrier. Subsequently, K. pneumoniae infiltrated the brain by breaching the blood-brain barrier. Significant neuroinflammatory phenotype was observed in mice with K. pneumoniae brain infection. K. pneumoniae-infected mice also exhibited impaired neurobehavioral function and elevated total tau levels in the brain. Metagenomic analyses revealed an inverse correlation of K. pneumoniae with gut biome diversity and commensal bacteria, highlighting how antibiotic-induced dysbiosis triggers an enteroseptic "pathobiome" signature implicated in gut-brain perturbations. CONCLUSIONS: The findings demonstrate how infectious agents following hospital-acquired infections and consequent antibiotic regimen may induce gut dysbiosis and pathobiome and increase the risk of sepsis, thereby increasing the predisposition to neuroinflammatory and neurobehavioral impairments via breaching the gut-blood-brain barrier.

Persistence and Sexual Dimorphism of Gut Dysbiosis and Pathobiome after Sepsis and Trauma.

OBJECTIVE: To evaluate the persistence of intestinal microbiome dysbiosis and gut-plasma metabolomic perturbations following severe trauma or sepsis weeks after admission in patients experiencing chronic critical illness (CCI). SUMMARY: Trauma and sepsis can lead to gut dysbiosis and alterations in the plasma and fecal metabolome. However, the impact of these perturbations and correlations between gut dysbiosis and the plasma metabolome in chronic critical illness have not been studied. METHODS: A prospective observational cohort study was performed with healthy subjects, severe trauma patients, and patients with sepsis residing in an intensive care unit for 2 to 3 weeks. A high-throughput multi-omics approach was utilized to evaluate the gut microbial and gut-plasma metabolite responses in critically ill trauma and sepsis patients 14 to 21 days after intensive care unit admission. RESULTS: Patients in the sepsis and trauma cohorts demonstrated strikingly depleted gut microbiome diversity, with significant alterations and specific pathobiome patterns in the microbiota composition compared to healthy subjects. Further subgroup analyses based on sex revealed resistance to changes in microbiome diversity among female trauma patients compared to healthy counterparts. Sex--specific changes in fecal metabolites were also observed after trauma and sepsis, while plasma metabolite changes were similar in both males and females. CONCLUSIONS: Dysbiosis induced by trauma and sepsis persists up to 14 to 21 days after onset and is sex-specific, underscoring the implication of pathobiome and entero-septic microbial-metabolite perturbations in post-sepsis and posttrauma chronic critical illness. This indicates resilience to infection or injury in females' microbiome and should inform and facilitate future precision/personalized medicine strategies in the intensive care unit.

Gut mycobiome dysbiosis after sepsis and trauma.

BACKGROUND: Sepsis 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. METHODS: We 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. RESULTS: We 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 by Candida spp; 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. CONCLUSIONS: The 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.

Deciphering the Impact of Defecation Frequency on Gut Microbiome Composition and Diversity.

This study explores the impact of defecation frequency on the gut microbiome structure by analyzing fecal samples from individuals categorized by defecation frequency: infrequent (1-3 times/week, n = 4), mid-frequent (4-6 times/week, n = 7), and frequent (daily, n = 9). Utilizing 16S rRNA gene-based sequencing and LC-MS/MS metabolome profiling, significant differences in microbial diversity and community structures among the groups were observed. The infrequent group showed higher microbial diversity, with community structures significantly varying with defecation frequency, a pattern consistent across all sampling time points. The Ruminococcus genus was predominant in the infrequent group, but decreased with more frequent defecation, while the Bacteroides genus was more common in the frequent group, decreasing as defecation frequency lessened. The infrequent group demonstrated enriched biosynthesis genes for aromatic amino acids and branched-chain amino acids (BCAAs), in contrast to the frequent group, which had a higher prevalence of genes for BCAA catabolism. Metabolome analysis revealed higher levels of metabolites derived from aromatic amino acids and BCAA metabolism in the infrequent group, and lower levels of BCAA-derived metabolites in the frequent group, consistent with their predicted metagenomic functions. These findings underscore the importance of considering stool consistency/frequency in understanding the factors influencing the gut microbiome.

Bifidobacterium bifidum BGN4 and Bifidobacterium longum BORI promotes neuronal rejuvenation in aged mice.

