Gut-brain axis in anesthesia and critical illness: Molecular crosstalk and its impact on delirium and outcome (Review)

Sepsis-associated encephalopathy (SAE) is defined as a dysfunction of the central nervous system experienced during sepsis with variable clinical features. The study aims to identify the prognostic role of urinary ketone bodies in relation to clinical outcomes in patients with SAE. The Medical Information Mart for Intensive Care III (MIMIC-III) database was used to conduct a retrospective cohort study. We recruited 427 patients with SAE admitted to the intensive care unit (ICU) from the MIMIC-III database. Patients with SAE were divided into a survival group (380 patients) and a non-survival group (47 patients). We used the Wilcoxon signed-rank test and the multivariate logistic regression analysis to analyze the relationship between the level of urinary ketone bodies and the clinical prognosis in patients with SAE. The primary outcome was the relationship between urinary ketone body levels and 28-day mortality of SAE. The secondary outcomes were the relationship between urinary ketone body levels and length of ICU stays, Simplified Acute Physiology Score II, Sequential Organ Failure Assessment (SOFA), Glasgow Coma Scale, mechanical ventilation, renal replacement therapy, and the use of vasopressors. The 28-day mortality of patients with SAE was 11.0%. Urinary ketone body levels were not significantly associated with the 28-day mortality of patients with SAE. Urinary ketone body levels were associated with SOFA score and the use of vasopressors in patients with SAE. The SOFA score was an independent risk factor for the 28-day mortality in patients with SAE. Urinary ketone body levels were significantly associated with SOFA score and the use of vasopressors in patients with SAE. Furthermore, the SOFA score can predict the prognosis of short-term outcomes of patients with SAE. Therefore, we should closely monitor the changes of urinary ketone bodies and SOFA score and intervene in time.

Sepsis-associated encephalopathy (SAE) is a significant cause of mortality in patients with sepsis. Despite extensive research, its exact cause remains unclear. Our previous research indicated a relationship between non-hepatic hyperammonemia (NHH) and SAE. This study aimed to investigate the relationship between NHH and SAE and the potential mechanisms causing cognitive impairment. In the in vivo experimental results, there were no significant abnormalities in the livers of mice with moderate cecal ligation and perforation (CLP); however, ammonia levels were elevated in the hippocampal tissue and serum. The ELISA study suggest that fecal microbiota transplantation in CLP mice can reduce ammonia levels.Reduction in ammonia levels improved cognitive dysfunction and neurological impairment in CLP mice through behavioral, neuroimaging, and molecular biology studies. Further studies have shown that ammonia enters the brain to regulate the expression of aquaporins-4 (AQP4) in astrocytes, which may be the mechanism underlying brain dysfunction in CLP mice. The results of the in vitro experiments showed that ammonia up-regulated AQP4 expression in astrocytes, resulting in astrocyte damage. The results of this study suggest that ammonia up-regulates astrocyte AQP4 expression through the gut-brain axis, which may be a potential mechanism for the occurrence of SAE.

Intestinal microbiota homeostasis and the gut-brain axis are key players associated with host health and alterations in metabolic, inflammatory, and neurodegenerative disorders. Sepsis-associated encephalopathy (SAE), which is closely associated with bacterial translocation, is a common secondary organ dysfunction and an urgent, unsolved problem affecting patient quality of life. Our study examined the neuroprotective effects of the gut microbiome and short-chain fatty acid (SCFA) metabolites on SAE. Male C57BL/6 mice were administered SCFAs in drinking water, then subjected to cecal ligation and puncture (CLP) surgery to induce SAE. 16S rRNA sequencing was used to investigate gut microbiome changes. The open field test (OFT) and Y-maze were performed to evaluate brain function. The permeability of the blood-brain barrier (BBB) was assessed by Evans blue (EB) staining. Hematoxylin and eosin (HE) staining was used to examine intestinal tissue morphology. The expression levels of tight junction (TJ) proteins and inflammatory cytokines was assessed by western blots and immunohistochemistry. In vitro, bEND.3 cells were incubated with SCFAs and then with lipopolysaccharide (LPS). Immunofluorescence was used to examine the expression of TJ proteins. The composition of the gut microbiota was altered in SAE mice; this change may be related to SCFA metabolism. SCFA treatment significantly alleviated behavioral dysfunction and neuroinflammation in SAE mice. SCFAs upregulated occludin and ZO-1 expression in the intestine and brain in SAE mice and LPS-treated cerebromicrovascular cells. These findings suggested that disturbances in the gut microbiota and SCFA metabolites play key roles in SAE. SCFA supplementation could exert neuroprotective effects against SAE by preserving BBB integrity.

