Fecal microbiota transplantation treatment for type 1 diabetes mellitus with malnutrition: a case report

Abstract

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease. Not only genetics, but the intestinal environment affected by gut microbiota is also the key to pathogenesis. Besides the occurrence of diabetes, gut microbiota dysbiosis may also contribute to the development of diabetes-related complications. Fecal microbiota transplantation (FMT) is an emerging technique that had shown its potential as a treatment for metabolic disease. Here, we report the first case of T1DM with malnutrition and gastrointestinal symptoms treated with FMT. A 24-year-old T1DM patient suffered from poor blood glucose control, recurrent nausea and vomiting, severe malnutrition, and intractable constipation after insulin treatment. The clinical response of the patients after FMT was well, especially nausea and vomiting were significantly relieved. In addition, constipation, nutritional status, and blood glucose control (fasting blood glucose, HbA1c) gradually improved. A degree of similarity was found in gut microbiota composition between the patient and healthy donor after FMT while it was totally different before the treatment. Furthermore, pathway function analysis of MetaCYC database implies that the potential mechanism of the response of FMT may be driven by specific bacteria involved in several metabolic pathways that need further exploration. To sum up, we believe that the reconstruction of intestinal flora by FMT may be a new choice for the treatment of T1DM patients with malnutrition.

Introduction

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by T-cell-mediated destruction of β-cells leading to absolute insulin deficiency. ¹ Recently, more and more evidence indicated that genetics is not the only factor in the occurrence and development of T1DM. ² T1DM is driven by genetic, immune, environmental, and other factors.^2,3 The interaction between gut microbiota and the immune system regulating the intestinal environment is one of the key factors. Gut microbiota is not only related to the occurrence of diabetes but also contributes to the development of diabetes-related complications, especially diabetes-related malnutrition. Research had revealed the association between malnutrition and the alteration of the intestinal flora, but the majority of them focused on children or animal experiments. ⁴ Fecal microbiota transplantation (FMT), a technology of transplanting gut microbiota of healthy people into patients’ intestines to restore the normal function of intestinal flora in the treatment of intestinal^5–7 and extra-intestinal diseases,^8,9 is also considered as a special ‘organ transplantation’. Its potential for diabetes and malnutrition treatment is worth exploring.

This reported case of T1DM with malnutrition was treated with FMT. And there is a significant improvement shown in blood glucose (Glu) concentration and nutritional status after the FMT treatment.

Case report

A 24-year-old patient was diagnosed with T1DM 1 year ago and the patient’s fasting Glu concentration was not well controlled after a subcutaneous injection of insulin. Since February 2021, the patient repeatedly visited hospitals because of some symptoms of diabetic ketoacidosis, such as abdominal pain, nausea, and vomiting. These symptoms continued after the relevant treatment, and the case was hospitalized in the endocrinology department, on August 14. Then, the patient was transferred to our department on August 27 with a weight of 25.5 kg and a body mass index (BMI) of 11.8 kg/m² and was diagnosed with type 1 diabetic ketosis with severe malnutrition after the Nutritional Risk Screening (NRS2002) with a score of 4/13. Besides, the patient had a history of depressive disorder and was treated with drugs.

Obvious gastrointestinal symptoms accompanied by intractable constipation are still repeated after conventional treatment, including proton pump inhibitors (PPIs), mosapride, Oryz-Aspergillus enzyme and pancreatin tablet, metoclopramide, and enteral nutrition. Therefore, we decided to treat the patient with FMT with informed consent. A routine examination was conducted to ensure that there are no contraindications of FMT. In order to enhance enteral nutrition supplement and digestive tract therapy in FMT, we performed nasojejunal tube implantation for the patients. The stool came from a 29-year-old healthy donor. The preparation of fecal microbial suspensions is carried out in accordance with the instructions of the automatic microfiltration system (GenFMTer; FMT Medical, Nanjing, China). The screening of healthy donor and the preparation and transplantation of microbial suspensions followed the Nanjing consensus ¹⁰ (Supplementary 1). The prepared fecal microbial suspension was stored at a low temperature of −80°C. Then rewarmed and allocated to 200 ml for injection through nasojejunal tube. This process was executed once on the 3rd and 6th of September, respectively. There were no adverse reactions during the FMT treatment.

Results

After the FMT treatment, the clinical response of patients was very well, especially nausea and vomiting were significantly relieved, and constipation gradually improved, so digestive drugs were gradually discontinued. Moreover, the patient’s weight and BMI increased gradually (Figure 1). Other clinical indexes, total protein (TP), albumin (ALB), and hemoglobin (HGB) also recovered to a normal level. In terms of glycemic control, Glu and glycosylated hemoglobin (HbA1c) were maintained at a fine level, and the dose of insulin was decreased accordingly. Moreover, fasting C-peptide was recovered to 0.12 nmol/l from an extremely low level.

Figure 1.

