Progressive Shifts in the Gut Microbiome Reflect Prediabetes and Diabetes Development in a Treatment-Naive Mexican Cohort

Abstract

Type 2 diabetes (T2D) is a global epidemic that affects more than 8% of the world’s population and is a leading cause of death in Mexico. Diet and lifestyle are known to contribute to the onset of T2D. However, the role of the gut microbiome in T2D progression remains uncertain. Associations between microbiome composition and diabetes are confounded by medication use, diet, and obesity.Here we present data on a treatment-naive cohort of 405 Mexican individuals across varying stages of T2D severity. Associations between gut bacteria and more than 200 clinical variables revealed a defined set of bacterial genera that were consistent biomarkers of T2D prevalence and risk. Specifically, gradual increases in blood glucose levels, beta cell dysfunction, and the accumulation of measured T2D risk factors were correlated with the relative abundances of four bacterial genera. In a cohort of 25 individuals, T2D treatment—predominantly metformin—reliably returned the microbiome to the normoglycemic community state. Deep clinical characterization allowed us to broadly control for confounding variables, indicating that these microbiome patterns were independent of common T2D comorbidities, like obesity or cardiovascular disease. Our work provides the first solid evidence for a direct link between the gut microbiome and T2D in a critically high-risk population. In particular, we show that increased T2D risk is reflected in gradual changes in the gut microbiome. Whether or not these T2D-associated changes in the gut contribute to the etiology of T2D or its comorbidities remains to be seen.

Gut Microbiota Composition in Prediabetes and Newly Diagnosed Type 2 Diabetes: A Systematic Review of Observational Studies

“…The two studies using qPCR to assess the microbiota had used ten and six pairs of specific bacterial 16S rRNA primers, respectively, to target Atopobium cluster, Bacteroides fragilis, Bifidobacterium, Clostridium coccoides, Clostridium leptum, Clostridium perfringens, Enterobacteriaceae, Enterococcus, Lactobacillus and Prevotella (Chen et al, 2019) and Akkermansia, Bacteroides, Bifidobacterium, E.coli, Faecalibacterium and Lactobacillus (Ghaemi et al, 2020). Following sequencing, the microorganisms were classified and reported as operational taxonomic units (OTUs) (Zhang et al, 2013;Lambeth et al, 2015;Egshatyan et al, 2016;Bhute et al, 2017;Allin et al, 2018;Nuli et al, 2019;Zhao et al, 2019;Gaike et al, 2020;Chavez-Carbajal et al, 2020;Ericson et al, 2020), metagenomic clusters (MGCs) (Karlsson et al, 2013;Wu et al, 2020), microbiota (log10 cell/g) (Chen et al, 2019;Ghaemi et al, 2020), metagenome (Wang et al, 2021), metagenomic linkage group (MLGs) (Zhong et al, 2019) or amplicon sequence variants (ASVs) (Diener et al, 2021).…”

“…The 18 observational studies had been conducted between 2013 and 2021. They included twelve case-control (Zhang et al, 2013;Lambeth et al, 2015;Bhute et al, 2017;Allin et al, 2018;Chen et al, 2019;Nuli et al, 2019;Zhao et al, 2019;Zhong et al, 2019;Gaike et al, 2020;Ghaemi et al, 2020;Wang et al, 2021), four cross-sectional studies (Diener et al, 2021;Egshatyan et al, 2016;Chavez-Carbajal et al, 2020;Wu et al, 2020) and two cohort studies (Karlsson…”

“…Search ((((((((("treatment naive") OR "newly diagnosed") OR "new diagnosis")) OR ((((((prediabetes) OR prediabetics) OR prediabetic) OR pre-diabetes) OR pre-diabetics) OR pre-diabetic)))) OR (("impaired glucose tolerance") OR "impaired fasting glucose"))) AND (((((microbiome) OR microbiota) OR microflora) OR "gut bacteria")) 9 Remove duplicates from 8 Ericson et al, 2020). Six studies were conducted in Asia [India (Bhute et al, 2017;Gaike et al, 2020), Iran (Ghaemi et al, 2020), Taiwan (Chen et al, 2019) and China (Zhang et al, 2013;Nuli et al, 2019;Zhao et al, 2019;Zhong et al, 2019;Wang et al, 2021)], five in Europe [Denmark (Allin et al, 2018), Russia (Egshatyan et al, 2016) and Sweden (Karlsson et al, 2013;Wu et al, 2020;Ericson et al, 2020)] and three in North America [USA (Lambeth et al, 2015) and Mexico (Diener et al, 2021;Chavez-Carbajal et al, 2020)]. These studies had compared the gut microbial profiles of either preDM alone (Allin et al, 2018;Ericson et al, 2020), newDM alone (Chen et al, 2019;, preDM and newDM (Zhang et al, 2013;Egshatyan et al, 2016;Nuli et al, 2019;Zhong et al, 2019;Wu et al, 2020), preDM and knownDM (Karlsson et al, 2013;Lambeth et al, 2015;Ghaemi et al, 2020;Chavez-Carbajal et al, 2020;Wang et al, 2021), newDM and knownDM (Bhute et al, 2017;Zhao et al, 2019) or all three preDM, newDM and knownDM (Diener et al, 2021;…”

“…On the other hand, another two studies, (Zhong et al, 2019) and (Wang et al, 2021) found no significant difference in a-diversity among preDM and newDM in comparison to nonDM. Diener et al (2021) found that genera Ruminococcaceae was the most positively correlated with a-diversity while Fusobacterium, Flavonifractor, and Parasutterella were the most negatively correlated with a-diversity (Diener et al, 2021). Allin et al (2018) went on to demonstrate that a-diversity in the total group of subjects was negatively correlated with T2DM biomarkers particularly plasma triacylglycerol and high sensitivity C-reactive protein (hsCRP), as well as body mass index (BMI), hip circumference (HC), fasting blood glucose (FBG), fasting plasma insulin (FINS), plasma C-peptide and HOMA-IR (Allin et al, 2018).…”

Circulating Nucleic Acid-Based Biomarkers of Type 2 Diabetes

“…Other metagenomics studies identified Akkermansia muciniphila , Ruminococcus torques , Ruminococcaceae , Lachnospiraceae , and Enterobacteriaceae to be associated with T2D [ 54 , 55 , 56 , 57 ]. In a critically high-risk population, a recent study demonstrated associations between Escherichia , Veillonella , Blautia and Anaerostipes with T2D [ 51 ]. Another study looked into the abundance of antibiotic resistance genes (ARG) in fecal microbiome profiles.…”