PurposeNeuroinflammation plays an important part in the pathophysiology of sepsis-associated encephalopathy (SAE). Gut microbiota and gut brain axis are considered as important mediators in the development of neurological diseases. The aim of this study was to investigate the role of intestinal microbiota in sepsis-related brain injury and to explore the underlying mechanisms.MethodsMouse model of SAE was established using cecal ligation and puncture (CLP). Based on the mouse mortality and the associated time of death, light SAE (LSAE) and severe SAE (SSAE) were classified. Fecal microbiota transplantation (FMT) was performed to verify the role of intestinal microbiota. Feces of mice in the two groups which collected before operation were sequenced for 16S and targeted short chain fatty acids.ResultsIntestinal microbiota from SSAE and LSAE mice displayed diverse functions. Interestingly, LSAE mice produced more butyric acid compared with SSAE mice. In the in vivo experiments, sodium butyrate (NaB) reduced the high oxidative stress levels in mice hippocampus and conferred a marked survival superiority to sepsis mice. In addition, NaB prevented the increase in intracellular reactive oxygen species (ROS) generation and inducible nitric-oxide synthase expression in LPS-stimulated primary microglia. The GPR109A/Nrf2/HO-1 signaling pathway was found to be involved in the activation of antioxidant response of primary microglia induced by sodium butyrate.ConclusionOur findings indicate a crucial role of gut microbiota in the susceptibility to SAE. Butyrate, a metabolite of intestinal microbiota, may have a neuroprotective effect in the process of sepsis by GPR109A/Nrf2/HO-1 pathway.

Rationale: Emerging evidence implicates the gut microbiota in epilepsy pathogenesis through the microbiota-gut-brain axis, yet the functional contribution of specific microbial taxa to epileptogenesis remains unclear. This study aimed to investigate whether Lachnospira eligens (L. eligens) can alleviate epileptic activity by modulating the gut-brain axis, with a focus on intestinal barrier integrity, blood-brain barrier (BBB) integrity, and neuroimmune responses. Methods: Using a cobalt wire-induced rat epilepsy model, we performed fecal 16S rDNA sequencing to assess gut microbiota alterations. Rats received daily oral gavage of L. eligens or PBS for 15 days, with colonization confirmed by qPCR. Seizure activity was monitored using long-term video electroencephalogram (EEG) and Racine scores. Barrier function, systemic inflammation, and microglial activation were assessed using FITC-dextran (FD-4, 4 kDa) assay, Western blotting (WB), immunohistochemistry (IHC), immunofluorescence (IF), ELISA, and qPCR. Serum short-chain fatty acids (SCFAs) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Epileptic rats exhibited early gut microbiota dysbiosis, with a significant decline in Lachnospira abundance both preceding and succeeding seizure onset (P = 0.041, P = 0.026). L. eligens stably colonized the gut (Day 6 and Day 15, both P < 0.001). Supplementation significantly reduced grade 4-5 seizure frequency (P = 0.002) and prolonged seizure latency (P = 0.005). Barrier integrity improved, as indicated by lower plasma FD-4 (P < 0.001), increased colonic (WB: P = 0.013; IHC: P = 0.003) and cortical occludin expression (WB: P = 0.002; IHC: P = 0.01), and decreased serum lipopolysaccharide-binding protein (LBP) (P = 0.011). Neuroinflammation was attenuated, including reduced microglial activation (P = 0.048), lower pro-inflammatory cytokines (IL-1β, P = 0.047; IL-6, P = 0.001; TNF-α, P = 0.002), and decreased M1 polarization (P = 0.004). Serum butyrate increased (P = 0.014), and SCFAs, especially butyrate, suppressed lipopolysaccharide (LPS)-induced iNOS (P = 0.031) in BV2 cells. Conclusions: These findings demonstrate that L. eligens mitigates epileptic activity by restoring intestinal barrier and BBB integrity and suppressing neuroinflammation. Our study highlights L. eligens as a promising microbiota-based intervention for epilepsy through modulation of the gut-brain axis.

