The gut microbiome and type 2 diabetes status in the Multiethnic Cohort

Abstract

Background The gut microbiome may play a role in inflammation associated with type 2 diabetes (T2D) development. This cross-sectional study examined its relation with glycemic status within a subset of the Multiethnic Cohort (MEC) and estimated the association of circulating bacterial endotoxin (measured as plasma lipopolysaccharide-binding protein (LBP)) with T2D, which may be mediated by C-reactive protein (CRP). Methods In 2013–16, cohort members from five ethnic groups completed clinic visits, questionnaires, and stool and blood collections. Participants with self-reported T2D and/or taking medication were considered T2D cases. Those with fasting glucose >125 and 100–125 mg/dL were classified as undiagnosed (UT2D) and pre-diabetes (PT2D) cases, respectively. We characterized the gut microbiome through 16S rRNA gene sequencing and measured plasma LBP and CRP by standard assays. Linear regression was applied to estimate associations of the gut microbiome community structure and LBP with T2D status adjusting for relevant confounders. Results Among 1,702 participants (59.9–77.4 years), 735 (43%) were normoglycemic (NG), 506 (30%) PT2D, 154 (9%) UT2D, and 307 (18%) T2D. The Shannon diversity index decreased (ptrend = 0.05), while endotoxin, measured as LBP, increased (ptrend = 0.0003) from NG to T2D. Of 10 phyla, Actinobacteria (ptrend = 0.007), Firmicutes (ptrend = 0.003), and Synergistetes (ptrend = 0.02) were inversely associated and Lentisphaerae (ptrend = 0.01) was positively associated with T2D status. Clostridium sensu stricto 1, Lachnospira, and Peptostreptococcaceae were less, while Escherichia-Shigella and Lachnospiraceae were more abundant among T2D patients, but the associations with Actinobacteria, Clostridium sensu stricto 1, and Escherichia-Shigella may be due metformin use. PT2D/UT2D values were closer to NG than T2D. No indication was detected that CRP mediated the association of LBP with T2D. Conclusions T2D but not PT2D/UT2D status was associated with lower abundance of SCFA-producing genera and a higher abundance of gram-negative endotoxin-producing bacteria suggesting that the gut microbiome may contribute to chronic systemic inflammation and T2D through bacterial translocation.

Genetically Predicted Causality of 28 Gut Microbiome Families and Type 2 Diabetes Mellitus Risk

“…A study showed that constructed microbiome risk score was consistently associated with T2DM and future glucose increment and was related to a variety of blood metabolites derived from gut microbiome (34). Maskarinec et al demonstrated that T2DM was related to the abundance of some intestinal floras and gut microbiome might cause chronic systemic inflammation and T2DM through bacterial translocation (35). A study showed that microbial-derived or microbial-modified metabolites in serum could predict the risk of T2DM (36).…”

The WWOX/HIF1A Axis Downregulation Alters Glucose Metabolism and Predispose to Metabolic Disorders

“…What is more, SNP rs9927590 (found within WWOX gene) has been reported to be involved in obesity and was associated with a metabolic pathway involved in short-chain fatty acid (SCFA) production [ 124 ]. The gut bacterial production of SCFA may prevent T2D through appetite control and energy homeostasis [ 125 , 126 ]. Additionally, butyrate, one of SCFA, has been displayed to have an influence on gut hypoxia by mitochondrial beta-oxidation and by interacting with HIF1α to maintain tight junctions [ 125 ].…”

“…The gut bacterial production of SCFA may prevent T2D through appetite control and energy homeostasis [ 125 , 126 ]. Additionally, butyrate, one of SCFA, has been displayed to have an influence on gut hypoxia by mitochondrial beta-oxidation and by interacting with HIF1α to maintain tight junctions [ 125 ]. It has been demonstrated that butyrate metabolism reduces local oxygen level which stabilizes HIF1α [ 125 ].…”

“…Additionally, butyrate, one of SCFA, has been displayed to have an influence on gut hypoxia by mitochondrial beta-oxidation and by interacting with HIF1α to maintain tight junctions [ 125 ]. It has been demonstrated that butyrate metabolism reduces local oxygen level which stabilizes HIF1α [ 125 ]. The basal HIF1α expression within the mucosa provides protection function, so existing a host-microbe crosstalk pathway wherein SCFAs may signal protective gut functions is important to maintain homeostasis to prevent the development of, e.g., metabolic disorders [ 125 ].…”

“…It has been demonstrated that butyrate metabolism reduces local oxygen level which stabilizes HIF1α [ 125 ]. The basal HIF1α expression within the mucosa provides protection function, so existing a host-microbe crosstalk pathway wherein SCFAs may signal protective gut functions is important to maintain homeostasis to prevent the development of, e.g., metabolic disorders [ 125 ]. All these mechanisms and WWOX/HIF1A axis participation need further investigation to be potentially useful in therapy.…”