Background/Objectives: Functional diarrhea (FDr) is a common gastrointestinal disorder, and alterations in the gut microbiota have been proposed as one of its potential pathophysiological mechanisms. Hydrogen/methane breath tests are commonly used to identify findings suggestive of small intestinal bacterial overgrowth (SIBO) and intestinal methanogen overgrowth (IMO), whereas fecal calprotectin (FC) serves as a marker of intestinal inflammation. However, the prevalence of these findings and their relationship in patients with FDr remain unclear. This study aimed to determine the prevalence of positive breath test findings (suggestive of SIBO/IMO) and detectable/elevated FC in patients with a diagnosis of FDr and to evaluate their cross-sectional relationship and phenotypic overlap. Methods: We retrospectively reviewed patients who underwent both a lactulose breath test and FC measurement between March 2015 and April 2021 and fulfilled the Rome IV criteria for FDr. Positive breath test findings suggestive of SIBO/IMO were defined as a hydrogen increase of ≥20 ppm within 90 min or a methane increase of ≥10 ppm at any time following ingestion of 10 g of lactulose. FC was evaluated at two thresholds: the analytical limit of detection (LOD ≥ 11.5 mg/kg), used as an exploratory threshold to distinguish detectable from non-detectable FC, and the conventional clinical cutoff (>50 mg/kg), used to identify clinically elevated FC levels. Results: Among 524 patients with FDr aged ≥ 20 years, 176 (33.6%) had positive breath test findings suggestive of SIBO/IMO, 177 (33.8%) had detectable FC (≥11.5 mg/kg), and 71 (13.5%) met the conventional cutoff (>50 mg/kg). Concurrent breath test positivity and detectable FC (≥11.5 mg/kg) were present in 52 patients (9.9%), while only 19 patients (3.6%) exhibited concurrent breath test positivity and clinically elevated FC (>50 mg/kg). Conclusions: Approximately one-third of patients with Rome IV-defined FDr demonstrated positive breath test findings suggestive of SIBO/IMO, and a similar proportion had detectable FC concentrations (≥11.5 mg/kg), whereas clinically elevated FC (>50 mg/kg) was present in 13.5% (71/524). Positive breath test findings and FC elevation showed no significant cross-sectional association at either threshold. These findings provide descriptive prevalence estimates and do not establish mechanistic relationships between breath test positivity and FC elevation in patients with Rome IV-defined FDr.

Sugar fatty acid esters have a wide range of applications in food, cosmetic, detergent, and pharmaceutical industries due to their excellent surface and antimicrobial properties. Additionally, some sugar esters are insecticides and acaricides. In this work, we described the enzymatic synthesis of lactulose monoesters, their purification, and qualitative and quantitative chromatographic analysis.

Hepatic encephalopathy (HE) is a neuropsychiatric complication of liver failure associated with hyperammonemia, oxidative stress, and neuroinflammation. This study investigated the hepatoprotective and neuroprotective effects of trans-ferulic acid (TFA), a dietary phenolic compound, administered alone or in combination with lactulose, in a thioacetamide-induced rat model of HE. TFA treatment significantly improved liver function, reduced serum ammonia, and restored hepatic and cerebral histoarchitecture. TAA-induced motor dysfunction and altered behavioral performance were also ameliorated by TFA and lactulose, with the combination treatment producing greater overall improvement. However, these behavioral effects were interpreted in the context of concomitant locomotor impairment, particularly for spatial learning and exploratory behavior. Mechanistically, TFA enhanced antioxidant defense by activating the Nrf2/HO-1 pathway, while suppressing hepatic and cerebral inflammation through inhibition of the TLR-4/NF-κB/NLRP3 inflammasome axis. These findings demonstrate that TFA exerts dual antioxidant and anti-inflammatory actions and enhances lactulose efficacy, highlighting its potential as a functional food-derived adjunctive strategy for HE management.

Hyperammonemic encephalopathy is an uncommon but potentially life-threatening and reversible cause of acute altered sensorium, most often associated with hepatic dysfunction but increasingly recognized in patients receiving chemotherapy. We report the case of a 50-year-old woman who developed progressive disorientation and reduced responsiveness one hour after completing her first cycle of FOLFOX-6 (5-fluorouracil, leucovorin, and oxaliplatin) following hemicolectomy for splenic flexure carcinoma. Initial neuroimaging and infectious workup were unremarkable. Despite correction of transient renal dysfunction, neurological status did not improve. Serum ammonia was markedly elevated, and a diagnosis of non-hepatic hyperammonemic encephalopathy secondary to chemotherapy was made. Prompt discontinuation of FOLFOX and initiation of lactulose resulted in rapid and complete clinical recovery. This case highlights the importance of early recognition of chemotherapy-induced metabolic encephalopathy, particularly fluoropyrimidine-associated toxicity, and emphasizes serum ammonia estimation in unexplained post-chemotherapy neurological deterioration to ensure timely management and favorable outcomes.

