Fecal Short-chain Fatty Acids Levels Research Articles

Disordered GPR43/NLRP3 expression in peripheral leukocytes of patients with atrial fibrillation is associated with intestinal short chain fatty acids levels

BackgroundAtrial fibrillation (AF) is associated with circulating inflammation. Short-chain fatty acids (SCFAs) derived from gut microbiota (GM) regulate leukocyte function and inhibit the release of inflammatory cytokines, which are partly mediated by the G-protein-coupled receptor 43 (GPR43) signaling. This study aimed to investigate the expression of GPR43/NOD-like receptors family pyrin domain containing 3 (NLRP3) in leukocytes and the interaction with intestinal SCFAs levels in AF patients.MethodsExpressions of GPR43 and NLRP3 mRNA in peripheral blood leukocytes from 23 AF patients and 25 non-AF controls were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Expressions of leukocyte GPR43 and NLRP3 protein were evaluated by western blot analysis. The levels of plasma IL-1β were measured by enzyme-linked immunosorbent assay (ELISA). The fecal SCFAs levels based on GC/MS metabolome of corresponding 21 controls and 14 AF patients were acquired from our published dataset. To evaluate the expression of NLRP3 and GPR43 and the release of IL-1β, human THP-1 cells were stimulated with or without SCFAs (acetate, propionate, and butyrate), lipopolysaccharide (LPS), and nigericin in vitro, respectively.ResultsCompared to the controls, the mRNA expression in peripheral leukocytes was significantly reduced in AF patients (P = 0.011) coupled with the increase in downstream leukocyte NLRP3 mRNA expression (P = 0.007) and plasma IL-1β levels (P < 0.001), consistent with changes in GPR43 and NLRP3 protein expression. Furthermore, leukocyte GPR43 mRNA levels were positively correlated with fecal GM-derived acetic acid (P = 0.046) and negatively correlated with NLRP3 mRNA expression (P = 0.024). In contrast to the negative correlation between left atrial diameter (LAD) and GPR43 (P = 0.008), LAD was positively correlated with the leukocyte NLRP3 mRNA levels (P = 0.024). Subsequent mediation analysis showed that 68.88% of the total effect of intestinal acetic acid on AF might be mediated by leukocyte GPR43/NLRP3. The constructed GPR43–NLRP3 score might have a predictive potential for AF detection (AUC = 0.81, P < 0.001). Moreover, SCFAs treatment increased GPR43 expression and remarkably reduced LPS/nigericin-induced NLRP3 expression and IL-1β release in human THP-1 cells in vitro.ConclusionsDisrupted interactions between GPR43 and NLRP3 expression in peripheral blood leukocytes, associated with reduced intestinal GM-derived SCFAs, especially acetic acid, may be involved in AF development and left atrial enlargement by enhancing circulating inflammation.

Idiopathic Rapid Eye Movement Sleep Behavior Disorder (iRBD) Shares Similar Fecal Short-Chain Fatty Acid Alterations with Multiple System Atrophy (MSA) and Parkinson's Disease (PD).

Idiopathic rapid eye movement sleep behavior disorder (iRBD) is considered as a prodromal stage of synucleinopathies. Fecal short-chain fatty acid (SCFA) changes in iRBD and the relationships with synucleinopathies have never been investigated. To investigate fecal SCFA changes among iRBD, multiple system atrophy (MSA), and Parkinson's disease (PD), and evaluate their relationships. Fecal SCFAs and gut microbiota were measured in 29 iRBD, 42 MSA, 40 PD, and 35 normal controls (NC) using gas chromatography-mass spectrometry and 16S rRNA gene sequencing. Compared with NC, fecal SCFA levels (propionic, acetic, and butyric acid) were lower in iRBD, MSA, and PD. Combinations of these SCFAs could differentiate NC from iRBD (AUC 0.809), MSA (AUC 0.794), and PD (AUC 0.701). Decreased fecal SCFAs were associated with the common reducing SCFA-producing gut microbiota in iRBD, MSA, and PD. iRBD shares similar fecal SCFA alterations with MSA and PD, and the combination of these SCFAs might be a potential synucleinopathies-related biomarker. © 2024 International Parkinson and Movement Disorder Society.

