Cold stress-induced ferroptosis in liver sinusoidal endothelial cells determines liver transplant injury and outcomes.

Although cold preservation remains the gold standard in organ transplantation, cold stress-induced cellular injury is a significant problem in clinical orthotopic liver transplantation (OLT). Because a recent study showed that cold stress activates ferroptosis, a form of regulated cell death, we investigated whether and how ferroptosis determines OLT outcomes in mice and humans. Treatment with ferroptosis inhibitor (ferrostatin-1) during cold preservation reduced lipid peroxidation (malondialdehyde; MDA), primarily in liver sinusoidal endothelial cells (LSECs), and alleviated ischemia/reperfusion injury in mouse OLT. Similarly, ferrostatin-1 reduced cell death in cold-stressed LSEC cultures. LSECs deficient in nuclear factor erythroid 2-related factor 2 (NRF2), a critical regulator of ferroptosis, were susceptible to cold stress-induced cell death, concomitant with enhanced endoplasmic reticulum (ER) stress and expression of mitochondrial Ca2+ uptake regulator (MICU1). Indeed, supplementing MICU1 inhibitor reduced ER stress, MDA expression, and cell death in NRF2-deficient but not WT LSECs, suggesting NRF2 is a critical regulator of MICU1-mediated ferroptosis. Consistent with murine data, enhanced liver NRF2 expression reduced MDA levels, hepatocellular damage, and incidence of early allograft dysfunction in human OLT recipients. This translational study provides a clinically applicable strategy in which inhibition of ferroptosis during liver cold preservation mitigates OLT injury by protecting LSECs from peritransplant stress via an NRF2-regulatory mechanism.

Simplified risk stratification in early cholecystectomy for acute cholecystitis based on age: A report from an institution with zero mortality.

BACKGROUND/PURPOSE: The existing risk stratification for early cholecystectomy in patients with acute cholecystitis (AC) is complex. This study aims to establish a simpler risk assessment for surgical complications after cholecystectomy based on age group. METHODS: This single-center retrospective observational study enrolled 350 patients diagnosed with AC who underwent early cholecystectomy within 72 h of diagnosis from 2013 to 2021. Patients were divided into three subgroups based on age: young (<65 years), elderly (65-79 years), and very elderly (≥80 years). Since no mortality was observed, risk factors for the Clavien-Dindo (CD) grade ≥ II complications were identified within the entire cohort and in each subgroup. RESULTS: There were 120 young, 130 elderly, and 100 very elderly patients. The overall prevalence of complications with CD grade ≥ II was 11.1%. Age and Tokyo Guidelines 18 (TG18) severity were independent risk factors for surgical complications in the whole cohort. Subgroup analysis revealed that there was no independent risk factor in the young group. Meanwhile, age and poor physical status were independent risk factors in the elderly group, and TG18 severity in the very elderly group. CONCLUSION: Evaluation of only age, physical status, and TG18 severity may be sufficient for risk stratification of surgical complications of AC.

Occult bacteremia in living donor liver transplantation: a prospective observational study of recipients and donors.

PURPOSE: To investigate the incidence and clinical impact of occult bacteremia in liver transplantation (LT). METHODS: This prospective observational study involved a fixed-point observation for up to 2 weeks after living donor LT in 20 recipients, with 20 donors as comparison subjects. Bacteria in the blood samples were detected using the ribosomal RNA-targeted reverse-transcription quantitative polymerase chain reaction method. To identify the causality with the gut microbiota (GM), fecal samples were collected and analyzed simultaneously. RESULTS: Occult bacteremia was identified in four recipients (20%) and three donors (15%) before the operation, and in seven recipients (35%) and five donors (25%) after the operation. Clostridium leptum subgroup, Prevotella, Colinesella, Enterobacteriaceae, and Streptococcus were the main pathogens responsible. Although it did not negatively affect the donor post-hepatectomy outcomes, the recipients with occult bacteremia had a higher rate of infectious complications post-LT. The GM analyses showed fewer post-LT predominant obligate anaerobes in both the recipients and donors with occult bacteremia. CONCLUSIONS: Occult bacteremia is a common condition that occurs in both donors and recipients. While occult bacteremia generally remains subclinical in the healthy population, there is potential risk of the development of an apparent post-LT infection in recipients who are highly immunosuppressed.