Hepatic encephalopathy remains an underserved complication of chronic liver disease. Reliable diagnostic and prognostic biomarkers linked to disease pathophysiology are currently lacking, as are options for treatment that reduce mortality beyond lactulose and rifaximin. However, with the advent of high-throughput sequencing and multi-omics techniques to interrogate microbial taxonomy and metabolic pathways, our understanding of the gut-liver-brain-axis has moved beyond the ammonia-inflammation hypothesis. This review summarises recent studies that have aimed to characterise the role of the gut-liver-brain axis in hepatic encephalopathy and how this can be leveraged to create novel diagnostic, prognostic and therapeutic agents.

BACKGROUND Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare liver malignancy affecting adolescents and young adults without underlying liver disease. Hyperammonemic encephalopathy (HAE) is an uncommon but severe complication in advanced FLHCC, resulting from progressive hepatic dysfunction or tumor-related metabolic derangements. Early recognition is essential to prevent neurologic decline and improve outcomes. CASE REPORT A 24-year-old man with metastatic FLHCC presented with worsening confusion for 1 month. His prior treatments included transarterial radioembolization, multiple resection surgeries, and multiple chemotherapies. On examination, he was oriented only to self and had asterixis. Laboratory evaluation showed severe hyperammonemia (251 µmol/L), suggesting HAE. MRI brain was unremarkable, and EEG showed moderate encephalopathy. Plasma amino acid analysis showed marked depletion of urea cycle intermediates (citrulline, arginine, ornithine) with low alanine and glutamine, and elevated urinary orotic acid, which suggests impaired ornithine transcarbamylase activity and an acquired urea cycle disorder. Treatment was initiated with rifaximin and lactulose initially, followed by ammonia scavenger therapy of sodium benzoate-sodium phenylacetate. Despite this treatment, ammonia levels remained elevated, prompting hemodialysis and continuous renal replacement therapy. However, he continued to deteriorate and eventually died of his illness. CONCLUSIONS HAE is a rare paraneoplastic manifestation of FLHCC. Conventional therapies for cirrhosis-related encephalopathy, such as lactulose and rifaximin, are often ineffective. Management instead relies on ammonia-scavenging agents and arginine supplementation, with renal replacement therapies reserved for refractory cases. Outcomes remain poor when encephalopathy persists despite dialysis, underscoring the need for multidisciplinary management and early integration of palliative care.

Epilactose is a promising functional disaccharide, but its biomanufacturing is limited by insufficient enzyme activity, poor thermostability, and costly catalyst preparation. We first used the REME platform to computationally evaluate candidate enzymes. Among them, cellobiose 2-epimerase from Caldicellulosiruptor saccharolyticus (CsCE) showed the highest epilactose synthesis activity. We therefore developed an integrated strategy combining computational design, SpyTag/SpyCatcher-mediated cyclization, and ethanol-permeabilized whole-cell catalysis. By combining enzyme ligand binding energy analysis, protein stability prediction, and catalytic constant prediction, the V52N variant was obtained. Its epilactose synthesis activity was 3.45 times that of the wild type, while lactulose formation was reduced to 14.8% of the wild-type level. Cyclized CCT increased the optimum temperature to 80 °C and extended the half-life at 85 °C by 5.52-fold. The optimized whole-cell process produced 65.81 g/L epilactose from 200 g/L lactose within 20 min, corresponding to 32.90% conversion. This strategy provides a practical route for efficient epilactose biomanufacturing.

Hepatic encephalopathy (HE) represents a severe neuropsychiatric manifestation secondary to advanced hepatic dysfunction, predominantly driven by hyperammonaemia and associated neuroinflammatory processes. Although lactulose remains a mainstay in the clinical management of HE due to its ammonia-lowering properties, its limited efficacy in attenuating neuroinflammation necessitates the use of adjunctive therapeutic strategies. Previously, we identified berberine, a plant-derived isoquinoline alkaloid, as an anti-HE agent via the reduction of neuroinflammation and NLRP3 inflammasome activation. Therefore, in the present study, we investigated the potential beneficial effects of co-administering berberine and lactulose in a rat model of thioacetamide (TAA)-induced hepatic encephalopathy. HE was induced via intraperitoneal injections of TAA (200 mg/kg) on alternate days for one week. Animals received oral pre-treatment with lactulose (8 mL/kg) alone or in combination with berberine (100 mg/kg) for 14 consecutive days. Comprehensive behavioural assessments were conducted alongside biochemical quantification of systemic ammonia, hepatic transaminases (ALT, AST), and oxidative stress markers (MDA, GSH) in both hepatic and cerebral tissues. Histopathological evaluations of the liver and brain further corroborated the biochemical findings. Notably, combination therapy significantly ameliorated cognitive deficits, reduced systemic ammonia burden, normalised liver and brain enzyme profiles, and markedly attenuated central neuroinflammatory signalling, as evidenced by reduced hippocampal NF-κB activation and GFAP immunoreactivity, in addition to suppressing hepatic NF-κB expression, surpassing the effects observed with monotherapy. Histological analyses revealed reduced neuronal degeneration and hepatic architectural disruption. These findings underscore the therapeutic potential of berberine-lactulose co-treatment in mitigating both hepatic and neuroinflammatory pathologies associated with HE, offering a promising adjunctive strategy for improving neurocognitive outcomes in liver failure.

