Reference
Baba Y, Azuma N, Saito Y, Takahashi K, Matsui R, Takara T. Effect of intake of Bifidobacteria and dietary fiber on resting energy expenditure: a randomized, placebo-controlled, double-blind, parallel-group comparison study. Nutrients. 2024;16(14):2345.
Study Objective
To evaluate the effects of the probiotic GCL2505 plus inulin on resting energy expenditure (REE) in overweight or mildly obese Japanese adults
Key Takeaway
Bacterial fermentation by gut microbes produces short-chain fatty acids (SCFAs) that may help reduce adiposity and improve metabolic syndrome.
Design
Parallel, placebo-controlled, randomized, double-blind study
Participants
Participants were overweight Japanese men and women aged 25 to 61 years. Inclusion criteria included:
- Good health (body mass index [BMI] between 25 kg/m2–30 kg/m2
- Body fat of at least 15% in men and 25% in women
- Among the top 40 study applicants with the lowest resting energy metabolism and who met the remaining criteria.
Exclusion criteria included a list of significant health conditions, following specific diets or consuming foods, supplements, or drugs with specific health claims, allergies, pregnancy, or participation in other clinical trials.
Intervention
For 4 weeks, participants ingested daily either 1×1010 colony forming units (CFUs) of GCL2505 plus 5.0 g of inulin or placebo.
Study Parameters Assessed
REE score at week 4 was the primary end point. Investigators measured participants’ oxygen uptake (VO2) and carbon dioxide production (VCO2) using a respiratory gas analyzer and used these measurements to calculate REE.
Primary Outcome
Resting energy expenditure
Key Findings
At week 4, the REE score of the GCL2505-plus-inulin group was significantly higher than that of the placebo group, with a difference of 84.4 kcal/day. In addition, fecal bifidobacteria counts were significantly increased in the GCL2505-plus-inulin group. Intake of GCL2505 plus inulin improved energy balance. This is the first report to demonstrate the effects of probiotics and dietary fiber on REE in humans.
Transparency
The authors are employed by Ezaki Glico Co, which also funded this study. Ezaki Glico Co, Ltd, is a Japanese multinational food-processing company headquartered in Nishiyodogawa-ku, Osaka. It manufactures a wide variety of foods, some of which are enriched with the probiotic studied in this trial.
Practice Implications & Limitations
In any given year during the past half century, about half of the US population thought that they should lose weight.1 Forty percent or more are actively trying to lose weight right now. A January 2021 study that interviewed people in 30 countries found that 45% were currently trying to lose weight. In some countries, this percentage is higher, increasing to 50% in Chile, Spain, Peru, Saudi Arabia, and Singapore.2 In Sweden, 69% of women and 59% of men report that they want to lose weight.”3
The desire to lose excess body weight is a global issue, and we should assume that desire is shared by at least half of our patients.
Being overweight or obese is basically due to an imbalance between energy intake and energy output. At the end of the day, excess energy is stored as fat. The standard approach to weight loss is caloric restriction to decrease energy intake and exercise to increase energy expenditure. Our bodies meet any net energy deficit by burning fat, which leads to weight loss. This is easier to describe than it is to achieve. Sixty percent of the world’s obese people now live in low- to middle-income countries.4 Low incomes are associated with diets that rely on cheap, high-calorie foods.
There’s another approach to treating obesity and preventing excess weight gain that has received minimal attention, and this is the idea of increasing what is called the resting energy expenditure. To use an analogy, if we were automobiles, the REE would be how much gas we burn if the car is left parked all day with the engine running. The idling engine will burn gas even if you don’t go anywhere. In people, REE accounts for about 60%—the majority—of the energy we expend each day. Physical activity accounts for just 30%, and dietary thermogenesis (the energy it takes to digest and assimilate food) makes up about 10%.5 (One might say that people spend a majority of their energy doing nothing.) It takes only a tiny but persistent imbalance or discrepancy (only about 2%) between daily energy intake and daily energy output to produce progressive and substantial weight gain.6
Attention has now turned toward REE to determine if and how it might be increased to raise total energy expenditure and tip the equation toward weight loss.
REE represents energy expenditure while a person lies quietly awake between meals. Under such conditions, a healthy adult will consume approximately 1 kcal/kg body weight/hour. Three things contribute to REE: respiration, visceral activity, and temperature maintenance. The liver, intestine, brain, kidneys, and heart, while together make up only about 10% of total body weight, account for approximately 75% of REE.7 Body temperature is maintained by thermogenesis in brown adipose tissues (BAT).8 BAT dysfunction has been associated with obesity.9 Thus, modifying the way BAT functions to increase thermogenesis has been 1 approach to control obesity. Acute cold exposure appears to activate BAT to generate heat.10 This may be justification for the ice baths that seem to be popular.
A January 2021 study that interviewed people in 30 countries found that 45% were currently trying to lose weight.