First Exploration of the Altered Microbial Gut–Lung Axis in the Pathogenesis of Human Refractory Chronic Cough

PurposeCough represents a natural mechanism that plays an important defensive role in the respiratory tract, but in some conditions, it may become persistent, nonproductive, and harmful. In general, refractory chronic cough (RCC) occurs in about 20% of individuals; hence, we aimed to assess the presence of altered gut–lung communication in RCC patients through a compositional and functional characterization of both gut (GM) and oral microbiota (OM).Methods16S rRNA sequencing was used to characterize both GM and OM composition of RCC patients and healthy controls (HC). PICRUST2 assessed functional changes in microbial communities while gas chromatography was used to evaluate fecal short-chain fatty acid levels and serum-free fatty acid (FFA) abundances.ResultsIn comparison with HC, RCC patients reported increased saliva alpha-diversity and statistically significant beta-diversity in both GM and OM. Also, a, respectively, significant increased or reduced Firmicutes/Bacteroidota ratio in stool and saliva samples of RCC patients has been shown, in addition to a modification of the abundances of several taxa in both GM and OM. Moreover, a potential fecal over-expression of lipopolysaccharide biosynthesis and lipoic acid metabolism pathways and several differences in serum FFA levels have been reported in RCC patients than in HC.ConclusionSince differences in both GM and OM of RCC patients have been documented, these findings could provide new information about RCC pathogenesis and also pave the way for the development of novel nutritional or pharmacological interventions for the management of RCC through the restoration of eubiotic gut–lung communication.

Association between fecal short-chain fatty acid levels and constipation severity in subjects with slow transit constipation.

We measured the fecal levels of short-chain fatty acids (SCFAs) in subjects with slow transit constipation (STC) and assessed the correlation between SCFA levels and disease severity as well as quality of life. We isolated the supernatant from fecal samples of healthy and STC subjects and measured the SCFA levels. To assess the correlation between fecal SCFA levels and disease severity as well as quality of life, we used the Constipation Scoring System, Patient Assessment of Constipation Symptoms, and Patient Assessment of Constipation Quality of Life questionnaires. 16 STC subjects and 16 healthy controls were enrolled. STC subjects had lower SCFA levels, but the difference was not statistically significant (475.85 ± 251.68 vs. 639.77 ± 213.97 µg/ml, P = 0.056). Additionally, STC subjects had lower acetic and propionic acid levels (149.06 ± 88.54 vs. 261.33 ± 109.75 µg/ml and 100.60 ± 60.62 vs. 157.34 ± 66.37 µg/ml, respectively, P < 0.05) and higher isobutyric and isovaleric acid levels (27.21 ± 15.06 vs. 18.16 ± 8.65 µg/ml and 31.78 ± 18.81 vs. 16.90 ± 10.05 µg/ml, respectively, P < 0.05). At 252.21 µg/ml acetic acid, the specificity and sensitivity to distinguish healthy from STC subjects were 93.7% and 56.3%, respectively. In STC subjects, there were significant negative correlations between acetic and propionic acid levels and Constipation Scoring System scores. Fecal SCFA, acetic acid, and propionic acid levels decreased in STC subjects. There were significant negative correlations between the levels of the two acids and constipation severity.

Aspartame Intake Delayed Puberty Onset in Female Offspring Rats and Girls.

The disturbance of the hypothalamic-pituitary-gonadal (HPG) axis, gut microbiota (GM) community, and short-chain fatty acids (SCFAs) is a triggering factor for pubertal onset. The study investigates the effects of the long-term intake of aspartame on puberty and GM in animals and humans. Aspartame-fed female offspring rats result in vaginal opening time prolongation, serum estrogen reduction, and serum luteinizing hormone elevation. , 60mgkg-1 aspartame treatment decreases the mRNA levels of gonadotropin-releasing hormone (GnRH), Kiss1, and G protein-coupled receptor 54 (GPR54), increases the mRNA level of RFamide-related peptide-3 (RFRP-3), and decreases the expression of GnRH neurons in the hypothalamus. Significant differences in relative bacterial abundance at the genus levels and decreased fecal SCFA levels are noted by 60mgkg-1 aspartame treatment. Among which, Escherichia-Shigella is negatively correlated with several SCFAs. In girls, high-dose aspartame consumption decreases the risk of precocious puberty. Aspartame reduces the chance of puberty occurring earlier than usual in female offspring and girls. Particularly, 60mgkg-1 aspartame-fed female offspring delays pubertal onset through the dysregulation of HPG axis and GM composition by inhibiting the Kiss1/GPR54 system and inducing the RFRP-3. An acceptable dose of aspartame should be recommended during childhood.

Association of the short-chain fatty acid levels and dietary quality with type 2 diabetes: a case-control study based on Henan Rural Cohort.