Sepsis-Associated Encephalopathy: Review of the Neuropsychiatric Manifestations and Cognitive Outcome

ObjectivesOur previous study shows that serum ammonia in sepsis patients without hepatic failure is associated with a poor prognosis. The relationship between serum ammonia level and the prognosis of sepsis-associated encephalopathy (SAE) patients without hepatic failure remains unclear. We aimed to explore the relationship between serum ammonia levels and the prognosis of patients with SAE.Materials and methodsThis study is a retrospective cohort study. We collected 465 patients with SAE admitted to the intensive care unit (ICU) from Medical Information Mart for Intensive Care IV (MIMIC IV) from 2008 to 2019. Patients with SAE were divided into a survival group (369 patients) and a non-survival group (96 patients). We used the Wilcoxon signed-rank test and the multivariate logistic regression analysis to analyze the relationship between serum ammonia levels and the prognosis of patients with SAE. R software was used to analyze the dataset.ResultsThe primary outcome was the relationship between serum ammonia level and hospital mortality of SAE. The secondary outcomes were the relationship between serum ammonia level and hospital stays, simplified acute physiology score (SAPS II), Charlson, Glasgow coma scale (GCS), sequential organ failure assessment (SOFA), and lactate level of SAE. The mortality of patients with SAE was 20.6%. The serum ammonia level was not significantly associated with hospital mortality, longer hospital stays, higher SAPS II and Charlson scores, and lower GCS of patients with SAE. The serum ammonia level was associated with higher SOFA scores and lactate levels in patients with SAE. The SAPS II and Charlson scores were independent risk factors for death in patients with SAE.ConclusionSerum ammonia level was associated with higher SOFA scores and lactate levels in patients with SAE. In addition, the SAPS II and Charlson scores can be used to assess the prognosis of patients with SAE. Therefore, we should closely monitor serum ammonia, SAPS II, and Charlson levels in patients with SAE.

Sepsis is defined as a condition of immune dysregulation in response to an infection, and sepsis-associated encephalopathy (SAE) is often the initial symptom that manifests in patients with sepsis. This condition is characterized by its high mortality rates and the potential to cause significant disability among survivors. Despite its severity, the underlying pathophysiologic mechanisms that contribute to the development of SAE are not yet fully understood. Additionally, there are no established strict diagnostic criteria or potent treatment options available for this condition. However, an increasing body of evidence suggests that an imbalance in the gut microbiota is associated with SAE, potentially through the gut-brain axis (GBA). The GBA axis refers to the bidirectional communication between the gut microbiota and the central nervous system. In this review, we discuss the changes in the gut microbiota in SAE and the mechanisms of the GBA axis, involving neural, immune, endocrine, and neurotransmitter pathways. Finally, we conclude by evaluating the preclinical and clinical evidence for fecal microbiota transplantation and probiotics in SAE. Targeting the GBA axis will be an actionable target to ameliorate the development and progression of SAE.

Nonhepatic hyperammonemia often occurs in patients with sepsis. Ammonia plays an essential role in the occurrence of hepatic encephalopathy. However, the relationship between nonhepatic serum ammonia levels and sepsis-associated encephalopathy (SAE) remains unclear. Thus, we aimed to evaluate the association between serum ammonia levels and patients with SAE. Data of critically ill adults with sepsis who were admitted to the intensive care unit were retrieved from the Medical Information Mart for Intensive Care IV (MIMIC IV) between 2008 and 2019 and retrospectively analyzed. Data of patients with sepsis patients and serum ammonia not related to acute or chronic liver disease were not included. Data from 720 patients with sepsis were included. SAE was found to have a high incidence (64.6%). After adjusting for other risk factors, a serum ammonia level of ≥45 μmol/L (odds ratio (OR): 3.508, 95% confidence interval (CI): 2.336-5.269, p < 0.001) was found to be an independent risk factor for patients with SAE; moreover, as the serum ammonia level increased, the hospital mortality of SAE gradually increased in a certain range (serum ammonia <150 μmol/L). Serum ammonia levels of ≥45 μmol/L were associated with higher Simplified Acute Physiology Score II and Sequential Organ Failure Assessment (SOFA) scores in patients with SAE. Besides, our study found that patients with SAE used opioid analgesics (OR:3.433, 95% CI: 1.360-8.669, p = 0.009) and the SOFA scores of patients with SAE (OR: 1.126, 95% CI: 1.062-1.194, p < 0.001) were significantly higher than those without SAE. Nonhepatic serum ammonia levels of ≥45 μmol/L evidently increased the incidence of SAE. Serum ammonia levels should be closely monitored in patients with sepsis.

