Microbiota transfer therapy can improve behavioral and physical symptoms of ASD

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Autism Spectrum Disorder currently affects 1 in 44 children in the U.S., according to the Centers for Disease Control and Prevention. For reasons that remain murky, these numbers appear to be trending upward as researchers and clinicians struggle to find effective treatments.

Recently, a new approach to treat symptoms associated with this disorder has emerged, thanks to the explosion of research on the trillions of non-human cells inhabiting the gastrointestinal tract – collectively known as the gut microbiome.

The treatment, called microbiota transfer therapy, is a process where healthy gut bacteria are transferred to children with autism.

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Most of the research on microorganisms is confined to infectious diseases and the role of microorganisms in human health is largely ignored. The average weight of these microorganisms is about 1.5 kg, equivalent to the weight of the liver. There are 1012–1014 microorganisms, which is 10 times the number of the human body’s own cells, and they are mainly parasitic in the intestinal tract[1]. These symbiotic microorganisms include bacteria, viruses, archaea, fungi and, in some cases, protists, collectively known as the microbiome. The most important advantage of fecal microbiota transplantation (FMT) is the determination of cause and effect of disease through microbiology[2] .

During the long process of human evolution, the intestinal flora has coevolved with its host, along with social development, changes in diet, lifestyle and environment. Intestinal symbiotic bacteria can regulate a variety of metabolic activities that cannot be carried out by the human body itself[3]. They can obtain energy by decomposing polysaccharides, proteins and fats in food that cannot be fully digested by the host, and produce a series of metabolites that affect the health of the host. In this process, the intestinal microecosystem is closely related to the host metabolic capacity[4].

As early as 3000 years ago, cow dung was used in India to treat gastrointestinal diseases. As early as the Eastern Jin Dynasty (317–420 AD), a treatment similar to fecal bacterial transplantation, called “Huanglong Soup”, was described in Ge Hong’s “Urgent Prescription for Elbow Reserve”, which was used to treat food poisoning and diarrhea. In traditional Chinese medicine, it is recorded that huanglian and rhubarb, among others, have the curative effect of “quenching thirst” (ancient term for diabetes). Berberine, a monomer component from huanglian, has been recognized internationally for its effect on improving glucose and lipid metabolism earlier. During World War II, German soldiers in North Africa treated diarrhea with camel excrement[5]. At present, FMT is mainly used for the treatment of recurrent Clostridium difficile infection (CDI) in clinical practice, and many clinical trials have confirmed that FMT is a feasible treatment[6].

At present, with the development of fast and accurate high-throughput sequencing technology and the improvement of bioinformatics technology methods, intestinal flora is closely related to metabolic syndrome (MS), type 1 diabetes (T1D) and type 2 diabetes (T2D), various cancers, and autoimmune diseases. Currently, it is believed that the FMT donor should be carefully selected and examined for infectious diseases[7]. However, due to the large difference in metabolism and diet of FMT donors, the effect of transplantation can be different. In this review, the mechanisms and deficiencies of FMT are discussed, and the optimal design of FMT is explored to maximize scientific research and clinical application methods.

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COMPOSITION AND METHOD OF FMT
The main components of FMT are the gut flora of humans and other species. Humans have evolved to come into contact with a variety of bacteria, including those produced by food fermentation. The oral cavity is an important location of intestinal microbiota, which has an important effect on human health. Studies have shown that children who grow up on farms have a lower risk of asthma; a phenomenon that may be linked to changes in their gut microbiota[8]. In addition, babies born by cesarean section are at increased risk of developing autoimmune diseases, mainly because the initial microbes passed from the vagina to the baby at birth are replaced by skin microbes from the mother and surgical team members, which alter the baby’s gut microbes[9]. An infant’s gut microbiome can be reshaped in breast milk by adding small amounts of bacteria from the mother’s feces, creating a pattern that more closely resembles that of babies born vaginally[10].

FMT has been processed into an odorless and tasteless preparation. In clinical practice, there are three methods of bacterial flora transplantation for patients willing to accept FMT: Upper, middle and lower digestive tract. The methods of transplanting upper digestive tract microflora mainly include oral microflora liquid and oral microflora capsule. The middle digestive tract approach includes a nasointestinal tube, endoscopic biopsy hole, percutaneous endoscopic gastrostomy and jejunal catheterization, endoscopic catheterization such as Transendoscopic enteral tubing (TET)[11]. The lower gastrointestinal pathway includes colonoscopy, colostomy, enema, and colonic pathway TET. Colonic pathway TET is not only used for microflora transplantation, but also for whole colon administration such as mesalazine, hormones and traditional Chinese medicine. As a new endoscopic technique, TET is an important supplement for interventional treatment of inflammatory bowel disease[12].

