The worldwide prevalence of childhood obesity has risen dramatically over the last 30 years. In the United States, approximately 20% of school-age children are considered obese, resulting in a significant public health concern. The etiology of childhood obesity is complex, and both genetic and environmental factors contribute to the development of the disease. Recently, early-life disruption to the gut microbiota by antibiotic treatment has been proposed as a risk factor for childhood obesity.
However, epidemiological surveys have produced conflicting results regarding whether early-life antibiotics correlate with a higher body mass index, prompting further research into how the early-life microbiota could be protective against obesity. Importantly, these epidemiological surveys did not consider the children’s diet and therefore may be missing relevant synergistic effects between antibiotics and other environmental factors. To answer this gap in knowledge, researchers developed a mouse model in which young mice were concurrently exposed to antibiotics and an obesogenic HF diet. Specifically, we investigated the effects of penicillin, which belongs to the most commonly prescribed class of antibiotics in the United States. They determined that early-life penicillin exposure accelerates the development of HF diet-induced obesity by disrupting interactions between the SI microbiota and IECs. They further demonstrated that depletion of Lactobacillus species in the SI of mice given antibiotics and an HF diet led to excess adiposity. Specifically, an HF diet and antibiotics reduced the abundance of the Lactobacillus-derived metabolite, PLA, which regulates PPAR-γ in IECs and protects against HF diet-induced obesity.
They determined that early-life concurrent exposure to antibiotics and an HF diet perturbs lipid metabolism in IECs and provides further evidence for the SI’s significant role in regulating whole-body lipid homeostasis. In obese patients, SI lipid metabolism is significantly altered, suggesting that dysregulation of intestinal lipid metabolism contributes to metabolic dysfunction. Interestingly, proteins increased in the SI of obese patients (FABP1, FABP2, MTP) corresponded to genes upregulated in the SI of mice exposed to an HF diet and antibiotics. They determined that mice given an HF diet and antibiotics accumulate significantly more triglycerides in their IECs and serum but did not absorb more fat from their diet. Together, these data support the hypothesis that concurrent exposure to an HF diet and antibiotics perturbs intestinal lipid metabolism and leads to greater lipoprotein secretion, consistent with what is observed in obese patients.
They propose that these changes in intestinal lipid metabolism, at least in part, are due to loss of PPAR-γ signaling. Previous research has demonstrated that disruption to the gut microbiota decreases PPAR-γ activity in the intestine, consistent with our observation that an HF diet and LDP treatment reduces PPAR-γ in the SI. The role of PPAR-γ in lipid metabolism is cell-type-specific. For instance, in the adipose tissue, PPAR-γ promotes lipid storage and lipogenesis, whereas in macrophages, PPAR-γ reduces free fatty acid and triglyceride accumulation. In the intestine, deletion of PPAR-γ resulted in elevated serum triglycerides, agreeing with the model in which depletion of intestinal PPAR-γ coincides with significantly greater triglycerides in fasted serum. Therefore, intestinal PPAR-γ presents a promising target to regulate lipid metabolism and reduce metabolic dysfunction during exposure to an HF diet. Indeed, treatment with the PPAR-γ agonist, Rosiglitazone, represses the expression of intestinal apoB and reduces triglyceride secretion in a hamster model. Collectively, these findings highlight the role of intestinal lipid metabolism, specifically PPAR-γ, in protecting against metabolic dysfunction.
Due to the transient colonization of probiotics, direct administration of the beneficial Lactobacillus-derived metabolite may have better success in preventing metabolic dysfunction. They identified a Lactobacillus-derived metabolite, PLA, that activates intestinal PPAR-γ and protects young mice from metabolic dysfunction due to concurrent exposure to an HF diet and antibiotics. Multiple bacterial species produce PLA, including species belonging to the Bifidobacteriaceae and Peptostreptococcaceae families. Interestingly, they see a depletion of Bifidobacteriaceae and Peptostreptococcaceae in mice fed an HF diet and mice exposed to an HF diet and antibiotics, suggesting that multiple bacterial species may contribute to PLA production in the intestine. Significantly, PLA is present in the feces of infants and correlates with the abundance of Bifidobacterium, indicating that this metabolite is a component of the early-life gut metabolome in humans. Previous work revealed that PLA upregulated an adipose tissue-specific isoform of PPAR-γ, and they have now determined that PLA also increases intestinal PPAR-γ activity and abundance. We then extended these findings by showing that PLA inhibits lipid secretion in IECs and prevents antibiotic-induced excess adiposity in young mice during consumption of an obesogenic HF diet. Collectively, they identified a previously unknown mechanism by which the early-life microbiota communicates with the intestinal epithelium to decrease HF-induced obesity, providing new evidence linking early-life antibiotic exposure to childhood obesity.
