bims-liverm 2023-05-14 papers

Issue of 2023–05–14
five papers selected by

Diabetes Obes Metab. 2023 May 10.

Bile acid metabolites in early pregnancy and risk of gestational diabetes mellitus: Results from a prospective cohort study.

Yuwan Wu, Zheng Wang, Zhi Zhao, Xiuxia Song, Maohua Miao, Xi Zhang.

AIMS: To evaluate the associations of plasma bile acid metabolites, especially in early pregnancy, with gestational diabetes mellitus (GDM) risk among pregnant women.
MATERIALS AND METHODS: Plasma concentrations of 15 bile acid metabolites were measured in 645 women at early pregnancy from the Jiashan Birth Cohort using a liquid chromatography-tandem mass spectrometry metabolomics platform. Using logistic and cubic spline models, we examined associations between baseline plasma bile acid metabolites and GDM risk during mid-late pregnancy. A meta-analysis of prospective studies of bile acid and GDM risk was performed.
RESULTS: The linear and nonlinear univariate models identified eight metabolites associated with GDM, including cholic acid, taurocholic acid (TCA), glycocholic acid, glycochenodeoxycholic acid, deoxycholic acid, lithocholic acid (LCA), ursodeoxycholic acid and taurolithocholic acid (all P <0.05). Multivariable analysis indicated that TCA and LCA levels were positively (odds ratio [OR] 2.07, 95% confidential interval [CI] 1.05, 3.96; P = 0.030) and negatively (OR 0.83, 95% CI 0.68, 1.01; P = 0.065) associated with GDM, respectively, after adjusting for confounders. The TCA-GDM association showed a positive linear shaped relationship (OR 2.07, 95% CI 1.05, 3.96; P = 0.030); while LCA was negatively related with GDM risk in linearity (OR 0.83, 95% CI 0.68, 1.01; P = 0.065). The meta-analysis of five studies showed a consistent bile acid and GDM association, with a risk ratio (RR) of 2.43 (1.95, 3.03).
CONCLUSIONS: This study indicated that, the levels of circulating bile acids in early pregnancy were associated with risk of GDM, independent of GDM risk factors. Most GDM-associated bile acids were primary conjugated and secondary unconjugated bile acids.

Keywords: bile acid metabolites; gestational diabetes mellitus; glucose; prospective cohort study

DOI: https://doi.org/10.1111/dom.15104

Mol Nutr Food Res. 2023 May 06. e2200595

Intermittent fasting alleviates non-alcoholic steatohepatitis by regulating bile acid metabolism and promoting fecal bile acid excretion in high-fat and high-cholesterol diet fed mice.

Xiaozhuan Lin, Xuan Zhu, Yan Xin, Peiwen Zhang, Yunjun Xiao, Taiping He, Honghui Guo.

SCOPE: Intermittent fasting (IF) has a protective role across a wide range of chronic disorders, including obesity, diabetes and cardiovascular disease, but its protection against non-alcoholic steatohepatitis (NASH) is still lacking. This study sought to investigate how IF alleviates NASH by regulating gut microbiota and bile acids (BAs) composition.
METHODS AND RESULTS: Male C57BL/6 mice were fed a high-fat and high-cholesterol (HFHC) diet for 16 weeks to establish a NASH model. Mice then continued HFHC feeding and were treated with or without every other day fasting for 10 weeks. Hepatic pathology was assessed using hematoxylin-eosin staining. Gut microbiota of the cecum were profiled using 16S rRNA gene sequencing and the levels of BAs in serum, colon contents, and feces were measured using UPLC-MS/MS. Results indicated that IF significantly decreased murine body weight, insulin resistance, hepatic steatosis, ballooning, and lobular inflammation. IF reshaped the gut microbiota, reduced the accumulation of serum BAs, and increased total colonic and fecal BAs. Moreover, IF increased the expression of cholesterol 7α-hydroxylase 1 in liver, but decreased the expressions of both farnesoid-X-receptor and fibroblast growth factor 15 in the ileum.
CONCLUSION: IF alleviated NASH by regulating bile acid metabolism and promoting fecal bile acid excretion. This article is protected by copyright. All rights reserved.

Keywords: bile acid; cholesterol; gut microbiota; intermittent fasting; non-alcoholic steatohepatitis

DOI: https://doi.org/10.1002/mnfr.202200595

Nature. 2023 May 10.

Profiling the human intestinal environment under physiological conditions.

The spatiotemporal structure of the human microbiome1,2, proteome3 and metabolome4,5 reflects and determines regional intestinal physiology and may have implications for disease6. Yet, little is known about the distribution of microorganisms, their environment and their biochemical activity in the gut because of reliance on stool samples and limited access to only some regions of the gut using endoscopy in fasting or sedated individuals7. To address these deficiencies, we developed an ingestible device that collects samples from multiple regions of the human intestinal tract during normal digestion. Collection of 240 intestinal samples from 15 healthy individuals using the device and subsequent multi-omics analyses identified significant differences between bacteria, phages, host proteins and metabolites in the intestines versus stool. Certain microbial taxa were differentially enriched and prophage induction was more prevalent in the intestines than in stool. The host proteome and bile acid profiles varied along the intestines and were highly distinct from those of stool. Correlations between gradients in bile acid concentrations and microbial abundance predicted species that altered the bile acid pool through deconjugation. Furthermore, microbially conjugated bile acid concentrations exhibited amino acid-dependent trends that were not apparent in stool. Overall, non-invasive, longitudinal profiling of microorganisms, proteins and bile acids along the intestinal tract under physiological conditions can help elucidate the roles of the gut microbiome and metabolome in human physiology and disease.