Dynamic curves of Glu, HbA1c, BMI, TP, ALB, and HGB.

Metagenomic sequencing (Supplementary 2) was performed on fecal samples from the donor and the patient (pre- and post-FMT). The Venn diagram (Figure 2) and principal coordinates analysis (PCoA) analysis (Figure 3) showed the α and β diversity of the gut microbiota among the fecal samples. In contrast to the patient, the fecal microbiota of healthy donor was more abundant in Bacteroides uniformis, Bifidobacterium pseudocatenulatum, Escherichia coli, and Faecalibacterium prausnitzii (Figure 4(b)). Significant changes were found in the distribution of the top 20 flora in relative abundances pre- and post-FMT. At the genus level (Figure 4(c)), the relative abundances of Adlercreutzia, Anaerobutyricum, Anaerostipes, Bacteroides, Bifidobacterium, Blautia, Collinsella, Eubacterium siraeum, Faecalibacterium, Faecalicatena, Flavonifractor, Mediterraneibacter, Phocaeicola, Siphoviridae sp., and Streptococcus increased, while those of Alistipes, Escherichia, Myoviridae sp., and Parabacteroides decreased post-FMT. At the species level (Figure 4(d)), the relative abundances of Adlercreutzia equolifaciens, Alistipes shahii, Anaerobutyricum hallii, Bacteroides cellulosilyticus, Bacteroides stercoris, Bacteroides xylanisolvens, Bifidobacterium pseudocatenulatum, Blautia sp. SC05B48, Faecalibacterium prausnitzii, Phocaeicola dorei, and Phocaeicola vulgatus increased, while those of Alistipes onderdonkii, Bacteroides caccae, Bacteroides ovatus, B. uniformis, Escherichia coli, Parabacteroides distasonis, Parabacteroides merdae, and Parabacteroides sp. CT06 decreased post-FMT.

Figure 2.

Venn diagram showed all OTUs obtained in fecal samples of donor and receiver (pre- and post-FMT).

Figure 3.

PCoA analysis showed the β diversity among the fecal samples of donor and receiver (pre- and post-FMT).

Figure 4.

The bar plot showed the distribution of the top 20 flora in relative abundance at the genus (a) and species (b) levels. The heatmap showed the clustering results of the top 20 flora in relative abundance at the genus (c) and species (d) levels.

Additional analysis of pathways and functions on the MetaCYC database was performed (Table 1). A total of 29 pathways associated with 20 functions were found altered post-FMT. They were ANAGLYCOLYSIS-PWY, COA-PWY-1, PEPTIDOGLYCANSYN-PWY, PANTO-PWY, PWY0-1319, PWY-1042, PWY-2942, PWY-3841, PWY5097, PWY-5659, PWY-5667, PWY-5686, PWY-5695, PWY-6121, PWY-6122, PWY-6123, PWY-6124, PWY-6151, PWY-6277, PWY-6385, PWY-6386, PWY-6387, PWY-6609, PWY66-400, PWY-7219, PWY-7220, PWY-7282, PYRIDOXSYN-PWY, and VALSYN-PWY.

Table 1.

MetaCYC database pathway function analysis.

