Today’s post will cover a recent paper published in the journal Proceedings of the National Academy of Sciences. (1) The research group responsible for this paper has been at the forefront of investigating how metabolic endotoxemia impacts numerous health outcomes, including weight regulation and glucose control.
This study sought to determine whether a particular intestinal bacteria by the name of Akkermansia muciniphila (A. muciniphila) could control weight gain in obese-prone C57BL/6 mice. As you may recall, these mice are particularly susceptible to packing on the weight when fed a high-fat lab chow, and are members of the “red-line” rodent club I’ve written about before.
Just to be clear, the high-fat diet used in this study is the D12492 rodent chow from Research Diet. I’ve written about the fatty acid composition of this chow previously:
“Of the total 270 grams of fat, (assuming soybean oil is 15% saturated, 24% monounsaturated and 61% polyunsaturated) 87.785 (32.51%) total grams were saturated fat, 101.305 (37.52%) total grams were monounsaturated fat, and 80.91 (29.96%) total grams were polyunsaturated fat. Of the three types of fat, omega-6 polyunsaturates would be the most prone to causing increased intestinal permeability, endotoxemia and liver inflammation.”
Now, the reason these researchers focused on this particular microbe is because leptin-deficient obese mice have a 3,300-fold lower abundance of this bacteria in their intestines in contrast to their lean counterparts. And in mice fed high-fat lab chow, the numbers of A. muciniphila are 100-times lower.
A. muciniphila resides in the mucus layer of the ileum and colon and comprises about 3% to 5% of the gut flora found there. It is a mucin-degrading bacteria that thrives in this environment.
To determine whether A. muciniphila would impact weight regulation, obese-prone mice were supplemented with this bacteria after being fed a control diet for sixteen weeks. Here are the results:
CT stands for control-diet fed mice, CT-Akk stands for control-diet mice supplemented with A. muciniphila, HF are the mice fed the high-fat diet, and HF-Akk are the mice fed the high-fat diet supplemented with A. muciniphila. For today’s post, we’ll be concentrating mainly on the last two bars of each chart.
For all measurements of fat accumulation–subcutaneous, mesenteric, and epididymal–amounts were lower in the high-fat group that also received A. muciniphila in contrast to the mice who were fed just the high-fat rodent chow. In this group, body weight also normalized to levels matching those seen in the control group. So much for fat always making you fat.
Now in the body of this paper, the authors claim these changes occurred without changes in food intake, although that stretches the truth a bit as seen here:
Food intake was lower in the HF-Akk group which would partly account for the normalization of weight. I say partly only because food consumption was still slightly higher than for the control group. Nevertheless, a reduction in appetite occurred, which is always of importance when trying to control weight. This reduction in eating behavior no doubt had something to do with the following:
This illustrates serum lipopolysaccharide (LPS) concentrations. As we all know, LPSs are derived from gram-negative bacteria. The high-fat mice had the highest levels, but once supplemented with A. muciniphila, levels approached those seen in the control group.
As I’ve said before, stress and the cortisol secretion that results from this, including cortisol secretion due to metabolic endotoxemia, will tend to increase appetite while decreasing metabolic rate. Decrease endotoxemia and both appetite and metabolism tends to normalize.
In keeping with lower levels of endotoxins flooding in from the GI tract, insulin resistance and fasting blood-glucose also improved:
These results, according to the researchers, were due to a 40% reduction in the hepatic enzyme glucose-6-phosphatase, an enzyme necessary for the new production of glucose (gluconeogenesis) by the liver.
Other interesting observations were that the supplementation of this microbe reduced inflammation in fat tissue, affected the differentiation of adipose cells, and led to increases in fat burning.
These charts measure levels of three different intestinal endocannabinoids or aclyglycerol compounds. As I covered in my post Prebiotics, Mice and Weight Regulation, the endocannabinoid system is:
“…composed of a series of receptors, CB1 and CB2, that exist throughout the central and peripheral nervous system. These two receptors affect many areas of the body, including the brain and immune function.
The system is involved in memory….appetite, energy balance and metabolism, stress response, social behavior, anxiety, pain sensation, immunity, fertility, pain control, body temperature, and sleep. The expression of at least one of its receptors, CB1, can be affected by both beneficial and pathogenic bacteria.”
Aclyglycerols are chemical compounds containing both glycerol and fatty acids. The increase in this bacteria elevated levels of these endocannabinoid compounds and would be expected to have impacts on CB1 receptors throughout the body as well as decrease intestinal permeability.
