Researchers at the University of Toronto and its partner hospitals are finding that changes in the intestinal microbiome after bariatric surgery can directly improve metabolism, independent of food intake, weight loss and other metabolic factors.
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The results of the study were published in the journal Cell Reports Medicine.
Intestinal microbiome: some details on the new research
The study focused on patients undergoing surgery, suggesting that microbiome-based therapies such as probiotics and fecal matter transplants have the potential to improve metabolic health.
They may even one day reduce the need for weight loss surgery.
“We know that the microbiome contributes to metabolic improvements after bariatric surgery, but we know very little about how,” said Johane Allard, a physician-scientist at University Health Network and professor in the Temerty School of Medicine at U of T. “We recently demonstrated that without other changes, the altered microbiome influences this outcome, and we identify potential mechanisms.”
Bariatric surgery is a cornerstone of the treatment of severe obesity. It changes the size and structure of the digestive system, limiting the amount patients can eat and the absorption of nutrients. But it also carries short- and long-term health risks, and in Canada it often costs the healthcare system more than $20,000 per procedure.
The surgery also releases gut hormones that improve insulin sensitivity and reduce appetite, and alters the composition and function of the gut microbiome, changes that have surprised and perplexed doctors, given that the annual number of procedures across the world has exceeded half a million.
Researchers have sought to understand how and how much these additional biochemical changes contribute to metabolic improvements and weight loss, with an eye to new treatments. But studies of microbiome-related changes that could be harnessed as broadly effective therapies have been hampered by large differences in the gut microbiota between individuals.
The recent preclinical study addresses this problem through paired fecal matter transplants. The Toronto team transferred fecal matter from four people to mice, both before and after the human participants had bariatric surgery. The team fed both groups of mice the same high-fat Western diet in a germ-free facility, then observed the effects for several weeks.
Mice undergoing the post-operative transplant showed much better blood sugar control and insulin sensitivity than those undergoing the pre-operative transplant, suggesting an important role of the microbiome in improving metabolism, despite no change in body weight. Participants in the human study also became more sensitive to insulin and lost weight, as expected.
Less expected, however, was an increase in mass and energy expenditure in brown fat among mice that received the transplant post-surgery.
“We were very surprised by the brown adipose tissue data,” said Dana Philpott, co-principal investigator of the study and professor of immunology at Temerty Medicine. “We thought what if we looked at normal adipose tissue [grasso bianco] we might have seen a decrease in fat or an ability to metabolize better, but the finding was very specific to brown fat.”
The heat was an early clue that something interesting was happening in brown fat, which plays a role in regulating body temperature.
“When we first put the post-operative transplanted mice into the metabolic cages, we noticed that they generated more heat,” said Jitender Yadav, a postdoctoral researcher in the Philpott lab and co-first author of the study. “We have also noticed in some literature articles that bariatric surgery in mice increases brown adipose tissue and energy expenditure, and in our study we were able to see a similar effect by simply translocating the post-surgery microbiome.”
Additionally, the team found biochemical and transcriptional markers of reduced inflammation in the white fat of post-surgery mice, another sign of improved metabolic health. To look for microbiota-related changes that could explain all these metabolic improvements, the researchers studied and compared metabolites in stool samples from mice pre- and post-surgery.
They found increases in tryptophan metabolites, short-chain fatty acids, and acylcarnitines, and decreases in amino acids, organic acid, and lactic acid, all of which correlated with improved metabolic health. Such changes in metabolites were consistent in post-surgery mice, despite changes in the four patients' constituents of their microbiome.
“The bacterial composition of the microbiota was not significant,” Yadav said. “We now think that microbiome-based therapies that induce the right mix of metabolites, such as prebiotics and probiotics, dietary changes and fecal matter transplants, could be an effective therapy for improving metabolism and losing weight.”
Co-principal investigator Herbert Gaisano, a physician-scientist at the Toronto General Hospital Research Institute and professor in the department of medicine at Temerty Medicine, aims to study how these metabolites work. Gaisano and his team, including co-first authors of the current study Tao Liang and Tairan Qin, will analyze metabolites in human fat and liver tissue samples obtained during bariatric surgery.