SIRT1 regulates hepatocyte programmed cell death via GSDME - IL18 axis in human and mouse liver transplantation.

Sirtuin 1 (SIRT1) is a histone/protein deacetylase in the cellular response to inflammatory, metabolic, and oxidative stressors. We previously reported that myeloid SIRT1 regulates the inflamed liver's canonical pyroptosis cell death pathway. However, whether/how hepatocyte SIRT1 is engaged in programmed cell death in the cold-stressed liver remains uncertain. Here, we undertook translational studies in human and mouse orthotopic liver transplantation (OLT) to interrogate the significance of hepatocyte-specific SIRT1 in cold-stored donor livers and liver grafts after reperfusion. In the clinical arm of sixty human OLT patients, hepatic SIRT1 levels in cold-preserved donor livers correlated with the anti-apoptotic Bcl-2 expression. After reperfusion, improved OLT function was accompanied by hepatic SIRT1 levels negatively associated with cleaved caspase-3 expression. In the experimental arm, we compared FLOX-control with hepatocyte-specific SIRT1-KO livers after orthotopic transplantation into WT mouse recipients, parallel with primary murine hepatocyte cultures subjected to cold activation with/without knockdown of SIRT1, GSDME, and IL18Rß. Indeed, hepatocyte SIRT1 deficiency upregulated apoptosis and GSDME-mediated programmed cell death, deteriorating hepatocellular function and shortening OLT survival. Augmented GSDME processing, accompanied by increased secretion of IL18 by stressed hepatocytes, was prominent in SIRT1-deficient, cold-stored livers. Hepatocyte SIRT1 expression regulated anti-apoptotic Bcl-2/XIAP proteins, suppressed cold stress-triggered apoptosis, and mitigated GSDME licensing to release IL18. Notably, consistent with the ability of IL18 to depress hepatocyte SIRT1 and Bcl-2/XIAP in vitro, IL18 neutralization in vivo prevented hepatocellular damage and restored the anti-apoptotic phenotype in otherwise injury-prone SIRT1-deficient OLTs. In conclusion, this translational study identifies a novel hepatocyte SIRT1-IL18 molecular circuit as a therapeutic target in the mechanism underpinning hepatocyte death pathways in human and mouse liver transplantation.

New therapeutic concepts against ischemia-reperfusion injury in organ transplantation.

INTRODUCTION: Ischemia-reperfusion injury (IRI) involves a positive amplification feedback loop that stimulates innate immune-driven tissue damage associated with organ procurement from deceased donors and during transplantation surgery. As our appreciation of its basic immune mechanisms has improved in recent years, translating putative biomarkers into therapeutic interventions in clinical transplantation remains challenging. AREAS COVERED: This review presents advances in translational/clinical studies targeting immune responses to reactive oxygen species in IRI-stressed solid organ transplants, especially livers. Here we focus on novel concepts to rejuvenate suboptimal donor organs and improve transplant function using pharmacologic and machine perfusion (MP) strategies. Cellular damage induced by cold ischemia/warm reperfusion and the latest mechanistic insights into the microenvironment's role that leads to reperfusion-induced sterile inflammation is critically discussed. EXPERT OPINION: Efforts to improve clinical outcomes and increase the donor organ pool will depend on improving donor management and our better appreciation of the complex mechanisms encompassing organ IRI that govern the innate-adaptive immune interface triggered in the peritransplant period and subsequent allo-Ag challenge. Computational techniques and deep machine learning incorporating the vast cellular and molecular mechanisms will predict which peri-transplant signals and immune interactions are essential for improving access to the long-term function of life-saving transplants.