Many of the observed improvements in weight and glucose control can be explained by a strengthening of gut-barrier function due to an increase in the thickness of the mucus layer as seen in this graphic. The thicker this layer, the less likely it is that endotoxins breach the gut wall, provoke an inflammatory response, and cause all sorts of down-stream metabolic mayhem.
As these researchers note:
“This study identified an association of obesity with a decrease in mucus thickness, which supports an additional mechanism of increased gut permeability (i.e., metabolic endotoxemia) that is characteristic of obesity and associated disorders. Furthermore, we demonstrated that A. muciniphila restored this mucus layer, which suggests that this mechanism contributes to the reduction in metabolic endotoxemia that was observed during A. muciniphila treatment.”
Now, what’s curious about all this is that these effects are also seen in mice who are fed prebiotics. They too experience reductions in serum endotoxins, improvements in weight control, and increases in A. muciniphila populations:
Pre is the abbreviation for the prebiotic oligofructose, so HF-Pre would be those mice fed a high-fat rodent chow with added prebiotics. Problem is, A. muciniphila does not feed on prebiotics so why these results?
The researchers don’t yet know although they do have some theories:
“We demonstrated that prebiotic (oligofructose) treatment restored A. muciniphila abundance and improved gut barrier and metabolic parameters. However, the mechanisms that were responsible for the bloom in A. muciniphila caused by prebiotic administration are not clear. A. muciniphila does not grow on oligofructose-enriched media (in vitro), which suggests that complex cross-feeding interactions contributed to this effect. However, it has been previously shown in rats that oligofructose feeding increases the number of goblet cells and mucus layer thickness. Thus, whether oligofructose feeding increases A. muciniphila by providing the main source of energy for this bacterium and thereby favoring its growth or whether the increase of A. muciniphila increases mucus production and degradation (i.e., turnover) remain to be demonstrated. Oligofructose changes more than 100 different taxa in mice. Therefore, we cannot exclude that oligofructose induces specific changes in the gut bacteria and cross-feeding promoting the growth of A. muciniphila.”
We know for a fact that bifidobacteria thrives on prebiotics, producing the short-chain fatty acids propionate, acetate and butyrate when fermenting them. One or more of these short-chain fatty acids may encourage the growth of A. muciniphila directly or by increasing the production of the mucins these bacteria feed on. Or perhaps the blooming of bifidobacteria creates a pH environment that encourages the growth of these bacteria.
Another explanation for these observed results may have to do with gut hormones. Remember that prebiotics stimulate the secretion of two gut peptides: glucagon peptide 1 (GLP-1) and glucagon peptide 2 (GLP-2).
As I wrote in my post How Gut Dysbiosis Impacts Digestion And Appetite:
“Glucagon-like peptides (GLPs) are also released by healthy L-cells of the small intestine and colon, and the alpha cells of the pancreas. These hormones influence insulin and glucagon secretion and their dysregulation may be a contributing factor in insulin resistance. These hormones reduce appetite and the rate of stomach emptying making you feel full.”
The abundance of A. muciniphila is associated with increased L-cell activity. By increasing L-cell activity, this is yet another way prebiotics may encourage the growth of this bacteria.
Now, can we expect to see A. muciniphila added to future probiotic formulations? I doubt it as this is a gram-negative bacteria that harbors lipopolysaccharides. For this reason, I wouldn’t expect the FDA to approve probiotics containing this bacteria anytime soon.
However, supplementation of this bacteria is really a moot point. As the addition of prebiotics to the diets of these mice resulted in a blooming of this species, you can expect the same to occur in humans. To encourage the growth of A. muciniphila in your intestines, include prebiotics in your diet.
It is mildly surprising that healthy colonies of a particular gram-negative bacteria are good for us. However, never forget that the mere presence of gram-negative bacteria in the ileum and colon is not the issue. Rather, it becomes an issue only when these types of bacteria translocate to systemic circulation due to a weakening of gut-barrier defenses, and are not inactivated by immune cells in the liver or serum lipoproteins. As this particular bacteria strengthens these defenses, the more the better!
Once again we have another study confirming how important gut flora is in maintaining proper weight regulation and health. As I’ve said before, and no doubt will say again, any theory about weight regulation that fails to take into account intestinal bacteria is woefully incomplete.