Evidence of the relationship between fecal short-chain fatty acids (SCFA) levels, dietary quality and type 2 diabetes mellitus (T2DM) in rural populations is limited. Here, we aimed to investigate the association between fecal SCFA levels and T2DM and the combined effects of dietar quality on T2DM in rural China. In total, 100 adults were included in the case-control study. Dietary quality was assessed by the Alternate Healthy Eating Index 2010 (AHEI-2010), and SCFA levels were analysed using the GC-MS system. Generalised linear regression was conducted to calculate the OR and 95 % CI to evaluate the effect of SCFA level and dietary quality on the risk of T2DM. Finally, an interaction was used to study the combined effect of SCFA levels and AHEI-2010 scores on T2DM. T2DM participants had lower levels of acetic and butyric acid. Generalised linear regression analysis revealed that the OR (95 % CI) of the highest acetic and butyric acid levels were 0·099 (0·022, 0·441) and 0·210 (0·057, 0·774), respectively, compared with the subjects with the lowest tertile of level. We also observed a significantly lower risk of T2DM with acetic acid levels > 1330·106 μg/g or butyric acid levels > 585·031 μg/g. Moreover, the risks of higher acetic and butyric acid levels of T2DM were 0·007 (95 % CI: 0·001, 0·148), 0·005 (95 % CI: 0·001, 0·120) compared with participants with lower AHEI-2010 scores (all P < 0·05). Acetate and butyrate levels may be important modifiable beneficial factors affecting T2DM in rural China. Improving dietary quality for body metabolism balance should be encouraged to promote good health.

P179 Decrease in Butyric Acid in fecal matter in patients with Inflammatory Bowel Disease is associated with the levels of secretory Immunoglobulin A and fecal calprotectin

Abstract Background Accumulating evidence shows that the development of IBD is always accompanied by dysbiosis of the intestinal microbiota. Short-chain fatty acids (SCFAs) are produced by prebiotic intestinal bacteria, with mportant anti-inflammatory functions, delaying the clinical progression of IBD. The aim of this study is to compare SCFA levels in fecal matter in patients with IBD versus patients with Spondyloarthritis (SpA) and healthy controls. Methods 24 patients were evaluated for the presence of gastrointestinal symptoms, demographic data and inflammatory markers: fecal calprotectin, C-reactive protein (CRP), secretory IgA (SIgA) and erythrocyte sedimentation rate (ESR). The quantification of SCFAs (acetic-AC, propionic-AP, butyric-AB and total SCFAs-ACCC-T) from fecal matter was analyzed by ultra-high pressure liquid chromatography coupled to mass spectrometry (UHPLC-Q/ TOFMS). Results 33.3% of patients with IBD were men, with body mass index &amp;gt;25 in 16.7%; 83.3% presented more than 2 gastrointestinal symptoms at the time of sample collection, 33.3% had high levels of fecal calprotectin, 50% had CRP levels higher than 3mg/L and high ESR in 33.3% and a mean SIgA. of 27.73±5.03 g/mL. Very decreased levels of butyric acid (BA)ug/mL and T-SCFA were observed in IBD (9.45±4.89 and 121.73±65.94, respectively), compared to CS (BA 20.84±8.83 and total SCFA.12±122.09)., SpA SG (AB 13.35±10.44 and total AGCC 150.73±128.52) and SpA without OS (AB 21.13±5.68 and AGCC-T 219.51±229.65). Significant differences were found in fecal BA levels between the study groups (p=0.027). Interestingly, this metabolite in the CS group and the SpA group without OS did not show differences between them, but compared to the IBD group p=0.015 and 0.009 respectively, with a decrease in IBD. And interestingly, no differences were evident between fecal SCFA levels between the IBD group and the SpA group with OS even without a diagnosis of IBD. A principal component analysis was performed for the IBD group where two components were identified that group where COMP.1 was defined by a high correlation between the levels of each of the ACCC (AB CCF= 0.994, AA CCF= 0.935, AP= 0.610 and AGCC-TCCF= 0.910) that had an inverse relationship with COMP.2 which was made up of SIgA (CCF=0.988) and fecal calprotectin (CCF= 0.988). Conclusion SCFAs play a key role in maintaining immune homeostasis both locally and systemically. BA levels were significantly lower in patients with IBD compared to CS and those with SpA. This evidence clearly supports the hypothesis that relates the lack of BA with an exacerbated inflammatory response that could give rise to a dysfunctional intestinal epithelial barrier by regulating the production of mucosal antibodies such as SIgA.

Gut microbiota and its metabolites in non-small cell lung cancer and brain metastasis: from alteration to potential microbial markers and drug targets.