An increasing number of studies have indicated that alterations in gut microbiota affect brain function, including cognition and memory ability, via the gut-brain axis. In this study, we aimed to determine the protective effect of Bifidobacterium bifidum BGN4 (B. bifidum BGN4) and Bifidobacterium longum BORI (B. longum BORI) on age-related brain damage in mice. We found that administration of B. bifidum BGN4 and B. longum BORI effectively elevates brain-derived neurotrophic factor expression which was mediated by increased histone 3 lysine 9 trimethylation. Furthermore, administration of probiotic supplementation reversed the DNA damage and apoptotic response in aged mice and also improved the age-related cognitive and memory deficits of these mice. Taken together, the present study highlights the anti-aging effects of B. bifidum BGN4 and B. longum BORI in the aged brain and their beneficial effects for age-related brain disorders.

The Role of Akkermansia muciniphila on Improving Gut and Metabolic Health Modulation: A Meta-Analysis of Preclinical Mouse Model Studies.

Akkermansia muciniphila (A. muciniphila) and its derivatives, including extracellular vesicles (EVs) and outer membrane proteins, are recognized for enhancing intestinal balance and metabolic health. However, the mechanisms of Akkermansia muciniphila's action and its effects on the microbiome are not well understood. In this study, we examined the influence of A. muciniphila and its derivatives on gastrointestinal (GI) and metabolic disorders through a meta-analysis of studies conducted on mouse models. A total of 39 eligible studies were identified through targeted searches on PubMed, Web of Science, Science Direct, and Embase until May 2024. A. muciniphila (alive or heat-killed) and its derivatives positively affected systemic and gut inflammation, liver enzyme level, glycemic response, and lipid profiles. The intervention increased the expression of tight-junction proteins in the gut, improving gut permeability in mouse models of GI and metabolic disorders. Regarding body weight, A. muciniphila and its derivatives prevented weight loss in animals with GI disorders while reducing body weight in mice with metabolic disorders. Sub-group analysis indicated that live bacteria had a more substantial effect on most analyzed biomarkers. Gut microbiome analysis using live A. muciniphila identified a co-occurrence cluster, including Desulfovibrio, Family XIII AD3011 group, and Candidatus Saccharimonas. Thus, enhancing the intestinal abundance of A. muciniphila and its gut microbial clusters may provide more robust health benefits for cardiometabolic, and age-related diseases compared with A. muciniphila alone. The mechanistic insight elucidated here will pave the way for further exploration and potential translational applications in human health.

Pathways linking microbiota-gut-brain axis with neuroinflammatory mechanisms in Alzheimer's pathophysiology.

Disturbances in the local and peripheral immune systems are closely linked to a wide range of diseases. In the context of neurodegenerative disorders such as Alzheimer's disease (AD), inflammation plays a crucial role, often appearing as a common manifestation despite the variability in the occurrence of other pathophysiological hallmarks. Thus, combating neuroinflammation holds promise in treating complex pathophysiological diseases like AD. Growing evidence suggests the gut microbiome's crucial role in shaping the pathogenesis of AD by influencing inflammatory mediators. Gut dysbiosis can potentially activate neuroinflammatory pathways through bidirectional signaling of the gut-brain axis; however, the precise mechanisms of this complex interweaved network remain largely unclear. In these milieus, this review attempts to summarize the contributing role of gut microbiome-mediated neuroinflammatory signals in AD pathophysiology, while also pondering potential mechanisms through which commensal and pathogenic gut microbes affect neuroinflammation. While certain taxa such as Roseburia and Escherichia have been strongly correlated with AD, other clades such as Bacteroides and Faecalibacterium exhibit variations at the species and strain levels. In order to disentangle the inflammatory aspects of neurodegeneration attributed to the gut microbiome, it is imperative that future mechanistic studies investigate the species/strain-level dependency of commensals, opportunistic, and pathogenic gut microbes that consistently show correlations with AD patients across multiple associative studies.

Resistant starches from dietary pulses improve neurocognitive health via gut-microbiome-brain axis in aged mice.

Introduction: Cognitive 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. Methods: Accordingly, 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 discussion: Following 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.

The Effects of Almond Consumption on Cardiovascular Health and Gut Microbiome: A Comprehensive Review.

