Links between gut microbiome, metabolome, clinical variables and non-alcoholic fatty liver disease severity in bariatric patients.

BACKGROUND AND AIMS: Bacterial species and microbial pathways along with metabolites and clinical parameters may interact to contribute to non-alcoholic fatty liver disease (NAFLD) and disease severity. We used integrated machine learning models and a cross-validation approach to assess this interaction in bariatric patients. METHODS: 113 patients undergoing bariatric surgery had clinical and biochemical parameters, blood and stool metabolite measurements as well as faecal shotgun metagenome sequencing to profile the intestinal microbiome. Liver histology was classified as normal liver obese (NLO; n = 30), simple steatosis (SS; n = 41) or non-alcoholic steatohepatitis (NASH; n = 42); fibrosis was graded F0 to F4. RESULTS: We found that those with NASH versus NLO had an increase in potentially harmful E. coli, a reduction of potentially beneficial Alistipes putredinis and an increase in ALT and AST. There was higher serum glucose, faecal 3-(3-hydroxyphenyl)-3-hydroxypropionic acid and faecal cholic acid and lower serum glycerophospholipids. In NAFLD, those with severe fibrosis (F3-F4) versus F0 had lower abundance of anti-inflammatory species (Eubacterium ventriosum, Alistipes finegoldii and Bacteroides dorei) and higher AST, serum glucose, faecal acylcarnitines, serum isoleucine and homocysteine as well as lower serum glycerophospholipids. Pathways involved with amino acid biosynthesis and degradation were significantly more represented in those with NASH compared to NLO, with severe fibrosis having an overall stronger significant association with Superpathway of menaquinol-10 biosynthesis and Peptidoglycan biosynthesis IV. CONCLUSIONS: In bariatric patients, NASH and severe fibrosis were associated with specific bacterial species, metabolic pathways and metabolites that may contribute to NAFLD pathogenesis and disease severity.

Relationship between dietary intake components and hepatic fibrosis in those with obesity before and 1 year after bariatric surgery.

OBJECTIVES: Non-alcoholic fatty liver disease is highly prevalent in the bariatric population but not all patients develop liver fibrosis. Considering that fibrosis may affect clinical outcomes, it is important to assess and treat contributing factors. In this population, it is not clear whether dietary intake is a contributor. The objective was to determine the relationship between dietary intake components and liver fibrosis before and 1 y after Roux-en-Y gastric bypass (RYGB). METHODS: This was a prospective cross-sectional (n = 133) study conducted between 2013 and 2022. In addition, a subgroup of 44 patients were followed for 1 y post-RYGB. Anthropometrics, biochemical measurements, and 3-d food records and liver biopsies were obtained presurgery and, in a subgroup of patients, as for the cohort, 1 y post-RYGB. RESULTS: In the cross-sectional study, 78.2% were female, with a median age of 48 y and body mass index of 46.8 kg/m2; 33.8% had type 2 diabetes mellitus and 57.1% had metabolic syndrome. In a multivariate analysis, age (odds ratio; 95% CI) (1.076; 1.014-1.141), alanine transaminase (1.068; 1.025-1.112), calorie intake (1.001; 1.000-1.002), and dietary copper (0.127; 0.022-0.752) were independently associated with fibrosis (<0.05). At 1 y post-RYGB, no independent risk factors were associated with persistent fibrosis. CONCLUSIONS: In bariatric patients before surgery, higher age, alanine transaminase, and total calorie and lower copper intakes were independent risk factors associated with liver fibrosis. These relationships were no longer observed after RYGB, likely due to the effect of surgery on weight and similar postsurgery diet among patients.

Adipose Tissue and Plasma Markers Associated with HbA1c Pre- and Post-bariatric Surgery: a Cross-sectional and Cohort Study.