While there are formulas that allow us to approximate REE in healthy individuals, they are not exact enough for the purpose of these studies. Instead, these values are calculated by precisely measuring oxygen consumption and/or carbon-dioxide production.11
An important study by Emanuel Canfora et al was published in 2017 that deserves specific mention. These researchers in the Netherlands administered different SCFA mixtures via colonic to 12 human subjects and, using indirect calorimetry, calculated changes in energy expenditure on 4 separate days of testing. These colonic mixtures were high in either acetate, propionate, or butyrate or were placebo without SCFAs. All 3 SCFA mixtures increased fasting fat oxidation. Resting energy expenditures, however, increased only after acetate and propionate infusions. The concentrations of SCFAs used in these experiments were about what would be produced by a healthy gut microbiome after a high-fiber meal.12
Short-chain fatty acids also seem to affect BAT activity, in particular, based on other research, the SCFAs propionate and butyrate. Indeed, animal studies have already shown that administering butyric acid increases BAT activity.13
So, we come to this current study by Baba et al, which is the focus of this discussion. Study participants received large doses of the probiotic Bifidobacterium animalis subsp lactis GCL2505 (sold commercially as BifiX in Japan) along with the prebiotic inulin. This probiotic strain was originally isolated from the feces of healthy adults. Oral GCL2505 “is able to survive passage through the intestines and proliferate,” report Tanaka et al.14 Many of the species in similar products may be unable to do either.14
GCL2025 seems to have already been well-studied in both animal and human trials. It has previously been reported to reduce visceral fat in overweight humans.15 Taking it in combination with inulin appears to enhance its effectiveness and to increase acetate and butyrate production.16,17 Animal studies suggest that the SCFAs produced by this strain might be useful in treating metabolic syndrome and improve glucose tolerance.18 Use was associated with suppression of body-fat accumulation.19 Clinical trials have also associated GCL2505 with improved cognitive function and improved endothelial function when given with inulin.20-22
The authors of this current study also conducted, in 2023, a clinical trial to evaluate the efficacy of GCL2505 and inulin on obesity. After 12 weeks of intake, GCL2505 and inulin “significantly decreased visceral and total fat area, increased the total number of bifidobacteria, and decreased the levels of several lipid markers,” the authors reported.23 “Because GCL2505 can proliferate in the gut, it may contribute to the increase in SCFA levels in the gut, thereby exerting anti-obesity effects.”23 This confirms what we expect.
A recent animal study suggests that the SCFA acetate may be the key component in treating metabolic syndrome. The authors noted that acetate “exerts anti-metabolic syndrome effects via the SCFA receptor G protein-coupled receptor 43 (GPR43...GCL2505 treatment suppressed body fat accumulation, improved glucose tolerance, and enhanced systemic fatty acid oxidation in high-fat diet (HFD)-fed wild type (WT) mice.”19
Returning to Baba et al, we have not considered up to this point an important detail they report. The authors found that at “At week 4, the REE score of the GCL2505 and inulin group was significantly higher than that of the placebo group, with a difference of 84.4 kcal/day.” Specifically, the active group had a score of 1,376.5±272.8 kcal/day, while the placebo group’s score was 1,303.2±188.1 kcal/day.
Study participants were also burning slightly more energy even at the 2-week study midpoint—nearly 102 more kcals per day (1,435.9±195.2 kcal/day) than the placebo group (1,345.5±231.6 kcal/day).
The rule of thumb long used in weight management is that to lose 1 pound of fat, you need to create a caloric deficit of 3,500 calories, so we might expect people following this Baba et al protocol of GCL2505 and inulin to drop about ¾ of a pound a month (–84 kcal/day multiplied by 30 days equates to –2,515 kcal. Dividing this by 3,500 suggests about 0.72 pounds weight loss per month). But this weight loss did not appear in the data. At the end of the 4-week study, there were no significant differences in any anthropomorphic measurements between the placebo and active groups, including changes in weight, BMI, body fat percentage, or muscle mass percentage.
Now for the bad news. It does not appear that the specific species of bifidobacterium used in this study, GCL2505, is available for sale in the United States. Many of us practitioners would eagerly have tried this protocol on patients to see if it works as well on North Americans as it has on the Japanese in these studies. But we can’t. At least not now.
These studies on GCL2505 tell us that SCFAs are important for regulating metabolism, weight, and blood sugar and that the SCFA acetate may be the most crucial for treating metabolic syndrome, whereas butyrate and propionate increase resting energy expenditure and might be key to stabilizing weight. As we already appreciate the value of butyrate in maintaining intestinal health, we can guess that anything that increases the gut yield of SCFAs might be helpful in the big picture. Certainly, we can figure out other probiotics that produce these SCFAs. We need to use probiotics that survive passage through the gut and can replicate. We also want those bacteria to have adequate substrates to ferment, so we should add a prebiotic along with the probiotics. The common name for the former is fiber. If the goal is weight loss, we may want to increase propionate and butyrate. If managing metabolic syndrome is the priority, acetate appears to be the SCFA that we want to see in abundance.
To paraphrase Dr Heather Zwickey, it’s not the specific bacteria that matter but the metabolites they make that are important and make things happen. This reminds me of the 2019 paper by Alessia Visconti et al in which they compared microbiomes between people and the resultant metabolites produced. It seems that microbes are not highly conserved among people (40% at best) but metabolites are (84% and more).24 Very different microbes can yield the same metabolite output.
For the time being, our goal need only be to increase SCFA yield through gut fermentation of fiber. At some point, if we find that GCL2505 is available on the market, we can try it to see if it is indeed superior to other products currently available. This isn’t the end of the story, and these suggestions may be amended over time.