Bariatric surgery is an effective treatment for obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Although most patients experience improvement in hepatic steatosis and fibrosis after surgery, severe hepatic decompensation has rarely been reported following malabsorptive procedures. Early recognition of potentially reversible causes of liver failure is essential to prevent progression to irreversible hepatic injury or liver transplantation. We report the case of a 54-year-old woman with obesity-related MASLD who underwent revisional single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) following weight regain after Roux-en-Y gastric bypass. Ten months after surgery, she developed progressive hypoalbuminemia, recurrent hyperammonemia, coagulopathy and worsening porto-systemic encephalopathy culminating in grade IV encephalopathy requiring intensive care admission and invasive mechanical ventilation. Extensive investigation excluded alternative causes of acute hepatic deterioration. Despite six weeks of intensive conservative management, including optimized nutritional rehabilitation with high-protein enteral supplementation, vitamin and micronutrient replacement, correction of electrolyte disturbances, and standard medical therapy for hepatic encephalopathy (lactulose and rifaximin), hepatic synthetic function continued to deteriorate. Following multidisciplinary discussion, surgical reversal of the malabsorptive anatomy was undertaken. Liver biopsy demonstrated advanced chronic liver disease with cholestatic changes, macrovesicular steatosis and severe secondary hepatic siderosis. Neurological improvement was observed within the first postoperative days, with complete resolution of hepatic encephalopathy and normalization of serum ammonia levels by postoperative day five, followed by progressive recovery of hepatic synthetic function. This case highlights persistent malabsorption as a reversible driver of subacute liver failure in patients with limited hepatic reserve following revisional bariatric surgery. Recognition of this rare complication is essential because timely surgical reversal may interrupt ongoing metabolic injury, restore hepatic function and prevent progression to irreversible liver failure or liver transplantation.

Functional bloating is a common disorder of gut-brain interaction with heterogeneous symptom patterns and uncertain underlying mechanisms. Small intestinal bacterial overgrowth and intestinal methanogen overgrowth have both been implicated in gas-related symptoms; however, the clinical utility of combined lactulose hydrogen-methane breath testing for phenotypic characterization in patients with functional bloating remains incompletely defined. This cross-sectional observational study evaluated whether lactulose hydrogen-methane breath testing could distinguish clinically relevant subgroups among symptomatic patients with functional bloating. Ninety adults with functional bloating underwent standardized lactulose hydrogen-methane breath testing with serial sampling over 120 min. Demographic characteristics, symptom duration, bloating severity, abdominal pain, bowel habit patterns, and breath gas profiles were recorded. Breath test results were categorized as hydrogen-positive, methane-positive, mixed-positive, or negative according to predefined interpretation criteria. Breath testing was positive in 42 of 90 patients, including 24 hydrogen-positive, 12 methane-positive, and 6 mixed-positive cases. Patients with positive breath tests exhibited greater bloating severity than those with negative breath tests. Methane-positive and mixed-positive groups demonstrated a higher prevalence of constipation-related features, whereas the hydrogen-positive group showed greater overlap with mixed bowel habits. These findings demonstrate that combined lactulose hydrogen-methane breath testing can identify clinically meaningful gas-production phenotypes in adults with functional bloating and may support symptom-based clinical stratification.

Hepatic encephalopathy (HE) is a complex neurocognitive disorder stemming from liver dysfunction, ranging from subtle cognitive impairments to profound coma. It develops when the liver's detoxification capacity is compromised, leading to an accumulation of neurotoxins like ammonia that disrupt brain function. From an intensivist's perspective, HE is more than mere confusion; it's a critical brain-liver syndrome demanding careful airway management, hemodynamic stability, and vigilance against cerebral edema and intracranial hypertension. HE is categorized into three types: Type A, associated with acute liver failure (ALF), poses the highest risk for rapid neurological decline and cerebral herniation, making it particularly relevant in critical care. Type C, prevalent in cirrhotic patients, is more common and often coexists with other organ failures. Type B HE, though less recognized, occurs with portosystemic shunting. For intensivists and anesthesiologists, prompt recognition and a structured management approach are paramount. This involves identifying and treating precipitating factors, stabilizing cardiorespiratory function, reducing ammonia levels, and preventing cerebral edema. Ongoing assessment of liver function and consideration for urgent liver transplantation, especially in Type A HE, are crucial. A deep understanding of HE's pathophysiology guides aggressive interventions such as continuous renal replacement therapy, plasma exchange, and intracranial pressure monitoring in select cases.