The consumption of almonds has been associated with several health benefits, particularly concerning cardiovascular and intestinal health. In this comprehensive review, we compile and deliberate studies investigating the effects of almond consumption on cardiovascular disease (CVD) risk factors and gut health. Almonds are rich in monounsaturated fats, fiber, vitamins, minerals, and polyphenols, which contribute to their health-promoting properties. Regular intake of almonds has been shown to improve lipid profiles by reducing LDL cholesterol and enhancing HDL functionality. Additionally, almonds aid in glycemic control, blood pressure reduction, and chronic inflammation amelioration, which are critical for cardiovascular health. The antioxidant properties of almonds, primarily due to their high vitamin E content, help in reducing oxidative stress markers. Furthermore, almonds positively influence body composition by reducing body fat percentage and central adiposity and enhancing satiety, thus aiding in weight management. Herein, we also contemplate the emerging concept of the gut-heart axis, where almond consumption appears to modulate the gut microbiome, promoting the growth of beneficial bacteria and increasing short-chain fatty acid production, particularly butyrate. These effects collectively contribute to the anti-inflammatory and cardioprotective benefits of almonds. By encompassing these diverse aspects, we eventually provide a systematic and updated perspective on the multifaceted benefits of almond consumption for cardiovascular health and gut microbiome, corroborating their broader consideration in dietary guidelines and public health recommendations for CVD risk reduction.

Postinjury Pneumonia Induces a Unique Blood Microbiome Signature.

BACKGROUND: Previous preclinical studies have demonstrated a pathobiome after traumatic injury; however, the impact of post-injury sepsis on gut epithelial permeability and bacterial translocation remains unknown. We hypothesized that polytrauma with post-injury pneumonia would result in impaired gut permeability leading to specific blood microbiome arrays. METHODS: Male and proestrus female Sprague-Dawley rats were subjected to either polytrauma (PT), PT plus 2-hours daily chronic restraint stress (PT/CS), PT with postinjury day 1 inoculation with pseudomonas pneumonia (PT + PNA), PT/CS + PNA, or naive controls. Whole blood microbiome was measured serially using high-throughput 16S rRNA sequencing and QIIME2 bioinformatics analyses. Microbial diversity was assessed using Chao1/Shannon indices and principle coordinate analysis. Intestinal permeability was evaluated by plasma occludin and lipopolysaccharide-binding protein (LBP) assays. RESULTS: PT/CS + PNA had increased intestinal permeability compared to uninfected counterparts (PT/CS) with significantly elevated occludin (p < 0.01). Bacteria was not detected in the blood of naïve controls, PT or PT/CS, but was present in both PT + PNA and PT/CS + PNA on days two and seven. The PT/CS + PNA blood biome showed dominance of Streptococcus compared to PT + PNA at day two (p < 0.05). Females PT/CS + PNA had a significant abundance of Staphylococcus at day two and Streptococcus at day seven in the blood biome compared to male counterparts (p < 0.05). CONCLUSIONS: Multicompartmental trauma with post-injury pneumonia results in increased intestinal permeability and bacteremia with a unique blood biome, with sexual dimorphisms evident in the blood biome composition. These findings suggest that post-injury sepsis has clinical significance and could influence outcomes after severe trauma and critical illness.

A combination of rebaudioside A and neohesperidin dihydrochalcone suppressed weight gain by regulating visceral fat and hepatic lipid metabolism in ob/ob mice.

Rebaudioside A (Reb A) and neohesperidin dihydrochalcone (NHDC) are known as intense sweeteners. This study aimed to examine the anti-obesity effects of Reb A and NHDC. C57BL/6 J-ob/ob mice were supplemented with Reb A (50 mg/kg body weight [b.w.]), NHDC (100 mg/kg b.w.), or their combination (COMB) for 4 weeks. COMB-supplemented mice showed significant reduction in b.w. gain, food efficiency ratio, and fat mass. Additionally, mice in the COMB group showed suppressed levels of genes related to adipogenesis, lipogenesis, and lipolysis in the perirenal fat and the levels of hepatic triglyceride, glutamic oxaloacetic transaminase, and glutamic pyruvic transaminase. The lipogenesis and pro-inflammatory gene expressions were also downregulated in the liver, whereas ß-oxidation related genes were upregulated in the COMB group. In addition, mice that received COMB showed distinct gut microbiota structure, enriched in Blautia and Parabacteroides, and depleted in Faecalibaculum and Mucispirillum, in relation to the control group. These results suggest that supplementation with Reb A and NHDC may be an effective treatment for obesity-related metabolic disorders. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01391-1.

A modified Mediterranean-style diet enhances brain function via specific gut-microbiome-brain mechanisms.