SIRT1 Regulates Hepatocyte Programmed Cell Death via GSDME - IL18 Axis in Human and Mouse Liver Transplantation.

Sirtuin 1 (SIRT1) is a histone/protein deacetylase involved in cellular senescence, inflammation, and stress resistance. We previously reported that myeloid SIRT1 signaling regulates the inflamed liver's canonical pyroptosis cell death pathway. However, whether/how hepatocyte SIRT1 is engaged in programmed cell death in the cold-stressed liver remains uncertain. Here, we undertook translational studies in human and mouse orthotopic liver transplantation (OLT) to interrogate the significance of hepatocyte-specific SIRT1 signaling in cold-stored donor livers and liver grafts after reperfusion. In the clinical arm of sixty human OLT patients, hepatic SIRT1 levels in cold-preserved donor livers correlated with anti-apoptotic Bcl-2 expression. After reperfusion, improved OLT function was accompanied by hepatic SIRT1 levels negatively associated with cleaved caspase-3 expression. In the experimental arm, we compared FLOX-control with hepatocyte-specific SIRT1-KO livers after orthotopic transplantation into WT mouse recipients, parallel with primary murine hepatocyte cultures subjected to cold activation with/without knockdown of SIRT1, GSDME, and IL18Rß signaling. Hepatocyte SIRT1 deficiency upregulated apoptosis and GSDME-mediated programmed cell death, which in turn deteriorated the hepatocellular function and shortened OLT survival. Augmented GSDME processing, accompanied by increased secretion of IL18 by stressed hepatocytes, was prominent in SIRT1-deficient, cold-stored livers. Hepatocyte SIRT1 signaling regulated anti-apoptotic Bcl-2/XIAP proteins, suppressed cold stress-triggered apoptosis, and mitigated GSDME licensing to release IL18. Notably, while crosslinking IL18R depressed SIRT1 and Bcl-2/XIAP signaling in vitro, IL18 neutralization in vivo prevented hepatocellular damage and restored the anti-apoptotic phenotype in otherwise injury-prone SIRT1-deficient OLTs. In conclusion, this translational study identifies a novel hepatocyte SIRT1-IL18 signaling circuit as a therapeutic target in the mechanism underpinning hepatocyte death in human and mouse liver transplantation.

T Cell CEACAM1-TIM-3 Crosstalk Alleviates Liver Transplant Injury in Mice and Humans.

BACKGROUND & AIMS: Carcinoembryonic antigen-related cell adhesion molecule 1 (CC1) acts through homophilic and heterophilic interactions with T cell immunoglobulin domain and mucin domain-containing protein 3 (TIM-3), which regulates innate immune activation in orthotopic liver transplantation (OLT). We investigated whether cluster of differentiation (CD) 4+ T cell-dependent CC1-TIM-3 crosstalk may affect OLT outcomes in mice and humans. METHODS: Wild-type (WT) and CC1-deficient (CC1 knock-out [KO]) mouse livers were transplanted into WT, CC1KO, or T-cell TIM-3 transgenic (TIM-3Tg)/CC1KO double-mutant recipients. CD4+ T cells were adoptively transferred into T/B cell-deficient recombination activating gene 2 protein (Rag2) KO recipients, followed by OLT. The perioperative liver-associated CC1 increase was analyzed in 50 OLT patients. RESULTS: OLT injury in WT livers deteriorated in CC1KO compared with CC1-proficient (WT) recipients. The frequency of TIM-3+CD4+ T cells was higher in WT than CC1KO hosts. Reconstitution of Rag2KO mice with CC1KO-T cells increased nuclear factor (NF)-κB phosphorylation and OLT damage compared with recipients repopulated with WT T cells. T-cell TIM-3 enhancement in CC1KO recipients (WT â†’ TIM3Tg/CC1KO) suppressed NF-κB phosphorylation in Kupffer cells and mitigated OLT injury. However, TIM-3-mediated protection was lost by pharmacologic TIM-3 blockade or an absence of CC1 in the donor liver (CC1KO â†’ TIM-3Tg/CC1KO). The perioperative CC1 increase in human OLT reduced hepatocellular injury, early allograft dysfunction, and the cumulative rejection rate. CONCLUSIONS: This translational study identifies T cell-specific CC1 signaling as a therapeutic means to alleviate OLT injury by promoting T cell-intrinsic TIM-3, which in turn interacts with liver-associated CC1 to suppress NF-κB in Kupffer cells. By suppressing peritransplant liver damage, promoting T-cell homeostasis, and improving OLT outcomes, recipient CC1 signaling serves as a novel cytoprotective sentinel.