FMT focuses on flora transplantation, but other components, such as phages, should not be ignored, which may be the reason for FMT’s effectiveness in the treatment of recurrent CDI. Therefore, phage research is important, and animal studies have shown that fecal virus transplantation also plays an important role. Analysis of the feces of adults on a classic British diet found that 25% of the 100 g/d excreted was made up of bacteria and 75% of fiber, protein, fat, bile acids and short-chain fatty acids (SCFAs). In most FMT, however, feces are simply mixed with salt water and filtered to remove insoluble substances[13]. Thus, the potential effects of FMT may be partly due to the combined effects of these compounds (Figure ​1).

reference link :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9254144/

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In a new study, Arizona State University researchers and their colleagues deeply explore changes in the gut microbiota following microbiota transfer therapy- specifically, by using whole genome sequencing, they looked at alterations in bacterial species and genes involved with microbial metabolism.

The researchers discovered that microbial taxa and genes that are important for microbial pathways associated with improvements in the physical and behavioral symptoms of autism spectrum disorder, improved following microbiota transfer therapy.

In first-of-its-kind research, the research team used a whole genome sequencing technology known as “shotgun metagenomics” to extract detailed data from more than 5,000 bacterial species found in the gut of children with autism spectrum disorder before and after microbiota transfer therapy. The researchers then compared these results with bacterial populations in the guts of healthy children.

The results showed considerable improvement in overall abundance of bacteria following the microbiota transfer therapy, and this confirmed previous findings published in Scientific Reports in 2019. Also, there were substantial increases in populations of beneficial bacterial species typically found in lower numbers in children with autism.

Additionally, two genetic indicators of dysregulation in the gut microbiome of children with autism improved following microbiota transfer therapy. These key genetic markers are the metabolism of sulfur and the failure to detoxify oxidative stress.

The findings are encouraging because the severity of gastrointestinal dysfunction in autistic children appears proportional to the degree of behavioral and cognitive issues, highlighting the importance of the gut-brain axis—a topic of intense interest in the world of microbiomics. The gut-brain axis is the communication system between your brain and your gut.

“This study highlights altered levels of important bacterial species and metabolic genes in children with autism and improvements after microbiota transfer therapy,” says Khemlal Nirmalkar, lead author and post-doctoral fellow working in the Rosa Krajmalnik-Brown lab at the ASU Biodesign Institute. “Our long-term goal is to understand the functional role of the gut microbiome, fill the knowledge gap of the gut-brain axis in autism, and identify therapeutic targets to improve GI health and behavior in children with autism.”

“Completing more in-depth microbiome sequencing is important because it can help us better understand what microbes in the gut are doing and why they are an important part of the gut-brain axis,” said Krajmalnik-Brown, who directs the newly established Biodesign Center for Health Through Microbiomes. She is also a professor with the ASU School of Sustainable Engineering and the Built Environment in the Ira A. Fulton Schools of Engineering.

Collaborators include James Adams, President’s Professor with the ASU School for Engineering of Matter, Transport and Energy, and researchers with the Rensselaer Polytechnic Institute in New York.

The study appears in a special issue of the International Journal of Molecular Sciences.

The research team used shotgun metagenomics, or whole genome sequencing, to better understand the bacterial populations at the species level. They also wanted to understand bacterial genes before and after microbiota transfer therapy.

The treatment not only increased the abundance of beneficial bacteria but also helped to normalize altered levels of bacterial genes, particularly those related to the synthesis of folate, oxidative stress protection and sulfur metabolism, and importantly, became similar to typically developing children.

Autism remains an enigmatic disorder, often emerging in early childhood and causing lifelong developmental disabilities that affect social skills, communication, personal relationships and self-control. So far, there is no cure for the affliction and therapies for treating associated symptoms remain limited.

The microbiota transfer procedure involves the transfer of gut microbiota from healthy donors to ASD patients over a period of seven to eight weeks. The procedure begins with a 2-week antibiotic treatment and bowel cleanse, followed by an extended transplant of fecal microbiota, applying a high initial dose followed by daily and lower maintenance doses for 7–8 weeks. This treatment was initially studied in children with autism ages 7-16 years old.

In a follow-up study, the same 18 participants were examined two years after treatment was completed. Most improvements in gastrointestinal symptoms were maintained, while autism-related symptoms continued to improve even after the end of treatment, demonstrating the long-term safety and efficacy of microbiota transfer therapy as a therapy for autism.

The treatment reduced the severity of gastrointestinal symptoms by roughly 80% and ASD symptoms by about 24% by the end of treatment. After two years, the same children showed an approximate 59% reduction in gastrointestinal symptoms and 47% reduction in ASD symptoms, compared with baseline levels established prior to treatment.

Krajmalnik-Brown and Adams are currently working on phase-2 double-blind placebo-controlled studies of microbiota transfer therapy for children and adults with autism, and they plan to verify whether these findings hold true in those two studies.

Future research will further explore the role of specific microbial species, functional gene expression and the production of a range of ASD-related metabolites before and after microbiota transfer therapy.



Original Research: Open access.
Shotgun Metagenomics Study Suggests Alteration in Sulfur Metabolism and Oxidative Stress in Children with Autism and Improvement after Microbiota Transfer Therapy” by Khemlal Nirmalkar et al. International Journal of Molecular Sciences

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