A week of supervised fasting temporarily reshaped the gut microbiome of people with type 1 diabetes, making it resemble that of healthy individuals, and improving cholesterol and weight without causing dangerous side effects.
Study: Fasting elicits gut microbiome signature changes that extend to type 1 diabetes patients. Image credit: EchelonIMG/Shutterstock.com
Type 1 diabetes (T1D) is a chronic disease that affects nine million people worldwide. It is marked by a deficiency of the glucose-lowering hormone insulin, produced in the pancreatic beta cells. A new report in Frontiers in Endocrinology tested the role of prolonged therapeutic fasting as a complementary treatment for T1D.
Introduction
T1D is managed with lifelong insulin therapy to replace beta-cell function, coupled with careful dietary management. These patients are at high risk for multiple other medical conditions, including cardiovascular disease.
T1D is a complex disease with underlying genetic and environmental factors. It has become more common in Western societies over the last three decades, suggesting the enhanced role of environmental factors in its causation. In these patients, the gut microbiome shows differences in composition and function compared to healthy controls, both before and after the onset of the disease.
Apart from the increased gut permeability in T1D, these differences could be due to the shared risk factors for autoimmune diseases (such as T1D) and gut dysbiosis. These include the mode of birth, diet, infections, antibiotic exposure, and mental stress.
All these factors cause a loss of beneficial gut bacteria and their metabolites. For instance, metabolites like short-chain fatty acids (SCFA) and immunomodulatory metabolites contribute to gut health by maintaining the balance of regulatory T cells and pro-inflammatory Th17 cells. They also preserve the integrity of the gut's epithelial barrier, keeping toxins and pathogens out of the body and the blood.
Such negative interactions in early life may predispose to colonization by pathogens, leading to intestinal inflammation. Other gut microbes may trigger autoimmunity by expressing antigenic sites closely resembling self-antigens, known as “molecular mimicry”. For example, Parabacteroides distasonis contains a sequence similar to an important insulin epitope. Its presence is associated with higher rates of T1D development in mice and children.
Besides insulin, approaches to managing T1D focus on slowing down beta cell destruction with immunomodulators and biologicals. These are costly, with significant side effects, and are required lifelong, like insulin.
Therapeutic fasting is a nutritional approach that improves the symptoms of multiple autoimmune diseases and alters the gut microbiome profile in healthy individuals. The question in this study was whether such changes also occur in T1D patients. Studies on fasting, including the month-long Ramadan fast observed by Muslims or a seven-day supervised fast, have shown their safety in selected T1D patients at least. Restricting metabolic fuel can rapidly weaken the autoimmune response, lending biological plausibility to this hypothesis.
In mouse models, repeated fasting cycles reduce the risk of autoimmunity and enhance beta cell regeneration and Treg proliferation. Fasting also affects the gut microbiome in mouse studies. For instance, it leads to the production of β-hydroxybutyrate, an important fuel molecule during fasting. This depletes Bifidobacteria, reducing intestinal Th17 activity.
Several species experience fasting-related shifts in abundance. It is possible that restricting dietary nutrients promotes the proliferation of gut microbes with a more diverse metabolic portfolio, enabling them to switch to host-derived nutrients.
Study findings
The current pilot study included 19 T1D patients and ten controls, primarily female. The mean body mass index (BMI) was 27.7 kg/m2 and 26.2 kg/m2, respectively.
Prolonged fasting periods acutely changed the gut microbiome's structure and composition in T1D patients, leveling it with that in controls. Immediately after the end of the fasting period, the gut microbiome closely resembled that of non-diabetic controls, but no long-term shift was established. Diabetic ketoacidosis did not occur with fasting in the T1D group.
Several fiber-associated Lachnospiraceae decreased, while mucin/glycosaminoglycan-degrading Lachnospiraceae and some Oscillospiraceae increased during fasting. These are among the largest producers of the SCFA butyrate, thriving on a fiber-rich diet, and typically break down fiber. As a result, these members may not thrive in fiber-deficient periods, as during fasting periods.
The fasting regimen in this study involved ~200 kcal/day of juices and broth, which provided very little dietary fiber. This could help explain why fiber-adapted taxa declined while mucin-degrading taxa thrived.
However, not all members of these families change the same way. Other taxa that break down mucin and glycosaminoglycans increase in response to fasting, as reported in different studies. This indicates a shift towards using host-derived energy sources, including β-hydroxybutyrate.
These taxonomic changes were correlated with fasting-related alterations in blood pressure and cholesterol levels. Both the BMI and the ratio of bad-to-good cholesterol (low-density lipoprotein, LDL, and high-density lipoprotein, HDL, respectively) improved during the fasting period and follow-up. This change was similar to that reported earlier in non-diabetic patients.
In controls, post-fast patterns mirrored those in T1D but did not reach statistical significance, likely due to the small sample size.
When compared with a small group of ten multiple sclerosis patients on repeated prolonged fasting, many areas of the gut microbiome picture showed overlaps, as did autoimmunity-free groups.
This suggests that fasting's effects on the microbiome are independent of the host's health status and the type of disease, though larger studies are needed to confirm this. The gut microbiome responds to fasting in a conserved manner, probably because the gut microbes are forced to use diverse metabolic pathways to utilize host-derived nutrients.
While the taxa that break down dietary sources of energy decrease in abundance during fasting, those that can switch to using other energy substrates thrive. “This suggests that, next to utilizing β-hydroxybutyrate for their own nutrition, the gut microbiota could play an important role in augmenting host ketone production during periods of fasting.”
Specific taxa that increase during fasting may induce immune tolerance to environmental stimuli, perhaps contributing to the reduced inflammation with fasting.
Conclusions
The findings of this study demonstrate that “fasting under medical supervision is safe and could prove beneficial for patients with T1D.” The results suggest that the gut microbiome is shaped by nutrient availability rather than the presence of disease.
The associations with clinical outcomes emphasize the need to explore the causal connections between gut microbiome changes and the reported clinical improvements with fasting. More research is needed to understand the long-term value of fasting as an adjunctive treatment in these patients. Moreover, the speed with which microbial restoration occurs during re-feeding also needs to be explored.
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