The elevated mortality rate associated with non-small-cell lung cancer (NSCLC) is a well-established global concern. Considerable attention has been directed toward exploring the association between gut microbiota and various malignant tumors. We herein investigated the associations between the intestinal microbiome and its metabolites, particularly short-chain fatty acids (SCFAs), in patients with NSCLC at different stages, including early and brain metastasis (BM) stages. The findings aim to offer a fresh perspective on the diagnosis and management of NSCLC. Fecal samples were collected from 115 participants, comprising healthy controls (n = 35) and patients with treatment-naive NSCLC at the early stage (ELC, n = 40) and the BM stage (n = 40). Characterization of the intestinal microbiome and fecal SCFA levels was performed using 16S rRNA gene sequencing and gas chromatography. The microbial diversity in patients with NSCLC was found to be less abundant and uniform, particularly in the BM stage. Significant alterations in the community structure of the gut microbiota were observed in patients with NSCLC, with an increase in pathogens in Fusobacteria and Proteobacteria and a decrease in SCFA-producing bacteria in Firmicutes and Actinobacteria, particularly in the BM stage. Meanwhile, microbial communities displayed intricate associations in patients with NSCLC. A biomarker panel (Faecalibacterium, Bifidobacterium, Butyricicoccus, Klebsiella, Streptococcus, and Blautia) successfully distinguished patients in the ELC and BM stages from healthy controls (area under the curve: 0.884). The overall concentration of fecal SCFAs was significantly lower in patients with BM compared to patients with ELC and healthy controls. Subgroup analysis of acetate and butyrate yielded similar results. Moreover, multiple disrupted pathways in the NSCLC group were identified using the Kyoto Encyclopedia of Genes and Genomes annotation, including lipid metabolism and genetic information processing, specifically in the BM stage. Compared with healthy controls, distinct host-microbe interactions were evident in different phases of patients with NSCLC. Furthermore, specific forms of the gut microbiome and SCFAs may serve as valuable biomarkers and therapeutic targets in the diagnosis and treatment of NSCLC.

Magnesium isoglycyrrhizinate attenuates nonalcoholic fatty liver disease by strengthening intestinal mucosal barrier

BackgroundNon-alcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) has recently risen to the top spot among chronic liver diseases in the world. However, there are no recognized treatments for it. Magnesium isoglycyrrhizate (MgIG) has potential as a NAFLD/NASH therapy. AimsTo investigate the efficacy of MgIG in improving NAFLD/NASH and the possible pathways and mechanisms. MethodsC57bl/6 mice were fed a high-fat diet (HFD) and 1 % dextran sulfate sodium (DSS) for 12 weeks to establish the NAFLD/NASH model. MgIG was administered by gavage during the last 7 weeks. First, the therapeutic effects of MgIG on hepatic steatosis and fibrosis, liver injury, and inflammation in the NAFLD/NASH mice were evaluated. Second, liver oxidative stress and hepatocyte apoptosis were detected. Finally, the effect of MgIG on intestinal permeability and short-chain fatty acid (SCFA) levels in mice’s intestinal contents were examined. ResultsMgIG administration attenuated HFD-induced hepatic steatosis and fibrosis, improved serum biochemical and NAFLD/NASH mice, reduced liver oxidative stress and hepatocyte apoptosis, improved intestinal permeability, and increased fecal SCFA levels in NAFLD/NASH mice. ConclusionMgIG protects against HFD-induced NAFLD/NASH through multiple pathways as well as mechanisms and holds promise as a potentially effective treatment for NAFLD/NASH.

The gut-lung axis in critical illness: microbiome composition as a predictor of mortality at day 28 in mechanically ventilated patients

BackgroundMicrobial communities are of critical importance in the human host. The lung and gut microbial communities represent the most essential microbiota within the human body, collectively referred to as the gut-lung axis. However, the differentiation between these communities and their influence on clinical outcomes in critically ill patients remains uncertain.MethodsAn observational cohort study was obtained in the intensive care unit (ICU) of an affiliated university hospital. Sequential samples were procured from two distinct anatomical sites, namely the respiratory and intestinal tracts, at two precisely defined time intervals: within 48 h and on day 7 following intubation. Subsequently, these samples underwent a comprehensive analysis to characterize microbial communities using 16S ribosomal RNA (rRNA) gene sequencing and to quantify concentrations of fecal short-chain fatty acids (SCFAs). The primary predictors in this investigation included lung and gut microbial diversity, along with indicator species. The primary outcome of interest was the survival status at 28 days following mechanical ventilation.ResultsSixty-two mechanically ventilated critically ill patients were included in this study. Compared to the survivors, the diversity of microorganisms was significantly lower in the deceased, with a significant contribution from the gut-originated fraction of lung microorganisms. Lower concentrations of fecal SCFAs were detected in the deceased. Multivariate Cox regression analysis revealed that not only lung microbial diversity but also the abundance of Enterococcaceae from the gut were correlated with day 28 mortality.ConclusionCritically ill patients exhibited lung and gut microbial dysbiosis after mechanical ventilation, as evidenced by a significant decrease in lung microbial diversity and the proliferation of Enterococcaceae in the gut. Levels of fecal SCFAs in the deceased served as a marker of imbalance between commensal and pathogenic flora in the gut. These findings emphasize the clinical significance of microbial profiling in predicting the prognosis of ICU patients.