Association Between Constipation and a Reduction in Lower Limb Muscle Strength in Preoperative Patients with Thoracic Spinal Tumors.

Objective To investigate the clinical symptoms experienced by patients with thoracic spinal tumors and verify the associated symptoms that are predictive of a decline in muscle strength in the lower limbs. Methods A single-center, retrospective cross-sectional study was conducted on in-patients diagnosed with epidural thoracic spinal tumors between January 2011 and May 2021. The study involved a review of electronic medical records and radiographs and the collection of clinical data. The differences in clinical manifestations between patients with constipation and those without constipation were analyzed. Binary logistic regression analyses were performed to identify risk factors associated with a decline in muscle strength in the lower limbs.Results A total of 227 patients were enrolled, including 131 patients with constipation and 96 without constipation. The constipation group had a significantly higher proportion of patients who experienced difficulty walking or paralysis compared to those without constipation prior to surgery (83.2% vs. 17.7%, χ2 = 99.035,P < 0.001). Constipation (OR = 9.522, 95%CI: 4.150-21.849, P < 0.001) and urinary retention (OR = 14.490, 95%CI: 4.543-46.213, P < 0.001) were independent risk factors for muscle strength decline in the lower limbs. Conclusions The study observed that patients with thoracic spinal tumors who experienced constipation symptoms had a higher incidence of lower limb weakness. Moreover, the analysis revealed that constipation and urinary retention were independent risk factors associated with a preoperative decline in muscle strength of lower limbs.

Comparison of clinical outcomes of modified laminoplasty with preservation of muscle group inserted into C2 and C7 spinous processes versus conventional C3-C7 laminoplasty: a prospective, randomized, controlled, noninferiority trial.