Alzheimer's disease (AD) is a debilitating brain disorder with rapidly mounting prevalence worldwide, yet no proven AD cure has been discovered. Using a multi-omics approach in a transgenic AD mouse model, the current study demonstrated the efficacy of a modified Mediterranean-ketogenic diet (MkD) on AD-related neurocognitive pathophysiology and underlying mechanisms related to the gut-microbiome-brain axis. The findings revealed that MkD induces profound shifts in the gut microbiome community and microbial metabolites. Most notably, MkD promoted growth of the Lactobacillus population, resulting in increased bacteria-derived lactate production. We discovered elevated levels of microbiome- and diet-derived metabolites in the serum as well, signaling their influence on the brain. Importantly, these changes in serum metabolites upregulated specific receptors that have neuroprotective effects and induced alternations in neuroinflammatory-associated pathway profiles in hippocampus. Additionally, these metabolites displayed strong favorable co-regulation relationship with gut-brain integrity and inflammatory markers, as well as neurobehavioral outcomes. The findings underscore the ameliorative effects of MkD on AD-related neurological function and the underlying gut-brain communication via modulation of the gut microbiome-metabolome arrays.

Acute emergence of the intestinal pathobiome after postinjury pneumonia.

BACKGROUND: Previous preclinical studies have demonstrated sex-specific alterations in the gut microbiome following traumatic injury or sepsis alone; however, the impact of host sex on dysbiosis in the setting of postinjury sepsis acutely is unknown. We hypothesized that multicompartmental injury with subsequent pneumonia would result in host sex-specific dysbiosis. METHODS: Male and proestrus female Sprague-Dawley rats (n = 8/group) were subjected to either multicompartmental trauma (PT) (lung contusion, hemorrhagic shock, cecectomy, bifemoral pseudofracture), PT plus 2-hour daily restraint stress (PT/RS), PT with postinjury day 1 Pseudomonas aeruginosa pneumonia (PT-PNA), PT/RS with pneumonia (PT/RS-PNA), or naive controls. Fecal microbiome was measured on days 0 and 2 using high-throughput 16S rRNA sequencing and Quantitative Insights Into Microbial Ecology 2 bioinformatics analyses. Microbial α-diversity was assessed using Chao1 (number of different unique species) and Shannon (species richness and evenness) indices. ß-diversity was assessed using principal coordinate analysis. Significance was defined as p < 0.05. RESULTS: All groups had drastic declines in the Chao1 (α-diversity) index compared with naive controls ( p < 0.05). Groups PT-PNA and PT/RS-PNA resulted in different ß-diversity arrays compared with uninfected counterparts (PT, PT/RS) ( p = 0.001). Postinjury sepsis cohorts showed a loss of commensal bacteria along with emergence of pathogenic bacteria, with blooms of Proteus in PT-PNA and Escherichia-Shigella group in PT/RS-PNA compared with other cohorts. At day 2, PT-PNA resulted in ß-diversity, which was unique between males and females ( p = 0.004). Microbiome composition in PT-PNA males was dominated by Anaerostipes and Parasuterella , whereas females had increased Barnesiella and Oscillibacter . The PT/RS males had an abundance of Gastranaerophilales and Muribaculaceae . CONCLUSION: Multicompartmental trauma complicated by sepsis significantly diminishes diversity and alters microbial composition toward a severely dysbiotic state early after injury, which varies between males and females. These findings highlight the role of sex in postinjury sepsis and the pathobiome, which may influence outcomes after severe trauma and sepsis.

Dietary fiber modulates gut microbiome and metabolome in a host sex-specific manner in a murine model of aging.

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 of Bacteroides, Blautia, and glycine, while decreasing Eggerthella, Lactococcus, Streptococcus, trimethylamine, 3-hydroxyisobutyrate, leucine and methionine in both sexes. However, we note sex-specific effects of inulin including suppression of f_Enteroccaceae:_, Odoribacter, bile acids, malonate, thymine, valine, acetoin, and ethanol while promotion of Dubosiella, pyruvate, and glycine in males. Whereas, suppression of Faecalibaculum, Lachnoclostridium, Schaedlerella, phenylalanine and enhancement of Parasutterella, 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.

Prebiotic mechanisms of resistant starches from dietary beans and pulses on gut microbiome and metabolic health in a humanized murine model of aging.