Considering the high incidence, mortality, and long-term effects of sepsis-associated encephalopathy (SAE), along with the availability of sedation therapy data and the significance of distress management, this study investigated the relationship between sedation therapy and one-year all-cause mortality in patients with SAE. This retrospective cohort study utilized the Medical Information Market for Intensive Care (MIMIC-IV) database. We gathered demographic data, vital signs, laboratory test results, microbial findings, comorbidities, scoring systems, treatments administered within the first 24 hours of patient admission to the intensive care unit (ICU), and follow-up data from 24 hours after ICU admission to one year. Cox regression models were employed to evaluate the relationship between sedation therapy and one-year all-cause mortality among patients with SAE. Propensity score matching (PSM) and subgroup analyses were used to assess the robustness of the findings. Four thousand six hundred eighteen patients with SAE were enrolled, including 3,343 in the sedative group and 1,275 in the non-sedative group; additionally, 511 pairs were matched. A protective correlation was observed between propofol monotherapy and one-year all-cause mortality in patients with SAE, with hazard ratios (HRs) of 0.51 (95% confidence interval (CI), 0.40-0.65), P < 0.001. Furthermore, the interaction between propofol monotherapy and ventilation support significantly increased one-year all-cause mortality, yielding an HR of 0.70 (95% CI, 0.49-1.00) with P for interaction = 0.041. The results of PSM remained robust. Our study indicated that compared to patients with SAE who did not receive sedation, administering propofol alone significantly reduced one-year all-cause mortality among patients with SAE. For patients undergoing ventilation support on the first day of ICU admission, the interaction between sedation therapy and ventilation support significantly influenced the one-year all-cause mortality of patients with SAE.

Sir, The human body is inhabited by a multitude of bacteria, viruses, fungi, phages constituting the microbiota, and their gene pool called the microbiome which is essential for human well-being.[1] The role of gut microbiome in peri-operative medicine is recently being explored. However, most of the literature available is that of animal studies and more extensive research would be needed in humans to establish an association. The mechanism of action of gut-microbiome on various systems of the human body can be explained by the “gut-brain axis.” This is a two-way interaction between the enteric nervous system (ENS) and central nervous system (CNS) [Figure 1]. The gut microbiota secrete various metabolites and products like-short chain fatty acids (SCFA), enzymes, polysaccharides, cytokines, and neurotransmitters, which are released in to the circulation to act on the CNS. The vagus nerve also carries inputs from ENS to CNS. The brain in-turn acts on the gut through the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system.[2] Immune mediated interaction and alteration of microglial activity are other proposed mechanisms of gut-brain interaction. All these mechanisms have been proven only by preclinical animal studies.[1]Figure 1: Gut brain axis. HPA = Hypothalamic pituitary adrenal axisAnaesthetic agents-like propofol and volatile anaesthetics have been found to alter the gut microbiota composition in animal studies. Han et al. studied gut microbiota of mice after sevoflurane exposure and found that microbiome composition was reduced on day-1, 3, 7, and 14 after sevoflurane anaesthesia compared to the control group. They also noted a significant difference in fecal metabolites of the experimental and control groups.[3] Also an infusion of propofol for 3 hours in rats was found to decrease the number of certain bacterial species for 14 days.[4] Postoperative delirium (POD) and post-surgical pain (PSP) have also been attributed to the gut-microbiome by animal studies. This means, why certain patients have more POD or PSP than others can be determined by their gut-microbiome constitution and may be pre-treatment with pre-biotics, post-biotics, or fecal microbiota transplantation reduces the risk of POD and PSP in these patients. However, this association between POD/PSP and gut-microbiome has been shown mostly in animal studies and human association is yet to be established.[1] Zhang et al. compared the gut-microbiota of rats who developed POD and those who did not develop POD after abdominal surgery. The composition of microbiota was significantly different between the groups. They also conducted fecal microbiota transplantation from rats with POD to antibiotic treated rats, which then developed POD.[5] A human study has proved association of gut microbiome with chronic PSP, where Yao et al. had preoperatively collected gut-microbiome samples for 132 patients undergoing breast cancer surgery. The gut microbiota of 66 patients who developed chronic PSP (CPSP) was significantly different from those who did not develop PSP. Fecal microbiome transplantation from CPSP patients to mice led to development of hyperalgesia in these mice.[6] The gut microbiome composition has been attributed to development of opioid tolerance. Chronic opioid exposure leads to activation of opioid receptors on gut epithelium and destruction of gut mucosal barrier, allowing translocation of gut bacteria leading to an inflammatory response and pain exacerbation.[1] The gut microbiota composition influences many chronic pain conditions like fibromyalgia, headache, neuropathic, visceral, and chronic pelvic pain. The mediators of gut microbiota can alter the neuronal excitability at the dorsal root ganglia and mediate neuro inflammation leading to central sensitization and peripheral sensitization in chronic pain. Thus, targeting the gut-microbiota seems to be a promising treatment of chronic pain.[1,2] In future, gut microbiome analysis might help to screen patients at risk of postoperative cognitive dysfunction, postoperative pain, chronic pain and opioid tolerance and alteration of gut microbiota by use of prebiotics, postbiotics, dietary, and life-style changes might provide therapeutic benefit in such patients. However, this hypothesis is based majorly on animal studies and gut microbiome still needs to be explored in humans. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Methionine Restriction Attenuates High-Fat Diet-Induced Gut-Brain Axis Circadian Rhythm Disorders and Cognitive Impairments (P08-052-19)