BACKGROUND: The efficacy and noninferior of performing modified double-door laminoplasty (MDDL) (C4-C6 laminoplasty plus C3 laminectomy, alongside a dome-like resection of the inferior part of the C2 lamina and the superior part of the C7 lamina) in patients with multilevel cervical spondylotic myelopathy (MCSM) is equivocal. A randomized, controlled trial is warranted. OBJECTIVE: The objective was to evaluate the clinical efficacy and noninferior of MDDL compared with traditional C3-C7 double-door laminoplasty. STUDY DESIGN: A single-blind, randomized, controlled trial. METHODS: A single-blind, randomized, controlled trial was conducted in which patients who with MCSM with greater than or equal to 3 levels of spinal cord compression from the C3 to the C7 vertebral levels were enrolled and assigned to undergo either MDDL group or conventional double-door laminoplasty (CDDL) group in a 1:1 ratio. The primary outcome was the change in the Japanese Orthopedic Association score from baseline to 2-year follow-up. The secondary outcomes included changes in the Neck Disability Index (NDI) score, the Visual Analog Scale (VAS) for neck pain, and imaging parameters. Operative complications were also collected and reported. The outcome measures were compared between the groups at 3 months, 1 year, or 2 years after surgery. RESULTS: A total of 96 patients (mean age 67 years, 39.8% women) underwent randomization. Of these patients, 93 completed 3-month follow-up, 79 completed 1-year follow-up, and 66 completed 2-year follow-up. The changes in the Japanese Orthopedic Association score did not differ significantly between the study groups at the three time points after surgery. With respect to amelioration of neck pain and disability related to neck pain, patients in the MDDL group had a significantly greater decrease in the VAS and NDI component summary score than did those in the CDDL group at 1-year (VAS: -2.5 vs. -3.2, difference -0.7, 95% CI -1.1 to -0.2, P =0.0035; NDI: -13.6 vs. -19.3, difference -5.7, 95% CI -10.3 to -1.1, P =0.0159) and 2-years (VAS: -2.1 vs. -2.9, difference -0.8, 95% CI -1.4 to -0.2, P =0.0109; NDI: -9.3 vs. -16.0, difference -6.7, 95% CI -11.9 to -1.5, P =0.0127). The changes in the range of motion (ROM), the C2-C7 Cobb angle, and the cervical sagittal vertical axis in the MDDL group were significantly less than those in the CDDL group (ROM: -9.2±6.4 vs. -5.0±6.0, P =0.0079; C2-C7 Cobb angle: -7.9±7.8 vs. -4.1±6.2, P =0.0345; cervical sagittal vertical axis: 0.6±0.9 vs. 0.2±0.6, P =0.0233). The MDDL group had less blood loss (428.1 vs. 349.1, P =0.0175) and a lower rate of axial symptoms (27.3 vs. 6.1%, P =0.0475) than the CDDL group. CONCLUSIONS: Among patients with MCSM, the MDDL produced similar cervical cord decompression compared with the conventional C3-C7 double-door laminoplasty. The modified laminoplasty was associated with meaningful improvement in amelioration of neck discomfort, maintaining a better cervical ROM and sagittal alignment, decreasing blood loss, and reducing the incidence of axial symptoms.

A peptide rich in glycine-serine-alanine repeats ameliorates Alzheimer-type neurodegeneration.

BACKGROUND AND PURPOSE: Repeated amino acid sequences in proteins are widely found, and the glycine-serine-alanine repeat is an element with a general propensity to form ß-sheet aggregates as found in key pathological factors, in several neurodegenerative diseases. Such properties of this repeat may guide development of disease-modifying therapies for neurodegenerative disease. However, details of its role and underlying mechanism(s) remain largely unknown. EXPERIMENTAL APPROACH: Actions of specific glycine-serine-alanine repeat peptides (SNPs), especially SNP-9, on Alzheimer's disease (AD)-like abnormalities were evaluated in transgenic mice and Caenorhabditis elegans, and in rat and cell models. Entry of SNPs into the brain, SNP activity in neuronal cells and peptide entry into cells were analysed in vivo and in vitro. Cell-free systems and the yeast two-hybrid system were also used to explore possible targets of SNP-9, and interactions of potential targets with SNP-9 were confirmed in cell-based systems. KEY RESULTS: We first identified SNP-9 as a potent neuroprotective peptide with the activity to decrease oligomeric amyloid ß (Aß) via co-assembling with the toxic Aß oligomer to form hetero-oligomers. Also, calcyclin-binding protein was found to act as a SNP-9-binding protein, by screening of a human brain cDNA library. Such binding showed that SNP-9 could regulate the abnormal hyperphosphorylation of tau via calcyclin-binding protein. CONCLUSION AND IMPLICATIONS: Our study provides a foundation for development of SNPs, especially SNP-9, as potential therapeutic interventions for AD. We propose SNP-9 as a potential therapeutic agent for the treatment of AD.

Surgeons' involvement in COVID-19 treatment: a practice by a regional core hospital in Japan to avoid physician burnout.

