VIENNA — Type 1 diabetes complications are associated with changes in the composition and function of the gut microbiome, a large data linkage study shows.
The largest changes were observed in those with diabetic nephropathy, but they were also observed to a lesser extent in those with glucose control (A1c), diabetic retinopathy, and other micro- and macro-vascular complications.
Ranko Gacesa, PhD, from the University Medical Center Groningen, Gastroenterology and Hepatology, Groningen, the Netherlands, presented the data at the United European Gastroenterology (UEG) 2022 meeting.
Gacesa's work shows that the gut microbiome plays an important role in type 1 diabetes, especially with respect to complications in those with long-standing disease. He explained that their data suggested a link between glucose control in the progression of type 1 diabetes and the gut microbiome. However, the direction of that link, or whether it was bidirectional, remained unknown.
"How our glucose is controlled over a long period of time matters to the gut environment. So, if we make the gut environment healthier, it might promote better control of diabetes," said Gacesa, speaking to Medscape Medical News.
With further research, Gacesa suggested that modifying the gut microbiome in people with type 1 diabetes — for example, with probiotics or a controlled diet — might improve their response to insulin.
"Gut microbiome-based therapies might have an effect on long-term diabetic complications, and based on our data, particularly diabetic nephropathy," he said.
Type 1 Diabetes: "A Very Different Beast"
Links are already established between the gut microbiome and both type 2 diabetes and obesity. Likewise, there are links between the gut microbiome and the risk of developing type 1 diabetes.
However, Gacesa noted that much less is known about any interactions between the gut microbiome and long-term, established type 1 diabetes and its complications.
"Type 1 diabetes is a very different beast," he remarked. "The clinical manifestations are similar, in that we lose the ability to process sugar, but the fundamental underlying mechanism — autoimmunity — is very different."
"With certain other autoimmune diseases, mainly inflammatory bowel disease, we know they have a big link to the gut bacteria," he said.
As such, Gacesa and colleagues set about investigating the role of the gut microbiome in long-standing type 1 diabetes and its complications.
He explained that there were two aspects to their exploration: "We asked what happens in type 1 diabetes in general, but also how are the microbiomes different in people with type 1 diabetes compared to those without it?"
Microbiome Changes Similar to Other Autoimmune Diseases
Gacesa and his colleagues accessed data from a Netherlands-based research program following patients with type 1 diabetes, mostly observing the genetic underpinnings to the disease, but also obtaining biological samples, including stool for microbiome research.
Using fecal samples, metagenomic sequencing determined the composition and function of the microbiome of 239 patients with long-standing type 1 diabetes, which was compared with the microbiome of 2937 age-, sex-, and BMI-matched individuals who did not self-report any serious or chronic diseases. Controls were from the Lifelines Dutch Microbiome Project cohort, which has followed up members of the general population for up to 15 years.
Among the patients, 53% were male (median age, 53 years), with a mean body mass index (BMI) 25.3 kg/m2, mean type 1 diabetes duration of 28 years, and mean A1c of 62 mmol/mol (9.9 mmol/L); 73% had complications.
The researchers determined type 1 diabetes-related phenotypes, including micro- and macro-vascular complications (eg, diabetic nephropathy, diabetic retinopathy), A1c levels, and disease duration, as associated with microbiome composition and function.
These phenotypes were then related to abundances (increases and decreases) of bacterial species, as well as biochemical functions and pathways encoded by the microbiota, while controlling for age, sex, BMI, sequencing depth, and use of antibiotics and proton-pump inhibitors.
The microbiome of people with type 1 diabetes is dysbiotic, said Gacesa, who reported that they found an increase in opportunistic pathogens (Clostridiales and Oscillibacter) and a reduction in commensal bacteria (Dorea sp, Bifidobacterium species, Alistipes putredinis, and Prevotella copri) in these people's gut microbiomes.
Overall, profiling identified 82 bacterial taxa that were significantly changed, with 37 bacterial species enriched and 43 depleted. In order of greatest significance, microbiome changes in type 1 diabetes were associated with age, medications (eg, proton-pump inhibitors), platelet aggregation inhibitors, diabetic retinopathy, and A1c level.
"Changes in the gut bacteria in people with type 1 diabetes are somewhat similar to what we see in other autoimmune diseases, specifically in inflammatory bowel disease," reported Gacesa. "The effects are not as big or dramatic, but there is a common pattern."
When Gacesa specifically looked at diabetic complications, he found that diabetic nephropathy was most strongly associated with a disrupted gut microbiome; in particular, there were changes to nine classes (taxa) of bacteria. These included a rise in multiple bacteria from the order Clostridiales, and changes to 29 microbial pathways, including those responsible for reduction in lipid metabolism and the biosynthesis of the amino acid methionine, as well as an increase in pathways involved in the biosynthesis of bacterial cell membranes.
Gacesa said that in people with diabetic nephropathy, "we see changes in the abundance of the 'bad' opportunistic bacteria, which increase in proportion, while the commensals go down."
"We also see an increase in bacteria normally only found in the oral cavity of people with a healthy gut," he added.
No Established Causal Link
Noting that he is not a diabetes specialist, Gacesa suggested that alterations in the pH of the gut environment in people with diabetic nephropathy might play a part in the disruption to the microbiome.
"Even a very small difference in our blood pH level could translate into a difference in our gut pH levels," he pointed out.
Gacesa stressed that because of the cross-sectional study design, it is not possible to establish a causal link based on these data alone.
Francesca R. Ponziani, MD, internal medicine specialist, Università Cattolica del Sacro Cuore, Rome, Italy, who moderated the session, pointed out that "it's hard to say the direction in which the effect occurs."
"The disease is complex, and the relationship between the gut and type 1 diabetes might have a complex mechanism such that the gut microbiome is changed by the disease, but the microbiome might worsen the disease in a feedback loop," she said.
She noted that people with type 1 diabetes are often younger and have autoimmune disease, in contrast to those with type 2 diabetes.
"The inflammatory and immunomodulatory triggers might be driven by the gut microbiome," she said. "It's important to know if there is a dysbiotic background in the gut of a person with type 1 diabetes because this might be relevant in preventing complications. A more inflammatory microbiome might worsen the profile of the disease."
"Probiotics or other ways to modify the microbiome might help," Ponziani added.
Gacesa and Ponziani report no relevant financial relationships.
United European Gastroenterology (UEG) 2022: Abstract OP019. Presented October 9, 2022.
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