Against dissing BIS. Comment on ‘An independent discussion of the ENGAGES trial’ (Br J Anaesth 2019; 123:112–7)

The complex bidirectional communication system existing between the gastrointestinal tract and the brain initially termed the “gut–brain axis” and renamed the “microbiota–gut–brain axis”, considering the pivotal role of gut microbiota in sustaining local and systemic homeostasis, has a fundamental role in the pathogenesis of Inflammatory Bowel Disease (IBD). The integration of signals deriving from the host neuronal, immune, and endocrine systems with signals deriving from the microbiota may influence the development of the local inflammatory injury and impacts also more distal brain regions, underlying the psychophysiological vulnerability of IBD patients. Mood disorders and increased response to stress are frequently associated with IBD and may affect the disease recurrence and severity, thus requiring an appropriate therapeutic approach in addition to conventional anti-inflammatory treatments. This review highlights the more recent evidence suggesting that alterations of the microbiota–gut–brain bidirectional communication axis may concur to IBD pathogenesis and sustain the development of both local and CNS symptoms. The participation of the main microbial-derived metabolites, also defined as “postbiotics”, such as bile acids, short-chain fatty acids, and tryptophan metabolites in the development of IBD-associated gut and brain dysfunction will be discussed. The last section covers a critical evaluation of the main clinical evidence pointing to the microbiome-based therapeutic approaches for the treatment of IBD-related gastrointestinal and neuropsychiatric symptoms.

The "brain–gut axis" is a bidirectional network of information exchange between the gut and the brain, in which tryptophan metabolism plays a central role, which is directly and indirectly regulated by the gut microbiota. Modulation of the gut microbiota composition is a promising therapeutic strategy for diseases associated with dysfunction of the "brain-gut axis". The aim of the study was to summarize the available literature data on the role of tryptophan metabolism in modulating the function of the "brain–gut axis". The current national and international scientific literature on the role of tryptophan metabolism in modulating the brain–gut axis was analyzed. To search for literature sources, the databases Scopus, PubMed, ResearchGate, Wiley Online Library, Google Scholar for 2018–2024 were studied, a total of 33 sources. The study described the mechanisms of serotonin and kynurenine synthesis. The impact of the gut microbiota on tryptophan metabolism in the gastrointestinal tract is considered. The role and place of serotonin, kynurenine and microbial tryptophan metabolites in the functioning of the "brain–gut axis" are described. We concluded that the gut microbiota modulates the function of the "brain–gut axis" through the interaction between the immune system, bacterial metabolites, and changes in tryptophan metabolism. Due to the fact that the composition of the gut microbiota of animals and humans is different, it is not possible to extrapolate the results of animal studies on the pathogenesis, pathophysiology and treatment of "brain–gut axis" disorders to the human population. There is a need for further human studies to explore the possibility of using tryptophan and its metabolites as biomarkers for diagnosis and development of new therapeutic strategies for diseases associated with "brain–gut axis" dysfunction. One of the options for such treatment may be methods of intestinal microbiota rebiosis that modulate tryptophan availability. Keywords: serotonin, kynurenine, central nervous system, gut, gut microbiota.