Dietary pulses, being a rich source of fiber and proteins, offer an ideal and inexpensive food choice for older adults to promote gut and metabolic health. However, the prebiotic effects of dietary pulses-derived resistant starches (RS), compared to RS from cereals and tubers, remain relatively underexplored, particularly in context to their gut modulatory potential in old age. We herein investigate the prebiotic effects of pulses-derived RS on the gut microbiome and intestinal health in aged (60-week old) mice colonized with human microbiota. C57B6/J mice were fed for 20 weeks with either a western-style high-fat diet (control; CTL) or CTL diet supplemented (5% w/w) with RS from pinto beans (PTB), black-eyed-peas (BEP), lentils (LEN), chickpeas (CKP), or inulin (INU; reference control). We find that the RS supplementation modulates gut microbiome in a sex-dependent manner. For instance, CKP enriched α-diversity only in females, while ß-diversity deviated for both sexes. Further, different RS groups exhibited distinct microbiome differences at bacterial phyla and genera levels. Notably, LEN fostered Firmicutes and depleted Proteobacteria abundance, whereas Bacteroidota was promoted by CKP and INU. Genus Dubosiella increased dominantly in males for all groups except PTB, whilst Faecalibaculum decreased in females by CKP and INU groups. Linear discriminant analysis effect size (LEfSe) and correlational analyzes reveal RS-mediated upregulation of key bacterial genera associated with short-chain fatty acids (butyrate) production and suppression of specific pathobionts. Subsequent machine-learning analysis validate decreased abundance of notorious genera, namely, Enterococcus, Odoribacter, Desulfovibrio, Alistipes and Erysipelatoclostridium among RS groups. CKP and LEN groups partly protected males against post-prandial glycemia. Importantly, RS ameliorated high-fat diet-induced gut hyperpermeability and enhanced expression of tight-junction proteins (claudin-1 and claudin-4), which were more pronounced for LEN. In addition, IL10 upregulation was more prominent for LEN, while TNF-α was downregulated by LEN, CKP, and INU. Together, these findings demonstrate that RS supplementation beneficially modulates the gut microbiome with a reduction in gut leakiness and inflammation, indicating their prebiotic potential for functional food and nutritional applications.

Resistant starches from dietary pulses modulate the gut metabolome in association with microbiome in a humanized murine model of ageing.

Emerging evidence suggests that plant-based fiber-rich diets improve ageing-associated health by fostering a healthier gut microbiome and microbial metabolites. However, such effects and mechanisms of resistant starches from dietary pulses remain underexplored. Herein, we examine the prebiotic effects of dietary pulses-derived resistant starch (RS) on gut metabolome in older (60-week old) mice carrying a human microbiome. Gut metabolome and its association with microbiome are examined after 20-weeks feeding of a western-style diet (control; CTL) fortified (5% w/w) with RS from pinto beans (PTB), black-eyed-peas (BEP), lentils (LEN), chickpeas (CKP), or inulin (INU; reference control). NMR spectroscopy-based untargeted metabolomic analysis yield differential abundance linking phenotypic differences in specific metabolites among different RS groups. LEN and CKP increase butyrate, while INU promotes propionate. Conversely, bile acids and cholesterol are reduced in prebiotic groups along with suppressed choline-to-trimethylamine conversion by LEN and CKP, whereas amino acid metabolism is positively altered. Multi-omics microbiome-metabolome interactions reveal an association of beneficial metabolites with the Lactobacilli group, Bacteroides, Dubosiella, Parasutterella, and Parabacteroides, while harmful metabolites correlate with Butyricimonas, Faecalibaculum, Colidextribacter, Enterococcus, Akkermansia, Odoribacter, and Bilophila. These findings demonstrate the functional effects of pulses-derived RS on gut microbial metabolism and their beneficial physiologic responses in an aged host.

Gut microbiome as a therapeutic target for liver diseases.

The prominent role of gut in regulating the physiology of different organs in a human body is increasingly acknowledged, to which the bidirectional communication between gut and liver is no exception. Liver health is modulated via different key components of gut-liver axis. The gut-derived products mainly generated from dietary components, microbial metabolites, toxins, or other antigens are sensed and transported to the liver through portal vein to which liver responds by secreting bile acids and antibodies. Therefore, maintaining a healthy gut microbiome can promote homeostasis of this gut-liver axis by regulating the intestinal barrier function and reducing the antigenic molecules. Conversely, liver secretions also regulate the gut microbiome composition. Disturbed homeostasis allows luminal antigens to reach liver leading to impaired liver functioning and instigating liver disorders. The perturbations in gut microbiome, permeability, and bile acid pool have been associated with several liver disorders, although precise mechanisms remain largely unresolved. Herein, we discuss functional fingerprints of a healthy gut-liver axis while contemplating mechanistic understanding of pathophysiology of liver diseases and plausible role of gut dysbiosis in different diseased states of liver. Further, novel therapeutic approaches to prevent the severity of liver disorders are discussed in this review.