The Philpott lab also continues to study metabolites in the offspring of the mice studied, and they hope to replicate their findings with a larger number of patients sooner rather than later.
More broadly, Yadav said the study should help shift the field of microbiome research away from its long-standing focus on bacteria. “One conclusion is that the amount and type of bacteria don't always matter,” he said. “It is the metabolites they produce and are absorbed downstream that can affect health.”
Fecal microbiome transplantation (FMT) from a lean donor does not reduce body weight or improve bariatric surgery outcomes among adults with severe obesity.
Perttu Lahtinen, MD, of Päijät-Häme Central Hospital in Lahti, Finland, and colleagues examined whether FMT from a lean donor reduces body weight and further improves bariatric surgery outcomes in a 2018 randomized clinical trial to 2021 involving adults with serious pathologies. obesity was followed for 18 months. Forty-one patients were recruited: 21 and 20 received FMT from a lean donor and autologous placebo, respectively.
The researchers found that six months after FMT, 34 and four patients underwent laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy, respectively. At six months, the percentage of total weight loss (TWL) was 4.8 and 4.6% in the FMT and placebo groups, respectively, with no significant difference observed between the groups. The rate of TWL was 25.3 and 25.2% in the FMT and placebo groups, res
pectively, at 18 months from baseline (12 months post-intervention), with no significant differences between groups.
“Fecal microbiome transplantation via gastroscopy into the duodenum did not affect body weight in participants with obesity,” the authors write. “Bariatric surgery six months after administration of microbiome or placebo reduced weight equally in both groups during the one-year follow-up.”
A further study conducted by researchers at the University of Copenhagen in Denmark has delved into the microbiome of patients suffering from the pathology of anorexia nervosa (AN) and identifies the mechanistic interaction between restricted eating habits and how the natural response of the intestinal microbiota negatively accentuates the pathology.
Furthermore, transplantation of fecal microbiota from AN cases to germ-free mice under low-energy feeding mirrored the feeding behaviors of AN.
A News & Views article was published in the same journal to outline the researchers' findings.
Anorexia has been strongly linked to various social and environmental factors, and an altered gut microbiome has been observed in individuals with AN using amplicon sequencing in relatively small cohorts.
In the present study, “Gut microbiota contributes to the pathogenesis of anorexia nervosa in humans and mice,” metagenomics was performed on fecal samples and metabolomics was conducted with blood samples from a cohort of 77 women with AN and 70 women in a healthy control study.
Women with AN were much leaner and had lower fasting serum glucose and insulin concentrations, greater insulin sensitivity, and lower serum C-reactive protein. Altered serum metabolite compounds have been identified, which may indicate that the compounds operate through the blood circulation, affecting brain regulation of appetite, emotion, and behavior. Or the metabolites could trigger gut-microbiome-brain neuronal signaling pathways.
When comparing stool samples, no significant difference in overall bacterial cell counts was found between AN and the healthy control. While cell counts and diversity were similar, there were marked differences in enriched or depleted bacterial taxa. Among the species depleted in AN were Roseburia intestinalis and Roseburia inulinivorans, species that have a high capacity to digest plant polysaccharides and are considered part of a healthy gut microbiome.
Bacterial functional modules that create metabolite compounds associated with neurotransmitter degradation have been enriched in AN, and various structural variants in bacteria have been linked to metabolic characteristics of AN.
The gut virome was also altered in the AN group, as the researchers noted a reduction in viral-bacterial interactions. Where healthy gut viruses typically reduce populations of certain bacteria, the decrease in interactions allowed some bacterial species to proliferate.
Mice on a low-calorie diet were given fecal transplants. Those who received AN transplants initially lost even more weight and then took longer to regain weight compared to mice transplanted with healthy control microbiomes.
Mice with AN feces had increased expression of appetite suppressant genes in the hypothalamus region of the brain and increased expression of thermogenesis-related genes in adipose tissue involved in energy regulation.
In a non-pathological scenario, bacterial metabolites that mediate some of the effects of hunger could be a good biological strategy, allowing energy to be focused on finding the next meal. In the case of anorexia, the survival strategy is accidentally aligned with a pathology that exploits mediated space to promote pathological behavior.
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