Probiotics are very helpful for blood sugar control in T2D patients, but they reject the "sulfonylureas" of hypoglycemic households, how to solve it?

It is estimated that there are about 1.
5 million newly diagnosed cases of diabetes in the United States each year, and about 90% of people with diabetes are diagnosed with type 2 (T2D).

While genetic factors influence susceptibility, it is becoming increasingly clear that Western lifestyles and diets play an important role in the pathogenesis of T2D, as do
the gut microbiota.
The therapeutic effects of T2D drugs are at least partially mediated by gut microbes, including the widely used metformin, and many T2D drugs have been shown to alter the gut microbiota
.

The gut microbiota plays an important role in predicting blood glucose responses, and lifestyle-induced changes in the gut microbiota are associated
with disease progression.
Even the positive metabolic outcomes of caloric restriction seem to depend on the state of the gut microbiota before the
intervention.
Metagenomic investigations have shown that alterations in these microbiomes often lead to a decrease in the ability or elasticity of the gut microbiome to produce short-chain fatty acids, particularly butyrate
.

Dietary fiber and other dietary oligomers are undigested in the human upper digestive tract and are hydrolyzed and fermented by the lower GI microbiota, releasing "short-chain fatty acids" (SCFAs): 95% of the typical short-chain fatty acid content is in the 2C-4C form, acetic acid, propionic acid, and butyric acid
, respectively.
SCFAs are currently one of
the most important bacterial metabolites identified.
The production of robust gut short-chain fatty acids is associated with a reduced risk of certain diseases, including irritable bowel syndrome, inflammatory bowel disease, cardiovascular disease, and cancer – especially colorectal cancer
.
Regarding cardiometabolic health, SCFAs are thought to effectively regulate glucose homeostasis and insulin sensitivity
through adipose tissue, skeletal muscle, and liver tissue function.

Researchers have previously reported the preliminary safety and efficacy of a novel probiotic preparation that significantly improves postprandial blood glucose response
in patients with type 2 diabetes.
This formulation ('WBF-011') is hypothesized to produce short-chain fatty acids in vivo, and it contains 5 strains, each with a different short-chain fatty acid production potential (Figure 1).

Participants randomized to the WBF-011 group showed an encouraging increase in fecal butyrate concentration, while not observed in participants receiving placebo, although this increase did not reach statistical significance
.
A known limitation of fecal short-chain fatty acid measurements is that the vast majority of short-chain fatty acids are absorbed before fecal excretion, and circulating short-chain fatty acids are better predictors of metabolic markers such as insulin sensitivity, lipolysis, and glucagon-like peptide-1 (GLP-1) concentrations
.

An overview of the concepts of research, analysis and experimentation

The researchers of the study extended these observations experimentally, showing that in vitro biosynthesis of metabolite-formulated strains appeared to increase
among participants randomly assigned to WBF-011.
In addition, in vitro growth inhibition of some WBF-010 strains exposed to specific sulfonylureas was demonstrated, and the use of sulfonylureas appeared to attenuate the improvement
of blood glucose during the course of the study.

Here, investigators report targeted and non-targeted metabolome measurements
of fasting plasma (n=104) collected at baseline examination and at the end of the intervention.
Among participants randomized to WBF-011, butyrate and ursodeoxycholate increased, while the trend between butyrate and glycated hemoglobin (HbA1c) was noted
.
In vitro monoculture experiments have shown that the Clostridium caseinate strain of this formula can effectively synthesize ursodeoxybile acid from the primary bile acid chenodeoxycholic acid during the growth of butyric acid
.
Non-targeted metabolomics also showed synergistic reductions in fatty acid oxidation intermediates and bilirubin, a potentially secondary feature of
metabolic improvement.
Finally, the improvement in glycated hemoglobin was almost exclusively limited to participants who did not use sulfonylureas, so the investigators demonstrated that these drugs could inhibit the growth
of the preparation strain in vitro.

Summary of targeted measurements of short-chain fatty acids in human plasma after fasting

Data on the microbiological effects of sulfonylureas are clearly lacking
.
Anti-diabetic SFU was first found in 1942 in the study of bacteriostatic sulfonamides, and its bacteriostatic properties
were demonstrated by inhibiting acetylhydroxy acid synthase (AHAS, EC 2.
2.
1.
6), which is essential for the synthesis of branched-chain amino acids (BCAA).
。 However, the unequivocal in vitro growth inhibition of glibenclamide and glimepiride supports the potential of this common T2D drug class to inhibit these probiotic strains in vivo, resulting in a significant unresponsiveness in participants taking SFU in this study, suggesting that future studies utilizing probiotic strains should consider the SFU use of recruited participants in advance
.

The observed effects of SFU use on HbA1c can be explained as: (1) SFU directly inhibits the activity or growth of one or more WBF-011 formulated strains, (2) SFU affects host glycemic control (e.
g.
, structural enhancement of insulin secretion), thereby eliminating the effects observed in non-SFU participants randomized to WBF-011s, and (3) SFU use correlates with the clinical phase of T2D, limiting the ability
to improve during the study.
The current study design cannot distinguish between these explanations, nor does it rule out that they work
together.

In conclusion, this is the first description of an increase in circulating butyrate or ursodeoxycholate following probiotic intervention in T2D patients, supporting the possibility of a microbe-based approach to assist T2D management
.
The efficient synthesis of UDCA by Clostridium butyric may also be of interest
to researchers for its use as a probiotic for other diseases.
When designing future studies, the possibility of
inhibitory interaction between sulfonylureas and intestinal flora should be carefully considered.

References:1.
McMurdie PJ, Stoeva MK, Justice N, et al.
Increased circulating butyrate and ursodeoxycholate during probiotic intervention in humans with type 2 diabetes.
BMC Microbiol.
2022 Jan 8; 22(1):19.
doi: 10.
1186/s12866-021-02415-8.
PMID: 34996347; PMCID: PMC8742391.

2.
Perraudeau F, McMurdie P, Bullard J, Cheng A, Cutcliffe C, Deo A, et al.
Improvements to postprandial glucose control in subjects with type 2 diabetes: a multicenter, double blind, randomized placebo-controlled trial of a novel probiotic formulation.
BMJ Open Diabetes Res Care.
2020; 8.

3.
Henquin JC.
The fiftieth anniversary of hypoglycaemic sulphonamides.
How did the mother compound work? Diabetologia.
1992; 35:907–912.