Functions (altered post-FMT)	Pathway IDs	Principal bacteria
4-Amino-2-methyl-5-phosphomethylpyrimidine biosynthesis	PWY-7282	Bacteroides ovatus/xylanisolvens
5-Aminoimidazole ribonucleotide biosynthesis	PWY-6121 PWY-6122 PWY-6277	Alistipes onderdonkii Clostridium bolteae Eggerthella lenta Eubacterium siraeum
Adenine and adenosine salvage III	PWY-6609	Alistipes shahii Bacteroides caccae/ovatus/xylanisolvens Odoribacter splanchnicus Ruminococcus gnavus
Adenosine deoxyribonucleotides de novo biosynthesis II	PWY-7220	Bacteroides cellulosilyticus
Adenosine ribonucleotides de novo biosynthesis	PWY-7219	Alistipes onderdonkii/shahii Bacteroides caccae/cellulosilyticus/ovatus/uniformis/vulgatus Parabacteroides distasonis/merdae Ruminococcus gnavus
CDP-diacylglycerol biosynthesis	PWY-5667 PWY0-1319	Bacteroides caccae/ovatus/stercoris/uniformis Parabacteroides distasonis/merdae
Coenzyme A biosynthesis	COA-PWY-1	Bacteroides caccae/ovatus/uniformis/vulgatus Eubacterium siraeum Megasphaera elsdenii Parabacteroides distasonis
Folate transformations	PWY-3841	Bacteroides caccae/ovatus/uniformis/vulgatus Parabacteroides distasonis/merdae
GDP-mannose biosynthesis	PWY-5659	Alistipes onderdonkii/shahii Bacteroides ovatus/xylanisolvens Eubacterium siraeum
Glycolysis	ANAGLYCOLYSIS-PWY PWY-1042 PWY66-400	Alistipes shahii Bacteroides caccae/ovatus Odoribacter splanchnicus
Inosine-5’-phosphate biosynthesis	PWY-6123 PWY-6124	Bacteroides ovatus
L-lysine biosynthesis	PWY-2942 PWY5097	Bacteroides caccae/cellulosilyticus /ovatus/stercoris/uniformis/vulgatus Parabacteroides distasonis/merdae
L-valine biosynthesis	VALSYN-PWY	Bacteroides caccae/cellulosilyticus/massiliensis/stercoris/vulgatus Eubacterium siraeum Parabacteroides distasonis
Peptidoglycan biosynthesis	PEPTIDOGLYCANSYN-PWY PWY-6385	Alistipes onderdonkii Bacteroides ovatus/uniformis/vulgatus Parabacteroides distasonis/merdae
Phosphopantothenate biosynthesis	PANTO-PWY	Bacteroides caccae/cellulosilyticus/ovatus /stercoris/uniformis/vulgatus Parabacteroides distasonis/merdae
Pyridoxal 5’-phosphate biosynthesis	PYRIDOXSYN-PWY	Bacteroides caccae/ovatus/stercoris/uniformis
S-adenosyl-L-methionine cycle I	PWY-6151	Bacteroides massiliensis/stercoris/uniformis/vulgatus Eubacterium hallii
UDP-N-acetylmuramoyl-pentapeptide biosynthesis	PWY-6386 PWY-6387	Alistipes onderdonkii Bacteroides ovatus/uniformis/vulgatus Parabacteroides distasonis
UMP biosynthesis	PWY-5686	Alistipes onderdonkii Bacteroides caccae/ovatus/stercoris/uniformis Collinsella aerofaciens Eubacterium siraeum Parabacteroides distasonis/merdae
Urate biosynthesis/inosine 5’-phosphate degradation	PWY-5695	Alistipes shahii Bacteroides caccae/ovatus/stercoris/vulgatus Megasphaera elsdenii Parabacteroides distasonis

Discussion

Gut microbiota plays an important role in human health and disease. Compared with the gut microbiota of healthy people, the abundance of butyric acid-producing anaerobic bacteria and firmicutes/bacteroides ratio of T1DM patients decreased,^11,12 which was consistent with our metagenomics results. De Groot et al. ¹³ have found that FMT treatment can improve Glu control in patients with T1DM and retain the function of residual β cells. The glucose concentration of our patient fluctuated from 4.66 to 14.10 mmol/l before FMT, and it was controlled at an average of 6.23 mmol/l after the treatment. These improvements in glucose metabolism might owe to the alteration in B. ovatus which was confirmed over-abundance in T1DM children as compared with healthy controls. ¹⁴ Cinek et al. ¹⁵ have found that the imbalance within the Bacteroides genus might be one of the key factors in T1DM. But some species, such as B. caccae and Bacteroides vulgatus, were found to increase in T1DM women in pregnancy while they were proved to decrease in islet autoimmunity children and inversely associated with it,^15,16 their roles in T1DM are still ambiguous. The results of our case were in line with the pregnant women study. These three species of Bacteroides were involved in 19 functions alteration post-FMT. Among them, pyridoxal 5’-phosphate that could protect islet beta-cell from streptozotocin-induced dysfunction might be the key pathway (PYRIDOXSYN-PWY) that benefits diabetes improvement. ¹⁷ But this specific mechanism still needs further exploration to illustrate.

Besides diabetes, our patient was also complicated with severe malnutrition. The application of FMT treatment in malnutrition was still relatively rare, only one case of weight gain after FMT was reported. ¹⁸ In our case, the improvement in the condition of nutrition is markedly reflected in the increase in BMI, TP, ALB, and HGB. The patient also came back from malnutrition-led amenorrhea after FMT. In the gut microbiota changes part, two bacteria came to our notice. Blautia is a kind of intestinal flora that had a positive correlation with weight. ¹⁹ We observed a significant increase in Blautia after FMT. Parabacteroides, a probiotic enriched in the patient’s flora before FMT and decreased after FMT. Evidence showed that P. distasonis improves lipid metabolism and decreases weight gain by elevating the level of succinate. ²⁰ Other research found that succinate-fed mice had a higher basic energy consumption. ²¹ These implied that the over-abundance of P. distasonis might turn it into a pathogenic bacterium, which led to malnutrition in our case.

In addition, the patient had been hospitalized for depressive disorder and had taken duloxetine previously. And our results were surprised to find changes in depression-related flora, such as A. onderdonkii, B. uniformis, and P. diatasonis.^22–25 Fortunately, the depression did not recur during the follow-up.

Conclusion

In summary, FMT treatment was successfully performed in a T1DM patient with malnutrition in this case. This means a new choice for the treatment of these diseases was now offered. Further research on its mechanism still needs to be done. Despite this being a case report, our results are highly suggestive for exploring the association between gut microbiota and metabolic diseases.