ß-Carotene suppresses cancer cachexia by regulating the adipose tissue metabolism and gut microbiota dysregulation.

Cancer cachexia is a metabolic disease affecting multiple organs and characterized by loss adipose and muscle tissues. Metabolic dysregulated of adipose tissue has a crucial role in cancer cachexia. ß-Carotene (BC) is stored in adipose tissues and increases muscle mass and differentiation. However, its regulatory effects on adipose tissues in cancer cachexia have not been investigated yet. In this study, we found that BC supplementations could inhibit several cancer cachexia-related changes, including decreased carcass-tumor (carcass weight after tumor removal), adipose weights, and muscle weights in CT26-induced cancer cachexia mice. Moreover, BC supplementations suppressed cancer cachexia-induced lipolysis, fat browning, hepatic gluconeogenesis, and systemic inflammation. Altered diversity and composition of gut microbiota in cancer cachexia were restored by the BC supplementations. BC treatments could reverse the down-regulated adipogenesis and dysregulated mitochondrial respiration and glycolysis in adipocytes and colon cancer organoid co-culture systems. Taken together, these results suggest that BC can be a potential therapeutic strategy for cancer cachexia.

Sex-specific intestinal dysbiosis persists after multicompartmental injury.

BACKGROUND: Preclinical studies of the gut microbiome after severe traumatic injury have demonstrated severe dysbiosis in males, with sex-specific microbial differences up to 2 days after injury. However, the impact of host sex on injury-driven dysbiosis over time remains unknown. We hypothesized that sex-specific differences in intestinal microbiome diversity and composition after traumatic injury with and without stress would persist after 7 days. METHODS: Male and proestrus female Sprague-Dawley rats (n = 8/group) were subjected to either polytrauma (lung contusion, hemorrhagic shock, cecectomy, bifemoral pseudofractures), polytrauma plus chronic restraint stress, or naïve controls. The fecal microbiome was measured on days 0, 3, and 7 using 16S rRNA sequencing and Quantitative Insights into Microbial Ecology bioinformatics analyses. Microbial alpha-diversity (Chao1 and Shannon indices) and beta-diversity were assessed. Analyses were performed in GraphPad and "R," with significance defined as P < .05. RESULTS: Polytrauma and polytrauma plus chronic restraint stress reduced alpha-diversity (Chao1, Shannon) within 3 days postinjury, which persisted up to day 7 in both sexes; polytrauma and polytrauma plus chronic restraint stress females had significantly decreased Chao1 compared to male counterparts at day 7 (P = .02). At day 7, the microbiome composition in polytrauma females had higher proportion of Mucispirillum, whereas polytrauma plus chronic restraint stress males demonstrated elevated abundance of Ruminococcus and Akkermansia. CONCLUSION: Multicompartmental trauma induces intestinal dysbiosis that is sex-specific with persistence of decreased diversity and unique "pathobiome" signatures in females after 1 week. These findings underline sex as an important biological variable that may influence variable host-specific responses and outcomes after severe trauma and critical illness. This underscores the need to consider precision medicine strategies to ameliorate these outcomes.

Partial convergence of the human vaginal and rectal maternal microbiota in late gestation and early post-partum.

The human vaginal and fecal microbiota change during pregnancy. Because of the proximity of these perineal sites and the evolutionarily conserved maternal-to-neonatal transmission of the microbiota, we hypothesized that the microbiota of these two sites (rectal and vaginal) converge during the last gestational trimester as part of the preparation for parturition. To test this hypothesis, we analyzed 16S rRNA sequences from vaginal introitus and rectal samples in 41 women at gestational ages 6 and 8 months, and at 2 months post-partum. The results show that the human vaginal and rectal bacterial microbiota converged during the last gestational trimester and into the 2nd month after birth, with a significant decrease in Lactobacillus species in both sites, as alpha diversity progressively increased in the vagina and decreased in the rectum. The microbiota convergence of the maternal vaginal-anal sites perinatally might hold significance for the inter-generational transmission of the maternal microbiota.