Early changes of fecal short‐chain fatty acid levels in patients with mild cognitive impairments

AbstractBackgroundMild cognitive impairment (MCI) is with great risk for the conversion to Alzheimer’s disease (AD). The aim of present study wanted to explore whether fecal Short‐chain fatty acids (SCFAs) could be used as the biomarker for the identification of MCI patients and to examine the relationship between fecal SCFAs and amyloid‐β deposition in the brain.MethodsA cohort of 32 MCI patients and 27 NC were recruited in our study. Fecal levels of SCFAs were measured using chromatography and mass spectrometry. Disease duration, ApoE genotype, body mass index, constipation, and diabetes were evaluated. To assess cognitive impairment, we used the Mini‐Mental Status Examination (MMSE). To assess brain atrophy, the degree of medial temporal atrophy (MTA score, Grade 0‐4) was measured by structural MRI. β‐amyloid positron emission tomography (PET) with 18F‐AV‐45 was performed in seven MCI patients to detect and quantify Aβ deposition in the brain.ResultsCompared with NC, MCI patients had significantly lower fecal levels of acetic acid, butyric acid, and caproic acid. Among fecal SCFAs, acetic acid performed the best in discriminating MCI from NC, achieved an AUC of 0.752 (p = 0.001, 95% CI: 0.628‐0.876), specificity of 66.7% and sensitivity of 75%. By combining fecal levels of acetic acid, butyric acid and caproic acid, the diagnostic specificity was significantly improved, reaching 88.9%. To better verify the diagnostic performance of SCFAs, we randomly assigned 80% of participants into training dataset and 20% into testing dataset. Only acetic acid showed significantly difference between these two groups in the training dataset. Based on the fecal levels of acetic acid, we achieved the ROC curve. Next, the ROC curve was evaluated in the independent test data and 66.7% (4 in 6) of MCI patients, and 80% (4 in 5) of NC could be identified correctly. Subgroup analysis showed that reduced fecal SCFAs in MCI group were negatively associated with Aβ deposition in cognition‐related brain regions.ConclusionOur findings suggest that gut metabolite SCFAs have the potential to serve as early diagnostic biomarkers for distinguishing patients with MCI from NC and could serve as potential targets for preventing AD.

Inhalation of diesel exhaust particulate matter induces locomotor hyperactivity and its relationship with brain and gut metabolism

Diesel exhaust particulate matter (DEPM) are important components of urban air pollution worldwide. Recent studies proved that airborne DEPM can enter the human brain, which was associated with brain and mental diseases. In this study, we investigated the effects of DEPM exposure on behavior, and explored potential mechanisms from the perspective of metabolism in specific brain regions and short chain fatty acids (SCFAs) in the gut using mice. The results showed that inhalation of DEPM induced locomotor hyperactivity and a tendency for memory decline in mice. Exposure to DEPM disrupted motor behavior generation related cerebellar Purkinje cells, induced widespread reduction of neurotransmitters in the frontal cortex, and downregulated expression of genes encoding Brain-derived neurotrophic factor (BDNF) and involved in the Brain-blood-barrier (BBB) in the hippocampus. Moreover, there was a DEPM dose-dependent increase in fecal SCFA levels. Correlation analysis showed that DEPM-induced locomotor hyperactivity was mainly associated with decreased neurotransmission in the frontal cortex and increased gut SCFAs, and those associations were discussed. This study provides new insights into the mechanisms underpinning behavioral changes caused by air pollution, and extends our knowledge on the toxicity and health effects of airborne pollutants.

Sodium Butyrate Regulates Gasdermin B Exerted Protection Effect on the MTX‐Induced NCM460 and Hum Cells