BACKGROUND: To prevent task accumulation on certain divisions, our institution developed a unique system of allocating inpatient treatment of COVID-19 patients to doctors who were not specialized in respiratory infections. The objective of this study was to investigate whether surgeons can be involved in the COVID-19 inpatient treatment without negatively affecting patient outcome, and how such involvement can affect the wellbeing of surgeons. METHODS: There were 300 patients diagnosed with COVID-19 and hospitalized from January to June 2021, and 160 of them were treated by the redeployed doctors. They were divided into 3 groups based on the affiliation of the treating doctor. Patient characteristics and outcomes were compared between the groups. In addition, the impact of COVID-19 duty on participating surgeons was investigated from multiple perspectives, and a postduty survey was conducted. RESULTS: There were 43 patients assigned to the Department of Surgery. There were no differences in the backgrounds and outcomes of patients compared with other groups. The surgeon's overtime hours were significantly longer during the duty period, despite no change in the number of operations and the complication rate. The questionnaire revealed that there was a certain amount of mental and physical burden from the COVID-19 duty. CONCLUSION: Surgeons can take part in inpatient COVID-19 treatment without affecting patient outcome. However, as such duty could negatively affect the surgeons' physical and mental wellbeing, further effort is needed to maintain the balance of fulfilling individual and institutional needs.

Impact of very early introduction of everolimus on liver regeneration after partial liver transplantation in rats.

BACKGROUND/PURPOSE: This experimental study in rats aimed to investigate the impact of very early introduction (within 3 h) of everolimus (EVR) + reduced-tacrolimus (TAC) after partial liver transplantation (LT) on liver regeneration, rejection, and survival. METHODS: Based on appropriate dose of EVR + reduced-TAC in 70% hepatectomy (Experiment 1), allogeneic 30% partial LT (Experiment 2) and whole LT (Experiment 3) were performed. RESULTS: After partial LT in EVR + reduced-TAC therapy, restoration of liver graft weight (to that of the whole liver) was delayed compared with standard dose TAC monotherapy (standard-TAC) on day 3 (59.3% vs. 72.9%; p < .001) and 14 (88.1% vs. 95.5%; p = .01). Survival was 75%, which was not as high as the value of 100% observed for standard-TAC, because neither infection nor rejection could be prevented. By contrast, survival after whole LT was 100% as neither infection nor rejection occurred. CONCLUSIONS: The very early introduction of EVR + reduced-TAC after partial LT delayed liver regeneration, and made it difficult to manage the dose required to suppress both infection and rejection. On the other hand, EVR + reduced-TAC could be introduced safely very early after whole LT.

Stepwise Approach for Acquisition of Microsurgical Skills through Rat Orthotopic Liver Transplantation Experiments.

Although rat liver transplantation (LT) is useful in training surgeons to perform microsurgery, mastering these surgical techniques remains difficult. Systematized training protocols that enable learning of the proper skills in a short period of time are needed. The present study describes an efficient five-step rat LT training protocol for surgeons designed to be mastered within 3 months through continuous training. The first step was to review all procedures by watching full videos of rat LT and to watch actual LT operations performed by a skilled surgeon, enabling recognition of the anatomy of rat abdominal organs. The second step was to perform ten donor operations, including ex vivo graft preparation, to learn the atraumatic and delicate techniques. The third step was to perform ten LTs, with the goal of achieving an anhepatic time <20 min and surviving until the next day. The fourth step was to perform ten additional LTs, with the goal of achieving 7 days of survival. The fifth step was to perform 5-10 more LTs, with the goal of achieving 7 days of survival in five consecutive LT operations. Systematizing the training was found to increase its efficiency. Furthermore, determining the specific number of operations in advance is useful to maintain motivation for training. Mastering efficient rat LT will not only enhance the success of preclinical research but will enable young surgeons to better perform vascular anastomoses under a microscope in humans.

Nonsuperiority of technetium-99m-galactosyl human serum albumin scintigraphy over conventional volumetry for assessing the future liver remnant in patients undergoing hepatectomy after portal vein embolization.