PURPOSE: Obesity can be associated with chronic inflammation and dysregulated expression of inflammatory adipokines that contribute to insulin resistance and type 2 diabetes. This may also affect the clinical response to bariatric surgery. Our objective was whether baseline visceral adipose tissue features and plasma adipokine are associated with HbA1c ≥0.06 at the time of Roux-en-Y gastric bypass (RYGB) surgery and with persistently elevated HbA1c at 12 months post-RYGB. METHODS: During the surgery, adipose biopsies and plasma were collected for adipokine/cytokine profile. Clinical and biochemical measurements were also collected at the time of RYGB and, in those with baseline elevated HbA1c, at 12 months post-RYGB. RESULTS: In the cross-sectional study, 109 patients (82.6% female; age 49 years; BMI 46.98 kg/m2) participated. Of those with elevated HbA1c at baseline (n = 61), 47 patients had repeated measurements at 12 months post-RYGB (23% drop-out). Using a multivariate logistic regression model, older age (adjusted odds ratio (aOR), 1.14; 95% confidence interval (CI), 1.06-1.22) and higher plasma resistin (aOR, 5.30; 95% CI, 1.25-22.44) were associated with higher odds of HbA1c ≥ 0.06, whereas higher plasma adiponectin (aOR, 0.993; 95% CI, 0.99-0.996) was associated with lower odds of HbA1c ≥0.06. In addition, baseline higher average adipose cell area (aOR, 1.0017; 95% CI, 1.0002-1.0032) and plasma resistin (aOR, 1.0004; 95% CI, 1.0000-1.0009) were associated with higher odds of having persistently elevated HbA1c at 12 months post-RYGB. CONCLUSION: Our study suggests that baseline plasma adipokine dysregulation, specifically high resistin, and adipocyte hypertrophy may affect the clinical response to RYGB.

In critically ill adult patients with COVID-19, lower energy and higher protein intake are associated with fewer mechanical ventilation and antibiotic days but not with ICU length of stay.

BACKGROUND: Coronavirus disease 2019 (COVID-19) nutrition management guidelines recommend hypocaloric, high-protein feeding in the acute phase of critical illness. This study aimed to determine, among critically ill adults with COVID-19, whether nutrition support affects outcomes in nonobese patients when providing a mean energy intake of ≥20 kcal/kg/day vs <20 kcal/kg/day and protein intake of ≥1.2 g/kg/day vs <1.2 g/kg/day, using actual body weight, and in patients with obesity when providing ≥20 kcal/kg/day vs <20 kcal/kg/day and a protein intake of ≥2 g/kg/day vs <2 g/kg/day using ideal body weight. METHODS: This retrospective study included adults with COVID-19 on mechanical ventilation (MV) admitted to the intensive care unit (ICU) from 2020 to 2021. Clinical and nutrition parameters were recorded the first 14 days of ICU stay. RESULTS: One hundred four patients were included: 79 (75.96%) were male and had a median age of 51 years and body mass index of 29.65 kg/m2 . ICU length of stay (LOS) was not affected by nutrition intake, but patients receiving <20 kcal/kg/day had fewer MV days (P = 0.029). In a subgroup analysis, MV days were lower in the nonobese group receiving <20 kcal/kg/day (P = 0.012). In the obese group, those receiving higher protein intake had fewer antibiotic days (P = 0.013). CONCLUSION: In critically ill patients with COVID-19, lower energy and higher protein intake were respectively associated with fewer MV days and, in patients with obesity, fewer antibiotic days, but they had no effect on ICU LOS.

Effect of faecal microbial transplant via colonoscopy in patients with severe obesity and insulin resistance: A randomized double-blind, placebo-controlled Phase 2 trial.