DOI: https://doi.org/10.1038/s41586-023-05989-7

Lipids. 2023 May 11.

Association of circulating branched chain fatty acids with insulin sensitivity and beta cell function in the PROMISE cohort.

Nagam A Yehia, Liridona Isai, Zhila Semnani-Azad, Kira Zhi Hua Lai, Ravi Retnakaran, Stewart B Harris, Jacqueline L Beaudry, Richard P Bazinet, Anthony J Hanley.

Branched chain fatty acids (BCFAs) are mainly saturated fatty acids with a methyl branch on the penultimate or antepenultimate carbon atom. While BCFAs are endogenously produced via the catabolism of branched chain amino acids, the primary exogenous source of BCFAs in the human body is via the diet, including dairy products. Recently, BCFAs have been identified as having a potentially protective role in the etiology of cardiometabolic disorders although current literature is limited. We aimed to investigate the longitudinal associations of circulating BCFAs across four serum pools with insulin sensitivity, beta cell function, and glucose concentrations in the PROMISE Cohort. Estimates of insulin sensitivity were assessed using Matsuda's insulin sensitivity index (ISI) and the homeostasis model assessment of insulin sensitivity (HOMA2). Estimates of beta cell function were determined using the insulinogenic index divided by HOMA insulin resistance and the insulin secretion-sensitivity index-2 (ISSI-2). Baseline serum samples were analyzed for BCFAs using gas-chromatography flame ionization detection. Longitudinal associations were determined using generalized estimating equations. In the free fatty acid (FFA) pool, iso15:0 and anteiso15:0 were positively associated with logHOMA2 (iso15:0 logHOMA2-%S: β = 6.86, 95% CI: [1.64, 12.36], p < 0.05, anteiso15:0 logHOMA2-%S: β = 6.36, 95% CI: [0.63, 12.42], p < 0.05) while anteiso14:0 was inversely associated with measures of insulin sensitivity (iso14:0 logHOMA2-%S: β = -2.35, 95% CI: [-4.26, -0.40], p < 0.05, logISI: β = -2.30, 95% CI: [-4.32, -0.23], p < 0.05, anteiso14:0 logHOMA2-%S: β = -4.72, 95% CI: [-7.81, -1.52], p < 0.05, logISI: β = -6.13, 95% CI: [-9.49, -2.66], p < 0.01). Associations in other pools were less consistent. We identified the potential importance of specific BCFAs, specifically iso14:0, anteiso14:0, iso15:0, anteiso15:0, in cardiometabolic phenotypes underlying type 2 diabetes.

Keywords: glucose; hyperglycemia; insulin resistance; lipids; oral glucose tolerance test; type 2 diabetes

DOI: https://doi.org/10.1002/lipd.12373

JCI Insight. 2023 May 09. pii: e169541. [Epub ahead of print]

Heterogeneity in the effect of marked weight loss on metabolic function in women with obesity.

Bettina Mittendorfer, Brandon D Kayser, Mihoko Yoshino, Jun Yoshino, Jeramie D Watrous, Mohit Jain, J Christopher Eagon, Bruce W Patterson, Samuel Klein.

BACKGROUND: There is considerable heterogeneity in the effect of weight loss on metabolic function in people with obesity.
METHODS: We evaluated muscle and liver insulin sensitivity, body composition, and circulating factors associated with insulin action before and after ~20% weight loss in women identified as "Responders" (n=11) or "Non-responders" (n=11), defined as the top (>75% increase) and bottom (<5% increase) quartiles of the weight loss-induced increase in glucose disposal rate (GDR) during a hyperinsulinemic-euglycemic clamp procedure, among 43 women with obesity (BMI: 44.1±7.9 kg/m2).
RESULTS: At baseline, GDR, which provides an index of muscle insulin sensitivity, and the hepatic insulin sensitivity index were >50% lower in Responders than Non-Responders, but both increased much more after weight loss in Responders than Non-responders, which eliminated the differences between groups. Weight loss also caused greater decreases in intrahepatic triglyceride content and plasma adiponectin and PAI-1 concentrations in Responders than Non-Responders and greater insulin-mediated suppression of plasma free fatty acids, branched-chain amino acids and C3/C5 acylcarnitines in Non-Responders than Responders, so that differences between groups at baseline were no longer present after weight loss. The effect of weight loss on total body fat mass, intra-abdominal adipose tissue volume, adipocyte size, and circulating inflammatory markers were not different between groups.
CONCLUSION: The results from our study demonstrate the heterogeneity in the effects of marked weight loss on muscle and hepatic insulin sensitivity in people with obesity is determined by baseline insulin action, and reaches a ceiling when "normal" insulin action is achieved.
CLINICAL TRIAL REGISTRATION: NCT00981500, NCT01299519, NCT02207777FUNDING. This study was supported by National Institutes of Health grants P30 DK056341 (Washington University Nutrition and Obesity Research Center), P30 DK020579 (Washington University Diabetes Research Center), P30 DK052574 (Washington University Digestive Disease Research Center), and UL1 TR002345 (Washington University Institute of Clinical and Translational Sciences), T32 HL130357 (Obesity and Cardiovascular Disease Postdoctoral Training Program), grants from the American Diabetes Association (1-18-ICTS-119), the Longer Life Foundation (2019-011), and the Atkins Philanthropic Trust.

Keywords: Metabolism; Obesity

DOI: https://doi.org/10.1172/jci.insight.169541