Highlights
• Early-life exposure to antibiotics and a HF diet exacerbates obesity
• Loss of small intestinal Lactobacillaceae leads to increased adiposity
• Antibiotics and a HF diet exacerbate adiposity via depletion of intestinal PPAR-γ
• Lactobacillus-derived phenyllactic acid protects against antibiotic-induced obesity
Summary
The mechanisms by which the early-life microbiota protects against environmental factors that promote childhood obesity remain largely unknown. Using a mouse model in which young mice are simultaneously exposed to antibiotics and a high-fat (HF) diet, we show that Lactobacillus species, predominant members of the small intestine (SI) microbiota, regulate intestinal epithelial cells (IECs) to limit diet-induced obesity during early life. A Lactobacillus-derived metabolite, phenyllactic acid (PLA), protects against metabolic dysfunction caused by early-life exposure to antibiotics and a HF diet by increasing the abundance of peroxisome proliferator-activated receptor γ (PPAR-γ) in SI IECs. Therefore, PLA is a microbiota-derived metabolite that activates protective pathways in the small intestinal epithelium to regulate intestinal lipid metabolism and prevent antibiotic-associated obesity during early life.
Brian Wang is a Futurist Thought Leader and a popular Science blogger with 1 million readers per month. His blog Nextbigfuture.com is ranked #1 Science News Blog. It covers many disruptive technology and trends including Space, Robotics, Artificial Intelligence, Medicine, Anti-aging Biotechnology, and Nanotechnology.
Known for identifying cutting edge technologies, he is currently a Co-Founder of a startup and fundraiser for high potential early-stage companies. He is the Head of Research for Allocations for deep technology investments and an Angel Investor at Space Angels.
A frequent speaker at corporations, he has been a TEDx speaker, a Singularity University speaker and guest at numerous interviews for radio and podcasts. He is open to public speaking and advising engagements.
This report is credible
Is there a way to restore the balance of gut bacteria via probiotics?
Consume live organisms on an empty stomach. Eat/drink yoghurt routinely – with NO extra ingedients. The Lactobacillus and bifidus therein will help push bad species out. Various medical probiotic formulations like VSL#3 and Visbiome are also available, but your results will vary.
Reintroducing helminths can completely rebalance the G.I. flora on their own, as tests in monkeys with IBD have found. Getting off processed food, eating a diet rich in fiber, herbs and the right fats is also important. You don’t simply need to replace bad flora with good, but keep them fed properly. Prebiotic fiber and post-biotic SCFAs like butyrate can help.
Chronic inflammation in the gut from disease, toxins or dietary allergies/intolerances also skews the flora.
Oral antibiotics, drugs like NSAIDs – even vitamins like folate and B12 can damage flora too.
Gut dysbiosis lies at the heart of all modern chronic disease and yet is completely ignored by most doctors. But there are thousands of species of bacteria, fungus and viruses in the gut, any one of which can cause problems when it goes missing or grows out of control. The topic is complicated.
Butyrate, also produced by friendly G.I. flora when they digest dietary fiber, is an epigenetic regulator and a life-extension compound. It stops or retards ALS, organ rejection (Tregs), fibrosis and Alzheimer’s. Butyrate also stimulates production of GLP-1, analogues of which cost thousands of dollars a year to control appetite and addiction. GLP-1 interferes with TLR4, a circuit driving opiate addiction, cancer development and viral infections like Covid-19.
palm oil -> TLR4 -> fatty acid synthase -> palm oil -> cancer, addiction, viral replication [notice the feed-forward loop from eating junk food: palmitate -> TLR4 -> FASN -> palmitate -> …]
Butyrate, of course, is unpatentable therefore doesn’t pay media companies through ads which explains why the science “news” won’t talk about its anti-obesity effects. Butyrate competes with unnecessary, expensive, patented molecules like Ozempic that puts money into the pockets of hedge funds, political campaigns, lobbyists and media execs/beltway babblebots.
The same blacklisting will happen to phenyllactate for the same reasons.
Antibiotics causing obesity is old news. They also cause or contribute directly to autoimmunity, autoinflammatory diseases, neurodegeneration, insulin resistant conditions, allergy, asthma, infections and all our other modern plagues via gut dysbiosis – but try to fix the problem with a fecal transplant and the FDA would come after you with a hatchet, like they did with me several years ago. They claimed this might give me the arthritis I already had from second-hand smoke exposure, antibiotics, leaky dental mercury and NSAIDs – none of which the FDA actually bother to protect me from. (Funny how the FDA never puts a black box warning on antibiotics, NSAIDs, junk food, opiates or anything else that actually does kill large numbers of people. Wonder if campaign donations has something to do with it? Thanks, Supreme Court. I never would have thought to legalize bribery by calling it protected free speech. Genius. But I guess that’s why they give you the big bucks. And the RVs. And vacation cruises.