AbstractInflammatory bowel disease (IBD) is a complex disorder with unclear etiology, and the impact of short‐chain fatty acids (SCFAs) on its pathogenesis is not well‐studied. This research explores the potential protective effects of sodium butyrate (NaB) in inflammatory bowel disease (IBD) through the Gasdermin B (GSDMB) non‐pyroptotic pathway. Fecal SCFA levels and GSDMB‐related proteins of IBD patients are analyzed. NCM460 and HUM cells are treated with methotrexate (MTX) for 24 hours. NaB is applied at concentrations of 1, 5, and 10 mm mL−1 to cells. It is found that a decrease in SCFAs content, zonula occludens‐1 (ZO‐1), and Occludin expression, along with an increase in GSDMB, focal adhesion kinase (FAK), and extracellular singal‐regulated kinase (ERK) in IBD patients is observed. NaB, at medium and high concentrations, promotes cell viability and migration and increased GSDMB expression. The low concentration of NaB has a significant protective effect on IBD‐affected cells, activating the GSDMB non‐pyroptotic pathway. This protection diminishes after the GSDMB knockdown. The study reveals that NaB may play a crucial role in protecting intestinal epithelial integrity in IBD through the GSDMB non‐pyroptotic pathway. These findings underline the potential of targeting this pathway for therapeutic strategies, highlighting the importance of SCFAs in understanding and treating IBD.

Fecal short-chain fatty acids in non-constipated irritable bowel syndrome: a potential clinically relevant stratification factor based on catabotyping analysis

ABSTRACT The gut microbiota is believed to be a critical factor in the pathogenesis of IBS, and its metabolic byproducts, such as short-chain fatty acids (SCFAs), are known to influence gut function and host health. Despite this, the precise role of SCFAs in IBS remains a topic of debate. In this study, we examined the bacterial community structure by 16S rRNA gene profiling and SCFA levels by UPLC-MS/MS in fecal samples from healthy controls (HC; n = 100) and non-constipated patients (IBS-D and IBS-M; NC-IBS; n = 240) enrolled in 19 hospitals in Italy. Our findings suggest a significant difference between the fecal microbiomes of NC-IBS patients and HC subjects, with HC exhibiting higher intra-sample biodiversity. Furthermore, we were able to classify non-constipated patients into two distinct subgroups based on their fecal SCFA levels (fecal catabotype “high” and “low”), each characterized by unique taxonomic bacterial signatures. Our results suggest that the fecal catabotype with higher SCFA levels may represent a distinct clinical phenotype of IBS that could have implications for its diagnosis and treatment. This study provides a new perspective on the intricate relationship between the gut microbiome and bowel symptoms in IBS, underscoring the importance of personalized strategies for its management.

Low Short-Chain-Fatty-Acid-Producing Activity of the Gut Microbiota Is Associated with Hypercholesterolemia and Liver Fibrosis in Patients with Metabolic-Associated (Non-Alcoholic) Fatty Liver Disease

The aim of this study was to investigate the short-chain fatty acid (SCFA) activity of the gut microbiota of patients with metabolic-associated fatty liver disease (MAFLD). The level and spectrum of short-chain fatty acids (SCFAs) were determined via gas–liquid chromatography. Liver fibrosis was assessed using the FIB-4 index and elastography. Among 42 non-cirrhotic MAFLD patients, 24 had high fecal SCFA levels (group H) and 18 had low fecal SCFA levels (group L). Patients in group H had lower serum uric acid, total cholesterol, and LDL cholesterol levels but a higher BMI than those in group L. All patients in group L and only 37.9% of those in group H were found to have hypercholesterolemia. In patients with hypercholesterolemia, the level of SCFAs was lower than that in patients without hypercholesterolemia. Patients in group H had less liver fibrosis than patients in group L. A total of 50.0% of the patients in group H and 92.3% of those in group L had significant liver fibrosis (≥F2). Patients with significant liver fibrosis had lower levels of fecal SCFAs—particularly acetate and butyrate. The fecal SCFA levels were positively correlated with gamma-glutamyl transferase, total bilirubin levels, BMI, and platelet count and were negatively correlated with FIB-4, liver stiffness, serum total, and LDL cholesterol levels.

Cholecystectomy Significantly Alters Gut Microbiota Homeostasis and Metabolic Profiles: A Cross-Sectional Study.

Cholecystectomy (CCE) is a standard clinical treatment for conditions like gallstones and cholecystitis. However, its link to post-CCE syndrome, colorectal cancer, and nonalcoholic fatty liver disease has raised concerns. Additionally, studies have demonstrated the disruptive effects of CCE on gut microbiota homeostasis and bile acid (BA) metabolism. Considering the role of gut microbiota in regulating host metabolic and immune pathways, the use of dietary and probiotic intervention strategies to maintain a stable gut ecosystem after CCE could potentially reduce associated disease risks. Inter-study variations have made it challenging to identify consistent gut microbiota patterns after CCE, a prerequisite for targeted interventions. In this study, we first meta-analyzed 218 raw 16S rRNA gene sequencing datasets to determine consistent patterns of structural and functional changes in the gut microbiota after CCE. Our results revealed significant alterations in the gut microbiota's structure and function due to CCE. Furthermore, we identified characteristic gut microbiota changes associated with CCE by constructing a random model classifier. In the validation cohort, this classifier achieved an area under the receiver operating characteristic curve (AUC) of 0.713 and 0.683 when distinguishing between the microbiota of the CCE and healthy groups at the family and genus levels, respectively. Further, fecal metabolomics analysis demonstrated that CCE also substantially modified the metabolic profile, including decreased fecal short-chain fatty acid levels and disrupted BA metabolism. Importantly, dietary patterns, particularly excessive fat and total energy intake, influenced gut microbiota and metabolic profile changes post-CCE. These dietary habits were associated with further enrichment of the microbiota related to BA metabolism and increased levels of intestinal inflammation after CCE. In conclusion, our study identified specific alterations in gut microbiota homeostasis and metabolic profiles associated with CCE. It also revealed a potential link between dietary patterns and gut microbiota changes following CCE. Our study provides a theoretical basis for modulating gut microbiota homeostasis after CCE using long-term dietary strategies and probiotic interventions.