BACKGROUND: Technetium-99m-galactosyl human serum albumin scintigraphy is preferred for assessing the liver functional reserve in patients undergoing hepatectomy, but its superiority over computed tomography volumetry after portal vein embolization and subsequent hepatectomy remains elusive. We aimed to compare technetium-99m-galactosyl human serum albumin scintigraphy with conventional computed tomography volumetry for predicting posthepatectomy liver failure in patients after portal vein embolization. METHODS: This retrospective study analyzed 152 consecutive patients who underwent hepatobiliary cancer resection after portal vein embolization between 2006 and 2021. Posthepatectomy liver failure was graded according to the International Study Group of Liver Surgery criteria. The predictive abilities for posthepatectomy liver failure were compared between the future remnant uptake (%) by technetium-99m-galactosyl human serum albumin scintigraphy and the future remnant volume (%) by computed tomography volumetry. RESULTS: Future remnant uptake (%) was significantly greater than future remnant volume (%) after portal vein embolization (47.9% vs 40.8%; P < .001), while the values were comparable before portal vein embolization (32.7% vs 31.2%; P = .116). Receiver operating characteristic curve analysis revealed that post-portal vein embolization future remnant volume (%) had a significantly higher area under the curve than post-portal vein embolization future remnant uptake (%) (0.709 vs 0.630; P = .046) for predicting posthepatectomy liver failure. Multivariable analysis revealed that post-portal vein embolization future remnant volume (%) independently predicted posthepatectomy liver failure, but future remnant uptake (%) did not. Although the incidence of posthepatectomy liver failure grade ≥B was 17.8% when indocyanine green-clearance of the future liver remnant based on both future remnant volume (%) and future remnant uptake (%) was ≥0.05, it was higher in other combinations: 55.6% for indocyanine green clearance of the remnant volume ≥0.05/indocyanine green clearance of the remnant uptake ≤0.05; 50.0% for indocyanine green clearance of the remnant volume ≤0.05/indocyanine green clearance of the remnant uptake ≥0.05; and 50% for indocyanine green clearance of the remnant volume ≤0.05/indocyanine green clearance of the remnant uptake ≤0.05. CONCLUSIONS: Technetium-99m-galactosyl human serum albumin scintigraphy is not superior to computed tomography volumetry for assessing the future liver remnant in patients undergoing major hepatectomy after portal vein embolization.

Chronological changes in the gut microbiota and intestinal environment in recipients and donors of living donor liver transplantation.

BACKGROUND/PURPOSE: This prospective study aimed to investigate the dynamic changes in the gut microbiota (GM) and associated intestinal environment, which were assessed by measuring fecal organic acid (OA) concentrations, during the early period after liver transplantation (LT). To understand the fundamental characteristics of the human GM, data obtained from living donors were also analyzed. METHODS: Fixed-point observation was performed in 23 recipients and 21 donors for up to 2 weeks after LT. The GM and OA concentrations were investigated using ribosomal RNA-targeted reverse-transcription quantitative polymerase chain reaction and high-performance liquid chromatography, respectively. RESULTS: Before LT, the recipients exhibited remarkable dysbiosis and OA depletion, which were proportional to the model for end-stage liver disease score. Correlations between the abundances of some specific strains and OA concentrations were observed. After LT, while donor lobectomy caused only slight, transient and reversible changes in the GM and OA concentrations, recipients exhibited delayed recovery in these factors. However, no clear evidence of causality was observed between the GM or OA concentrations and LT outcomes. CONCLUSIONS: The GM and intestinal environment in LT recipients exhibited characteristics that were clearly different from those in donors. LT did not normalize but rather disrupted the GM during the early post-LT period, but its negative clinical impact could be minimized with perioperative management.

Is Palliative Gastrojejunostomy for Malignant Gastric Outlet Obstruction an Optimal Choice for Very Elderly Patients? A Report from a Long-Lived Country.

