This Reading Room is a collaboration between MedPage Today® and:
Expert Critique
FROM THE ASCO Reading Room
In March, the 8th annual Gut Microbiota for Health World Summit, sponsored by the AGA and the European Society of Neurogastroenterology and Motility, explored the latest research in this fast-moving area of medicine. The organizers singled out the following original scientific presentations outlining early research with potential for microbiome-based strategies of prevention and therapy.
P-glycoprotein Controls Inflammation
Researchers at the University of Massachusetts Medical School in Worcester reported on the microbiome-driven regulation of P-glycoprotein expression on the intestinal epithelium. Sage Foley, a PhD candidate, and associates discovered a novel mechanism by which P-glycoprotein, expressed on the apical surface of intestinal epithelial cells, suppresses neutrophil infiltration via secretion of endocannabinoids. This transporter protein is highly expressed in healthy mice and humans but when diminished or impaired, is associated with intestinal inflammation and inflammatory bowel disease.
In mice, the investigators used oral and injected broad-spectrum antibiotics to reduce levels of certain subsets of Clostridium bacteria involved in producing the gut-healthy short-chain fatty acid butyrate. Butyrate induces expression of the P-glycoprotein gene.
The researchers also showed that recolonization with these diminished bacteria was sufficient to rescue P- glycoprotein expression in microbiome-depleted mice: "We conclude that the commensal microbiota regulates P-glycoprotein function, playing a key role in controlling the balance between health and disease," the team wrote.
Bioactive natural products may potentially be used to upregulate P-glycoprotein expression and functionality, Foley and co-authors said.
Diet Contra Clostridium difficile
In another study, Keith Z. Hazleton, MD, PhD, and colleagues at the University of Colorado Anschutz Medical Campus in Aurora, reported that a Western-style diet modulates the pathogenesis of Clostridioides difficile through host and microbe bile acid metabolism.
Emerging data suggest that low fiber intake is associated with increased colonization of pathogenic Clostridioides difficile in mice. Additionally, saturated fat intake increases excretion of taurine-conjugated primary bile acids, which are known germination factors for C. diff, but these bile acids can be converted by a healthy microbiota to secondary bile acids that can kill this pathogen.
The investigators studied the impact of diet on susceptibility to C. diff infection, which affects an estimated 500,000 Americans a year. The researchers found that in mice with antibiotic-induced microbiota disturbance, a high-fat, low-fiber Western diet created a pro-C. diff environment in the gut.
"The most striking thing we saw was that mice on a Western diet had a six to eight times increase in mortality rate," Hazleton told the Reading Room.
Compared with mice on standard chow, the mice on a Western diet also showed more microbiome disturbance after antibiotic challenge, with a greater increase in facultative anaerobes such as Proteobacteria and Lactobacillales and disappearance of the strictly anaerobic Clostridiales.
In addition, Western-fed mice demonstrated higher levels of taurine-conjugated bile acids, decreased unconjugated primary bile acids, and a near absence of secondary bile acids.
"The ecologic and metabolic differences between chow-fed and Western diet-fed mice suggest that the double-insult of Western diet and antibiotic treatment leads to a pro-C. difficile bile acid composition and drives increased disease severity," Hazleton and co-authors wrote. They concluded that nutritional intervention with a low-fat, high-fiber diet has potential for reducing or preventing C. diff infection in high-risk populations.
"The take-home message for humans is to eat more fruits, vegetables, and whole grains and fewer processed foods," said Hazleton. His group is now seeking funding support for human dietary studies in vulnerable patients.
Prebiotics Protect Against Radiation
Robert R. Jenq, MD, and colleagues at the University of Texas of MD Anderson Cancer Center in Houston reported that reduced oral nutrition contributed to gastrointestinal toxicity in mice exposed to total body irradiation and did so via changes to the gut microbiome. But prebiotic dosing prevented weight loss, maintained intestinal barrier function, and improved overall survival.
"Our results indicate that nutrition and the microbiome could interact to modulate risk for bacterial translocation in hematologic cancer patients," Jenq told the Reading Room.
Following 9 Gy radiation, the mice were limited to 50% of their usual oral nutrition intake, and displayed adverse changes in the microbiome, including expansion of the mucolytic bacteria. The mice lost 20% of their body weight and showed compromise of intestinal barrier function.
The researchers also limited food access in a control group of non-irradiated mice to 2 g/day. "This produced remarkably similar changes, including expansion of mucolytic bacteria," Jenq said. "The colonic mucus layer was thinned, and metabolic activity of colonic bacteria during reduced oral nutrition was also perturbed." Lower concentrations of acetate, propionate, butyrate, and lactate, and elevated succinate were also observed.
Finally, the researchers evaluated oral administration of glucose, an easily absorbed sugar, and a poorly absorbed prebiotic sugar. "We found that prebiotic supplementation acidified the colonic lumen and prevented thinning of the mucus layer," Jenq said.
Other presentations tackled the role of the microbiome in obesity:
No-cal Sweeteners Promote Obesity
"I've never seen a thin person drink diet soda" is a common comment. More support for this observation came from Norwegian investigators who reported a significant negative association between intake of non-nutritive sweeteners (NNS) and fecal levels of the anti-obesogenic short-chain fatty acid butyrate.
Recruiting 14 men and 75 women with a mean age of 44.6 and a mean body mass index of 42, Per G. Farup, PhD, of Norwegian University of Science and Technology in Trondheim, and a colleague found that both NNS and starch correlated with reduced butyric acid:
- NNS: B = –0.159 (95% CI –0.280 to –0.037, P=0.011, partial correlation –0.274)
- Starch: B = 0.030 (95% CI 0.06-0.054, P=0.015, partial correlation 0.264)
Fiber Foils Simple and Genetic Obesity
Liping Zhao, PhD, of Rutgers University in New Brunswick, N.J., presented a study involving 17 children with Prader-Willi syndrome – the most common genetic cause of morbid obesity in children – and 21 with simple obesity due to eating habits.
In a strict hospital setting, the children received a high-fiber diet of 40 g/day for 1 month or 3 months, respectively, in order to alter their gut microbiota. "It provided very diverse types of fiber from whole grains, traditional Chinese medicinal foods, and prebiotics, so many different types of bacteria had the largest possible range of carbohydrates to ferment and feed on," Zhao told the Reading Room.
Both groups shed pounds – 10% of body weight in the Prader-Willi group and 20% in the simple obesity group – and insulin sensitivity and systemic inflammation improved. In response to the high-fiber regimen, the gut microbiota also underwent structural changes, with an increase in beneficial bifidobacteria and a decrease in pro-inflammatory toxin-producing strains.
When the researchers performed a co-abundance network analysis of 161 prevalent bacterial draft genomes, they found a relative increase in functional genome groups for protective acetate production from carbohydrate fermentation. In addition, urine profiling showed that the diet induced overall changes in the host metabotype, reducing the detrimental metabolites trimethylamine N-oxide and indoxyl sulfate.
When transplanted into germ-free mice, the pre-intervention gut microbiota of a volunteer induced higher inflammation and larger adipocytes than the volunteer's post-intervention microbiota.
The team also identified bacteria that use dietary components to produce toxic metabolites involved in obesity, and these could become targets for obesity therapies in the future, Zhao said.
The research hypothesizes that the gut microbiome is an ecosystem similar to that of a rain forest whose continuing existence depends on a few cooperating foundational species, Zhao explained. Some are good for overall health, others bad, and still others are simply neutral commensals. The team found that many bacterial species that are taxonomically very different work together in interdependent guilds, rising and falling in abundance together, much like synergistic species in sylvan ecosystems.