**8. The microbiota in type 2 diabetes**

Genetics, lifestyle and increased bodyweight all contribute to the development of type 2 diabetes. Around 80% of individuals with T2D are overweight thus suggesting an important role of diet and microbiota in the pathophysiology of this disease. The link between microbiota and T2D first became evident in studies on germ-free mice. Thus, colonization of germfree animals with microbiota harvested from conventionally raised mice lead to a significant increase in body fat and insulin resistance [82]. A following study showed that germ-free mice were resistant to diet-induced obesity [83].

Subsequently, several studies have documented the microbiota shifts associated with T2D. After analysing a cohort of Chinese patients with T2D, Qin et al. showed that the diabetic microbiome is low in butyrate-producing bacteria such as Clostridiales sp., *F. prausnitzii, Roseburia intestinalis* and *E. rectal* [84]. Moreover, the T2D intestinal niche contained opportunistic pathogens including the sulfate-reducing *Desulfovibrio*, *Bacteroides caccae* and *E. coli*. In line with these findings, a study in Scandinavian post-menopausal women revealed decreased levels of *F. praunitzii* and *R. intestinalis* in T2D compared with individuals having impaired glucose tolerance. In addition, both Chinese and Scandinavian T2D cohorts exhibited elevated *Lactobacillus* levels. Obesity and impaired glucose metabolism were reported to have an altered ratio between Bacteroidetes and Firmicutes [85]; however, neither the Chinese nor the Scandinavian study found this microbiota change.

The Chinese study revealed an increase of *E. coli* in T2D patients and another Danish study showed that Proteobacteria levels were elevated in T2D [86]. These Gram-negative bacteria could potentially be involved in the pathophysiology of T2D. Specifically, the lipopolysaccharides (LPS) released by these bacteria could promote a subclinical proinflammation, which is typical to both diabetes and obesity. Recent studies revealed that T2D is characterized by elevated endotoxemia. Indeed, mice receiving high fat (HF) diet until they developed diabetes had endotoxemia, increased intestinal permeability and a distinct microbiots [87]. In addition, the term of metabolic infection has emerged in order to describe the role of the microbiome in endotoxemia-associated inflammation together with insulin resistance in T2D. Endotoxin of microbial origin could play a role in the insulin resistance associated with T2D since blood levels of bacterial DNA (mostly Proteobacteria) were shown to be increased in prediabetes.

**9. Probiotic interventions**

*Intestinibacter* sp.

Due to their anti-inflammatory, hypoglycaemic, insulinotropic, antioxidative and satietogenis properties, probiotics can be employed as a treatment for T2D. The insulinotropic effect of genetically engineered *Escherichia coli Nissle 1917* for GLP-1 was investigated in Caco-2 cells; it was observed that the probiotic strain stimulated the epithelial cells leading to the secretion of insulin corresponding to blood insulin concentration of 164 pmol/ml to 164 nmol/ml [90]. In addition, Paszti-Gere et al. reported that oxidative stress causing damage to insulin-secreting ß-cells was counteracted by metabolites of *Lactobacillus plantarum* 2142. Specifically, the spent culture supernatant of *L. plantarum 2142* decreased the oxidative stress-induced overexpression of proinflammatory cytokines IL-8 and TNF-α in IPEC-J2 cell line [91]. The multiple mechanisms of probiotics in T2D treatment have emerged from studies by using animal models. Oral administration (0.05%) or diet supplementation (0.1%) of heat-killed *L. casei* in different mouse models including KK-Ay mice, NOD mice and Alloxan-induced diabetic mice reduced the plasma glucose level and diabetes development [92, 93]. Feeding neonatal STZ-induced diabetic (n-STZ) rats with a diet containing *Lactobacillus rhamnosus GG* for a period of 9 weeks determined a lower blood haemoglobin level and an improved glucose tolerance in comparison to the control group

**Figure 2. The microbiota in type 2 diabetes.** Overweight and obese individuals consuming an unhealthy diet such a Western diet are prone to develop type 2 diabetes. While healthy individuals consuming a balanced diet with a high content of monounsaturated and polyunsaturated fatty acids, elevated vegetable protein content, and high levels of antioxidants and fibre harbour a microbiota rich in *R. intestinalis, F. prausnitz ii, E. rectale, Lactobacillus* sp. and Clostridiales, individuals with type 2 diabetes have a microbiota characterized by higher levels of *Desulfovibrio* sp*., Bacteroides* sp. and

The Intricate Relationship between Diabetes, Diet and the Gut Microbiota

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One caveat of the currently available human studies is the lack of information regarding the role of antidiabetic medication in altering the microbiota. The first-line drug of choice for type 2 diabetes treatment is represented by metformin. In the Swedish study, the diabetic patients received metformin treatment and their microbiota was enriched in Enterobacteriaceae and had low levels of *Eubacterium* and *Clostridium*. In mice-fed a high-fat diet, metformin was shown to affect both the host glucose metabolism as well as the microbiota by increasing the levels of *Akkermansia* [88]. Recently, metformin treatment has also been shown to alter the microbiota composition in T2D patients by increasing *Escherichia* sp. and decreasing the abundance of *Intestinibacter* sp. (**Figure 2**) [89].

**Figure 2. The microbiota in type 2 diabetes.** Overweight and obese individuals consuming an unhealthy diet such a Western diet are prone to develop type 2 diabetes. While healthy individuals consuming a balanced diet with a high content of monounsaturated and polyunsaturated fatty acids, elevated vegetable protein content, and high levels of antioxidants and fibre harbour a microbiota rich in *R. intestinalis, F. prausnitz ii, E. rectale, Lactobacillus* sp. and Clostridiales, individuals with type 2 diabetes have a microbiota characterized by higher levels of *Desulfovibrio* sp*., Bacteroides* sp. and *Intestinibacter* sp.
