A fatty diet with sugar produces hydrogen sulfide in the intestines—is it good or not?

This post will once again be dedicated to hydrogen sulfide (H2S). The studies mentioned in previous posts have shown quite clearly how beneficial hydrogen sulfide produced in liver cells by the enzyme CSE can be. It can even be transported further into the whole body through S-sulfhydration of blood albumin. But will this also apply to hydrogen sulfide produced in the large intestine? Let’s take a look at what the authors of a study examining the influence of hydrogen sulfide on intestinal epithelial cell metabolism found. They also studied this in connection with obesity and a diet rich in fats and sugars.

The basic idea is that the effect of a diet high in saturated fats on the development of obesity could be either supported or, conversely, blocked by hydrogen sulfide. We first need to clarify the conditions under which this research was conducted. It was done on obese mice, where obesity was induced by a fatty diet high in coconut oil and sugar, together with a low content of polyunsaturated vegetable oils.

The experimental diet is called D12331 and was designed by Prof. R. Surwit. It contains 58% of calories from fat, but only about 4% of calories from soybean oil; all other fat comes from coconut oil, that is, medium-chain triglycerides (MCT), saturated fatty acids with a chain length of 8 to 12 carbons. It might seem that this is not a good diet to induce obesity, but it really does work on mice. The cause is the added sugar. Carbohydrate content is 25.5%, half of which is in the form of sugar, i.e., about 6% of calories from fructose. As we already know, this limits fat oxidation.

Prof. R. Surwit’s experimental diet (HFD) causes reversible obesity induced by intestinal permeability and endotoxin (LPS) poisoning from the digestive tract. Could hydrogen sulfide play a role in this?

Unlike obesity studies based on consumption of high levels of monounsaturated and polyunsaturated vegetable oils (e.g., diet D12492), diet D12331 quite effectively prevents problems with adipocyte damage due to overeating during the first days of the study. I wrote about this in an earlier post here. A high content of linoleic acid together with a lack of short- and medium-chain fats leads to damage of differentiated adipocytes and to cellular senescence of adipose stem cells. This results in long-term overeating, hypertrophy—meaning very large cell volume—and the inability to increase the number of fat cells. The tissue is practically permanently damaged already at the beginning of the study, and recovery is almost impossible. This does not happen with a diet based on coconut oil.

Medium-chain fats accelerate metabolic adaptation when switching to a diet rich in fats and sugars, reducing the initial extreme overeating. If this diet is changed to a standard diet after 18 weeks, the mice’s body weight almost returns to normal. The only difference is that adipocytes become more active and more readily store excess energy when switching back to an obesogenic diet. That does not work with diets based on adipose tissue damage. In those cases, mice permanently consume more food and cannot lose weight without removing senescent cells from adipose tissue.

Obesity induced by a diet rich in fats and sugars (DIO) increases hydrogen sulfide (Sulfides) production.

But let’s return to hydrogen sulfide. The authors state that the intestinal epithelial cells themselves are not significantly altered by fat metabolism, but the environment in the colon has changed. It contains more bile and fats, which leads to a change in the microbiome composition and increased hydrogen sulfide production. At very low concentrations, hydrogen sulfide S-sulfhydrates enzymes, usually increasing their activity and improving metabolism. But the dependency is strongly nonlinear—in this case, H2S concentration rises so much that it blocks oxidative metabolism (OxPhos), specifically cytochrome c oxidase, that is, mitochondrial complex IV of the electron transport chain. And that is not good—the intestinal wall then becomes permeable, and remnants of bacterial membranes, so-called endotoxins or lipopolysaccharides (LPS), enter the bloodstream, activate TLR receptors, and cause chronic inflammation.

Obesity induced by a diet rich in fats and sugars (DIO) reduces energy (ATP molecule) production both at rest and under stress.

Unlike hydrogen sulfide produced enzymatically from sulfur amino acids in liver cells, hydrogen sulfide as a product of gut bacteria is at too high a concentration and does not help. On the contrary, it impairs mitochondrial function and oxidative metabolism by suppressing cytochrome c oxidase. It blocks ATP production through oxidative metabolism, so intestinal wall cells cannot maintain tight junctions, thereby increasing intestinal wall permeability. As a result, more toxic substances from the digestive tract enter the bloodstream.

Acute exposure of mitochondria to hydrogen sulfide suppresses oxygen consumption, i.e., suppresses energy production through oxidation.

Citation:

"In conclusion, we showed here that consumption of an obesogenic diet provoked colon dysbiosis, favoring sulfide production and colonic endothelial cells mitochondrial dysfunction, regardless of CEC lipid metabolism, but likely due to H2S-driven impairment of cytochrome c oxidase. This CEC energy supply failing could promote the loss of intestinal homeostasis and notably its permeability, aggravating metabolic endotoxemia or even increasing susceptibility to intestinal  inflammation."

End of citation


Let’s recall an older post pointing out that in animal studies often only certain parameters are measured, while for some unknown reason other, less well-known but very important parameters are not measured—for example acetate in mouse obesity studies. I think hydrogen sulfide falls precisely into this category of completely uncontrolled parameters that fundamentally affect the results of studies examining the impact of different diets on obesity. It is related to overeating, just like acetate. Most rodent studies actually show the effect of overeating and feeding the gut microbiota more than the studied effect. Overeating may be only short-term, linked to a diet change. If the study does not include an antibiotic arm, researchers cannot know whether the observed effect was caused by a change in the microbiome or by the monitored variable. This is a major problem in many studies.


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References:

Sulfhydrated albumin transmits H2S signaling and ameliorates DOX-induced multiorgan injuries

Weight cycling exacerbates glucose intolerance and hepatic triglyceride storage in mice with a history of chronic high fat diet exposure

Obesogenic diet leads to luminal overproduction of the complex IV inhibitor H2 S and mitochondrial dysfunction in mouse colonocytes


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