The Effect of a Low Carbohydrate- High Fat Diet on Clinical Symptoms and Gut Microbiome in m.3243A>G Related Mitochondrial Diabetes

Mitochondrial disease (MD) is a clinically and genetically heterogenous group of disorders. The dysfunction of the mitochondrial respiratory chain results in ATP shortage and energy depletion resulting in multi system disease. Therapeutic interventions are currently limited and focus on relieving symptoms, since no curative therapies exist. The m.3243A>G related MD is presumably the most frequent MD affecting at least 1 in 5000 people, and the MIDD (Mitochondrial Inherited Diabetes and Deafness) phenotype is its most frequent clinical phenotype. The role of nutrition, providing the essential nutrients for mitochondria to produce energy, is an important disease modifier in MIDD.

A ketogenic diet (KD) is a very low-carbohydrate ( ±20 grams a day) high-fat diet that shifts metabolism towards β-oxidation and ketone body production. In cell studies and mice models for MD, ketone bodies or KD significantly affect different dimensions of mitochondrial function. KD has been proven to effectively treat intractable epilepsy in children with MD. The investigators recently performed a 12 week pilot study with KD in 20 adults with different types of mtDNA related MD. The KD improved glucose tolerance, yielded less migraine, and alleviated gastrointestinal symptoms. Despite these positive effects, it proved the KD is a difficult diet to follow and only 8/20 participants finished the 12 week KD intervention. The individuals with m.3243A>G related MD had the longest diet adherence. Because of the positive effects, over half of all participants switched to the more feasible and less restrictive low carbohydrate (± 50-100 gram/dag), high fat (LCHF) diet after completing the study. The positive effect of KD on the subtype of m.3243A>G related MD was very recently confirmed in another study. The LCHF diet however provides no ketone bodies and its effect in mitochondrial disease is not studied properly yet.

In irritable bowel syndrome, specific dietary regimens as low-fermentable, oligo-, di-, monosaccharides and polyols (FODMAPs) but also LCHF diets are considered therapeutic. A diet low in fermentable carbohydrates reduces the fermentation by the gut microbiota and is therefore thought to reduce bloating and other gastro intestinal complaints. Based on the results of a previous study from the investigators and the effect of LCHF diets in irritable bowel syndrome, the investigators hypothesize the same positive effect in the cohort of m.3243A>G related MD in which gastro intestinal complaints are very common.

An adult diabetes team studied the gut microbiome and observed significant differences in various species and pathways between the faecal stool samples of diabetes patients and healthy controls, and that gut microbiome composition is associated with glycemic control. The gut microbiome is a very promising study field. More insight in patients gut microbiome and the way it can be altered with nutrition could lead to new treatment options and symptom relieve which is very relevant to MD patients. Therefore it is interesting to compare the gut microbiome of MIDD patients with already analysed stool samples of healthy controls and diabetes patients, and study the effect of an LCHF diet intervention.

The LCHF diet is an established treatment option in diabetes, with positive effects on glucose homeostasis. The investigators have initially chosen the subgroup of m.3243A>G related MIDD patients as they hypothesize that the LCHF could help slow down the progression of diabetes severity and reduce the necessity for treatment with insulin in these patients in particular. Since the team could not find enough participants with MIDD they intent to include also participants with MD caused by the m3243A>G mutation but without diabetes. These patients still have a lot of gastro intestinal problems as well as fatigue and headaches, all relevant symptoms that possibly can be affected with the low carbohydrate diet. So the primary outcomes as mentions in the title of the study: effect on clinical symptoms and the gut microbiome are relevant for this patient population aswell.