FRI010 Human Gut Microbiota And Metabolic Profiles Are Associated With Obesity In Five African-Origin Populations

Abstract Disclosure: J. Jorgensen: None. C. Choo-Kang: None. G. Ecklu-Mensah: None. J. Gilbert: None. A. Luke: None. K. Bedu-Addo: None. T.E. Forrester: None. P. Bovet: None. E.V. Lambert: None. D. Rae: None. L. Dugas: None. Y. Dai: None. B.T. Layden: None. Obesity is a global public health crisis, which since 1975 has tripled world-wide. Concomitantly, obesity-related conditions such as cardiovascular disease, stroke, and type 2 diabetes have also increased. An accepted common obesogenic factor has been a shift away from fiber-rich diets to ultra-processed foods. Fiber is digested by the gut microbiota, resulting in the production of short-chain fatty acids (SCFAs), and diets that are rich in fiber are associated with greater microbial diversity and increased serum and fecal SCFA levels. Yet, the mechanistic link between dietary fiber and improved metabolic outcomes, via SCFAs, is not clearly defined. We analyzed data from a large ongoing prospective study of African-origin adults from 5 countries (Ghana, South Africa, Jamaica, Seychelles &amp; US), each with distinct dietary fiber intakes. Standard methods were used to assess taxonomy, Shannon alpha diversity and beta diversity, as well as taxonomic differences by fecal SCFA levels as a proxy for fiber intake. Thereafter, microbiota taxa were used to predict functional metabolite profiles, as well as the metabolic pathway abundances to identify differential metabolites correlated with SCFA levels. These profiles and pathways were correlated with SCFA levels within and between sites. As microbes interact and impact each other, we constructed differential microbial co-occurrence networks to identify hub species and differences in community configuration across sites comparing SCFA levels via Network Construction and comparison for Microbiome data (NetCoMi). The final sample included 1904 participants (age=42.57±8.04 yr). The mean BMI was lowest in Ghana (BMI=26.72±5.88 kg/m2), and highest in the US (BMI=34.42±9.06 kg/m2) with a p-value &amp;lt; 2.2e-16. Conversely, diets in Ghana had the highest fiber intake resulting in the highest fecal SCFA levels (8026.97±2605.38 µg/g) which was significantly greater than US SCFA levels (p-value &amp;lt; 2e-16). Not surprisingly, differences in microbial diversity were unique to each site as well as adiposity levels. Overall, non-obese individuals had a higher proportion of Prevotella, Allaprevotella compared to obese individuals who had higher proportions of Firmicutes. Prevotella and Allaprevotella are known SCFAs producers and previously shown to be anti-inflammatory in the gut, while Firmicutes are positively correlated with gut inflammation. We provide evidence that fiber-rich diets may act through the anti-inflammatory pathways associated with the gut microbiota in humans. Future research should elucidate the gut microbial mediated anti-inflammatory effects and the metabolic pathways to develop novel anti-inflammatory therapeutics. Presentation: Friday, June 16, 2023

Fecal short chain fatty acids and urinary 3-indoxyl sulfate do not discriminate between patients with Crohn´s disease and ulcerative colitis and are not of diagnostic utility for predicting disease severity