AIM: To assess the effects of faecal microbial transplant (FMT) from lean people to subjects with obesity via colonoscopy. MATERIAL AND METHODS: In a double-blind, randomized controlled trial, subjects with a body mass index ≥ 35 kg/m2 and insulin resistance were randomized, in a 1:1 ratio in blocks of four, to either allogenic (from healthy lean donor; n = 15) or autologous FMT (their own stool; n = 13) delivered in the caecum and were followed for 3 months. The main outcome was homeostatic model assessment of insulin resistance (HOMA-IR) and secondary outcomes were glycated haemoglobin levels, lipid profile, weight, gut hormones, endotoxin, appetite measures, intestinal microbiome (IM), metagenome, serum/faecal metabolites, quality of life, anxiety and depression scores. RESULTS: In the allogenic versus autologous groups, HOMA-IR and clinical variables did not change significantly, but IM and metabolites changed favourably (P < 0.05): at 1 month, Coprococcus, Bifidobacterium, Bacteroides and Roseburia increased, and Streptococcus decreased; at 3 months, Bacteroides and Blautia increased. Several species also changed significantly. For metabolites, at 1 month, serum kynurenine decreased and faecal indole acetic acid and butenylcarnitine increased, while at 3 months, serum isoleucine, leucine, decenoylcarnitine and faecal phenylacetic acid decreased. Metagenomic pathway representations and network analyses assessing relationships with clinical variables, metabolites and IM were significantly enhanced in the allogenic versus autologous groups. LDL and appetite measures improved in the allogenic (P < 0.05) but not in the autologous group. CONCLUSIONS: Overall, in those with obeisty, allogenic FMT via colonoscopy induced favourable changes in IM, metabolites, pathway representations and networks even though other metabolic variables did not change. LDL and appetite variables may also benefit.

Reliability of Non-invasive Liver Fibrosis Assessment Tools Versus Biopsy in Pre- and Post-bariatric Surgery Patients with Non-alcoholic Fatty Liver Disease.

PURPOSE: Liver biopsy (LBx) remains the gold standard to assess fibrosis in non-alcoholic fatty liver disease (NAFLD). Biochemical markers are also useful, but their reliability is not clear in patients with morbid obesity. We assessed the performance of six non-invasive fibrosis assessment tools before and after bariatric surgery (BSx) using LBx. MATERIALS AND METHODS: This is a cross-sectional and prospective cohort study. LBx was performed at the time of BSx and 12-month post-operatively and assessed using the Brunt system. Clinical and biochemical measurements were collected at the same time points and six non-invasive fibrosis assessment tools were calculated. RESULTS: One hundred seventy patients had BSx; 79.4% female; age was 46.6 ± 9.8 years, and BMI was 48.6 ± 7.5 kg/m2. From liver histology, 88% had F0-F2 and 11.2% F3-F4. At BSx, aspartate aminotransferase to platelet ratio index (APRI) and FIB-4 had better accuracy (0.86 and 0.88) with specificity of 96.6% and 94.0% and negative predictive values (NPV) of 88.9% and 93.7%. However, sensitivity (6.7% and 40.0%) and positive predictive values (PPV) (20.0% and 46.2%) were low. Twelve months post-surgery (n = 54), 88.9% of patients had F0-F2 and 11.1% had F3-F4. Fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS) had the best accuracy (0.79 and 0.77) with specificity of 83.7% and 86.9% and NPV of 92.3% and 86.9%. However, sensitivity (25% and 0%) and PPV (12.5% and 0%) were low. CONCLUSION: Overall, FIB-4, APRI, and NFS showed similar performances with higher accuracy, specificity, and NPV. Sensitivity and PPV were low. These tests are more useful at excluding advanced fibrosis.

Manipulation of intestinal microbiome as potential treatment for insulin resistance and type 2 diabetes.

PURPOSE: Increasing evidence suggests that the intestinal microbiome (IM) and bacterial metabolites may influence glucose homeostasis, energy expenditure and the intestinal barrier integrity and lead to the presence of systemic low-grade inflammation, all of which can contribute to insulin resistance (IR) and type 2 diabetes (T2D). The purpose of this review is to explore the role of the IM and bacterial metabolites in the pathogenesis and treatment of these conditions. RESULTS: This review summarizes research focused on how to modulate the IM through diet, prebiotics, probiotics, synbiotics and fecal microbiota transplant in order to treat IR and T2D. CONCLUSION: There is an abundance of evidence suggesting a role for IM in the pathogenesis of IR and T2D based on reviewed studies using various methods to modulate IM and metabolites. However, the results are inconsistent. Future research should further assess this relationship.