Bifidobacterium breve [PMID: 37125172] also produces phenyllactate, the PPARgamma agonist mentioned in this study.
Phenyllactate inhibits the growth of various pathogenic bacteria and fungi helping to explain why loss of keystone species like lactobacillus and bifidus lead to dysbiosis and chronic inflammatory diseases. Low bifidus populations directly correlate to risk of Covid-19, probably – I suspect – by LPS/TLR4 signaling. It’s also interesting from a historical perspective because fermentation with lactic acid producing bacteria killed many pathogens and preserved food before modern refrigeration.
At some point, you might want to look at the other seven deadly sins of modern medical/nutritional malpractice: pollution/toxins, deworming, low fiber/high sugar diets, missing essential fatty acids, lack of regular night/day light cycles and lack of exercise. Fix all of these and there’s no colon cancer, arthritis, Crohn’s, M.S., Alzheimer’s or – I suspect – Covid-19 (short or long), not to mention atherosclerosis while vastly reducing autism, PCOS, endometriosis, infertility and a host of other diseases. We’ve known, for instance, sine the 1970s that there’s no arthritis or M.S. in societies until they’re dewormed.
Butyrate, also produced by friendly G.I. flora when they digest dietary fiber, is an epigenetic regulator and a life-extension compound. It stops or retards ALS, organ rejection (Tregs), fibrosis and Alzheimer’s. Butyrate also stimulates production of GLP-1, analogues of which cost thousands of dollars a year to control appetite and addiction. GLP-1 interferes with TLR4, a circuit driving opiate addiction, cancer development and viral infections like Covid-19.
palm oil -> TLR4 -> fatty acid synthase -> palm oil -> cancer, addiction, viral replication [notice the feed-forward loop from eating junk food: palmitate -> TLR4 -> FASN -> palmitate -> …]
Butyrate, of course, is unpatentable therefore doesn’t pay media companies through ads which explains why the science “news” won’t talk about its anti-obesity effects. Butyrate competes with unnecessary, expensive, patented molecules like Ozempic that put money into the pockets of hedge funds, political campaigns, lobbyists and media execs/beltway babblebots.
The same blacklisting will happen to phenyllactate for the same reasons.
It may be a factor but it’s pretty clear the driving force behind the global obesity epidemic is just sugar and other carb consumption especially in liquid form via sodas. Coke and Pepsi have been working hard for decades to confuse the obvious as they diversify.
Not that free sugars and processed starchy crap is beneficial, but what fits better is linoleic acid.
Toxic waste oils such as cotton oil and soybean oil where converted into “vegetable” oils by various bleaching, deodorizing, solvent extraction, addition of antioxidants and other steps. It’s still toxic, but it is way more palatable than raw cotton seed oil.
These oils are very unstable and toxic above the miniscule amounts necessary (~1% of calories, and preferably not as oxidized chip fat but as fresh nuts and seeds and similar). On frying they create toxic aldehydes (e.g. 4-Hydroxynonenal, among many others). This oxidation also occurs in the body and the system for dealing with it is overwhelmed with modern junk food diets. In animal models it is clearly seen they promote “diabesity”, cardiovascular illness and macular degeneration. They also lower LDL slightly which is used by industry shills to push for them. Oxidized LDL is what correlates with heart disease, not LDL; heart disease starts with oxidized linoleic acid in LDL particles. Fat composition of humans have drastically tended towards LA with increased consumption of high LA seed oils.
If you look at almost any country you will see the same picture; disease closely follows linoleic acid. In the US total calories and calories from sugar is down slightly starting around the 80’s. What’s continued to increased is the vegetable oils and is now 20% of calories on average. Saturated fat like butter, lard and tallow are down; especially the latter two. The average american eats 80 g of vegetable oil per day now and it is still increasing. That’s not olive oil which is mostly monounsaturated, and it is mostly not canola oil which is slightly less bad than most of the other seed oils; it is mainly things like soybean oil which are very high in LA. Heart disease mortality is down slightly, this is just due to better treatment; episodes of heart attacks and similar continue up. Heating these kinds of oils to high temperature gives the tail end of the energy distribution enough energy to flip the double bond into a trans bond, creating trans fat right the pan as you’re frying. Deep fryers sit at temperature for days before changing the oil.
The idea of obesity seems malleable. In the USA millions of immigrants came in over the past 30 years who are shorter and rounder and quite unlike european offspring who dominated the landscape previously, so of course the average of today can’t match that of yesterday by definition. Plus, the BMI number definitions that dictate obesity have changed over the years. When I was young a 185 lb 6 foot tall male was the picture of healthy, then deemed a slight bit overweight, and today is seen as borderline obese. Half of today’s pro atheletes are obese according to some venues. When you have multiple systemic problems it’s difficult to take any variety of nutrition science seriously, which is a shame.
They weren’t round before the last 30 years when the effects of massive increases in sugars in their diets started.