BackgroundUrinary 3-indoxyl sulfate levels as well as fecal short chain fatty acid (SCFA) concentrations are surrogate markers for gut microbiota diversity. Patients with inflammatory bowel diseases (IBDs) and patients with primary sclerosing cholangitis (PSC), a disease closely associated with IBD, have decreased microbiome diversity. In this paper, the fecal SCFAs propionate, acetate, butyrate and isobutyrate of patients with IBD and patients with PSC-IBD and urinary 3-indoxyl sulfate of IBD patients were determined to study associations with disease etiology and severity.MethodsSCFA levels in feces of 64 IBD patients and 20 PSC-IBD patients were quantified by liquid chromatography with tandem mass spectrometry (LC–MS/MS). Urinary 3-indoxyl sulfate levels of 45 of these IBD patients were analysed by means of reversed-phase liquid chromatography-electrospray ionization-tandem mass spectrometry. Feces of 17 healthy controls and urine of 13 of these controls were analyzed in parallel. These cohorts had comparable sex distribution and age.ResultsUrinary 3-indoxyl sulfate concentrations (normalized to urinary creatinine levels) was increased (P = 0.030) and fecal isobutyrate levels (normalized to dry weight of the stool sample) of IBD patients were decreased (P = 0.035) in comparison to healthy controls. None of the analyzed metabolites differed between patients with Crohn´s disease (CD) and patients with ulcerative colitis (UC). Fecal acetate and butyrate positively correlated with fecal calprotectin (P = 0.040 and P = 0.005, respectively) and serum C-reactive protein (P = 0.024 and P = 0.025, respectively) in UC but not CD patients. UC patients with fecal calprotectin levels above 150 µg/g, indicating intestinal inflammatory activity, had higher fecal acetate (P = 0.016), butyrate (P = 0.007) and propionate (P = 0.046) in comparison to patients with fecal calprotectin levels < 50 µg/g. Fecal SCFA levels of PSC-IBD and IBD patients were comparable.ConclusionsCurrent findings suggest that analysis of urinary 3-indoxyl-sulfate as well as fecal SCFAs has no diagnostic value for IBD and PSC-IBD diagnosis or monitoring of disease severity.

Disruption of the microbiota-gut-brain axis is a defining characteristic of the α-Gal A (-/0) mouse model of Fabry disease

ABSTRACT Fabry disease (FD) is an X-linked metabolic disease caused by a deficiency in α-galactosidase A (α-Gal A) activity. This causes accumulation of glycosphingolipids, especially globotriaosylceramide (Gb3), in different cells and organs. Neuropathic pain and gastrointestinal (GI) symptoms, such as abdominal pain, nausea, diarrhea, constipation, and early satiety, are the most frequent symptoms reported by FD patients and severely affect their quality of life. It is generally accepted that Gb3 and lyso-Gb3 are involved in the symptoms; nevertheless, the origin of these symptoms is complex and multifactorial, and the exact mechanisms of pathogenesis are still poorly understood. Here, we used a murine model of FD, the male α-Gal A (-/0) mouse, to characterize functionality, behavior, and microbiota in an attempt to elucidate the microbiota-gut-brain axis at three different ages. We provided evidence of a diarrhea-like phenotype and visceral hypersensitivity in our FD model together with reduced locomotor activity and anxiety-like behavior. We also showed for the first time that symptomology was associated with early compositional and functional dysbiosis of the gut microbiota, paralleled by alterations in fecal short-chain fatty acid levels, which partly persisted with advancing age. Interestingly, most of the dysbiotic features suggested a disruption of gut homeostasis, possibly contributing to accelerated intestinal transit, visceral hypersensitivity, and impaired communication along the gut-brain axis.

Altered levels of fecal short-chain fatty acids are associated with subclinical inflammation and worse cognitive performance in patients with schizophrenia

Schizophrenia is a multi-systemic disorder that is associated with lipid profile disturbances, altered glucose homeostasis and subclinical inflammation. It has been proposed that dysfunction of the gut-brain axis might underlie these alterations. Short-chain fatty acids (SCFAs) are considered to play a pivotal role in the gut-brain axis. In this study, we aimed to compare fecal levels of SCFAs in patients with schizophrenia and healthy controls (HCs), taking into consideration their relationship with common peripheral blood alterations observed in schizophrenia. The study included 100 stable outpatients with schizophrenia and 55 HCs. The levels of SCFAs (acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, and lactic acid) in fecal samples were measured. Also, lipid profile together with the levels of C-reactive protein, glucose and insulin were determined. The levels of isovaleric acid were significantly higher in patients with schizophrenia after co-varying for age, sex, and the adherence to the Mediterranean diet. Moreover, there were significant positive correlations of the levels of valeric acid, isovaleric acid and CRP in patients with schizophrenia. In this group of participants, higher levels of isovaleric acid were associated with significantly lower scores of delayed memory after adjustment for potential covariates and interactions with CRP levels. Our results indicate that individuals with schizophrenia show altered levels of isovaleric acid that might be associated with impairments of delayed memory. The association with cognitive impairments might be independent of interactions with immune-inflammatory processes. Longitudinal and experimental studies are needed to test causal mechanisms of observed correlations.