Hyposalivation is prevalent in bariatric patients but improves after surgery.

BACKGROUND: Obesity and type 2 diabetes can be associated with poor oral health. This can be because of hyposalivation leading to chronic oral inflammation (OI) and periodontal disease. OBJECTIVE: To assess the prevalence of hyposalivation and OI in individuals undergoing Roux-en-Y gastric bypass (RYGB) and determine the relationship with metabolic and anthropometric parameters before and after RYGB. SETTING: University hospital in Canada. METHODS: This was a cross-sectional and prospective cohort study of 59 patients undergoing RYGB from September 2015 to December 2019. Anthropometric, biochemical, and oral measurements were taken before surgery and 1 and 6 months post RYGB. Oral parameters included salivary flow rate and neutrophil count as marker of OI. RESULTS: Fifty-nine patients were enrolled with 29 completing this study. At baseline, the median age was 47 years and body mass index was 46.5 kg/m2, 52 (88.1%) were female and 14 individuals (23.7%) had type 2 diabetes; 54.2% (n = 32) of patients had hyposalivation and 13.6% (n = 8) had high neutrophil count. Patients with hyposalivation had significantly higher fasting glucose (5.7 mmol/L) compared with those without hyposalivation (5.2 mmol/L) but no difference was found between high versus low neutrophil count. At 6 months post RYGB, all variables except oral neutrophil count significantly improved. Hyposalivation persisted in 7 (24%) individuals. CONCLUSIONS: In our bariatric patients, more than half the patients had hyposalivation before RYGB and this was associated with higher fasting glucose. Hyposalivation improved post RYGB in parallel with improvements in metabolic parameters but there was no change in OI. Increased salivation may reduce the risk of periodontal disease.

Obstructive Sleep Apnea and Non-alcoholic Fatty Liver Disease in Obese Patients Undergoing Bariatric Surgery.

BACKGROUND: Morbid obesity is associated with multiple comorbidities including obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD). It has been suggested that OSA may contribute to NAFLD pathogenesis due to intermittent nocturnal hypoxia. PURPOSE: The objective of this study was to assess the apnea-hypopnea index (AHI) and lower minimum oxygen saturation, markers of OSA, in patients undergoing bariatric surgery (BSx) with perioperative liver biopsy to detect NAFLD. METHODS: This was a single center cross-sectional study of 61 patients undergoing BSx who consented to have a perioperative wedged liver biopsy. Biochemical, clinical, anthropometric variables, and a sleep study test were performed prior to BSx. RESULTS: NAFLD was diagnosed in 49 (80.3%) patients; 12 had normal liver (NL). Those with NAFLD had significantly higher (p < 0.05) AST (42.6 vs 18.1 U/L) and ALT (35.0 vs 22.1 U/L) but similar clinical, anthropometric, and metabolic parameters to NL. There was a higher AHI (32.03 vs 14.35) and significantly lower minimum oxygen saturation (SaO2) (78.87 vs 85.63) in NAFLD compared with NL (p < 0.05). When assessing associations between OSA parameters and liver histology in NAFLD, AHI correlated significantly with lobular inflammation (p < 0.05). In a multivariate analysis, BMI was significantly correlated with lobular inflammation with mean SaO2 nearing significance. CONCLUSIONS: These results indicate that in a homogeneous bariatric population sample with similar characteristics, those with NAFLD had higher AHI and lower minimum SaO2 compared with NL. AHI correlated with liver inflammation suggesting a potential role for intermittent nocturnal hypoxia in the pathogenesis and progression of NAFLD.