BACKGROUND: Gastrojejunostomy (GJ) is a surgical option for malignant gastric outlet obstruction (mGOO). Confronting an aging society, the demand to treat elderly cancer patients with unresectable malignancies is increasing; however, the benefit of GJ to the very elderly (≥ 80 years of age) has never been investigated. METHODS: This multicenter, retrospective review included 108 patients who had undergone GJ for mGOO from two medical centers in Japan, one of the most long-lived countries. Patients were divided into two groups, with 80 years of age as the cut-off. Various factors, including surgical complications and patient survival, were compared. RESULTS: GJ in the very elderly (aged ≥ 80 years) was associated with a higher incidence of surgical complications (p = 0.049), such as delayed gastric emptying (DGE; p < 0.001), aspiration pneumonia (p = 0.029), and consequent mortality (p = 0.016). Age ≥80 years was also identified as an independent predictor of DGE (odds ratio 6.444, p = 0.005) and survival after GJ (hazard ratio 7.767, p = 0.016). In particular, the median survival time after GJ in the population aged ≥80 years with gastric cancer was only < 2 months. About the surgical procedure, antiperistaltic anastomosis with partial stomach partitioning (PSP) yielded the lowest occurrence rate of DGE (3.4%) and aspiration pneumonia (1.7%). CONCLUSIONS: GJ does not seem to be the optimal choice for very elderly patients, particularly those with gastric cancer. If performed, antiperistaltic anastomosis with PSP should be employed to reduce the surgical complications.

Dysbiosis and Depletion of Fecal Organic Acids Correlate With the Severity of Rejection After Rat Liver Transplantation.

The impact of T cell-mediated rejection (TCMR) after liver transplantation (LT) on the alterations in the gut microbiota (GM) and associated intestinal environment represented by fecal organic acids (OAs) require further elucidation. A rat allogeneic LT model was prepared without immunosuppressants or antibiotics, and a syngeneic model was used as a control. Qualitative and quantitative analyses of fecal samples at fixed time points were performed. Correlation analyses were also performed between liver function and GMs and OA levels. In the allogeneic TCMR group, the number of predominant obligate anaerobes decreased as liver function declined. Clostridioides difficile, Enterobacteriaceae, Enterococcus, Streptococcus, and Staphylococcus were significantly increased. Regarding fecal OA concentration, short-chain fatty acid (SCFA) concentrations were depleted as liver function declined. In contrast, in the syngeneic group, GM and OAs exhibited only slight, transient, and reversible disturbances. In addition, alanine aminotransferase and total bilirubin were positively correlated with the number of Enterobacteriaceae and Enterococcus, and negatively correlated with the fecal concentration of SCFAs. The allogeneic TCMR model demonstrated distinct dysbiosis and depletion of fecal OAs as TCMR progressed after LT. The degree of graft injury was closely related to the number of specific bacterial strains and the concentrations of fecal SCFAs.

Perioperative Oral ß-Hydroxy-ß-Methylbutyrate Supplementation Ameliorates Sarcopenia in Rats Undergoing Major Hepatectomy.

ß-Hydroxy-ß-methylbutyrate (HMB), a metabolite of leucine, is known to increase muscle mass and strength. However, the effect of perioperative HMB supplementation in liver surgery is unclear. Moreover, the impact of HMB on the skeletal muscle fiber type also remains unclear. We investigated the impact of HMB on the body composition and skeletal muscle fiber type in sarcopenic rats undergoing major hepatectomy. Nine-week-old male F344/NSlc rats were maintained in hindlimb suspension (HLS) and were forcedly supplemented with HMB calcium salt (HMB-Ca, 0.58 g/kg×2 times) or distilled water in addition to free feeding. After 2 wk of HLS, the rats underwent 70% hepatectomy and were sacrificed 3 d after surgery. Body composition factors and the proportion of slow-twitch fibers in hindlimb muscles were evaluated. HMB maintained the body composition and hindlimb force and acted against their deterioration in sarcopenic rats, exerting a particular effect on lean mass weight, which was significant. In the histological study, HMB significantly increased the proportion of slow-twitch fibers in the soleus (p=0.044) and plantaris (p=0.001) of sarcopenic rats. HMB ameliorated deterioration of the body composition and increased the proportion of slow-twitch fibers in sarcopenic rats undergoing major hepatectomy.