Furthermore, "a calorie is a calorie" ignores the incredibly complex relationships in our microbiome between bacteria, fungi, and yes even viruses (which apparently can and do absorb nutrients when they are in a host cell), that constitute a significant portion of the metabolism going on in our bodies. Dietary changes can alter the microbiome dramatically in relatively short periods of time, with some studies showing measurable microbiome composition shifts in as little as 3 weeks! [0] (note that while most of the examples in this review are on mice, there are human studies included further down that also demonstrate this rapid shift)

Processed carbs, and especially refined sugar, is rapidly absorbed in the upper GI, bypassing most of the beneficial microbes that 'preprocess' much of our raw food intake (especially complex carbs, like the prebiotic fibers and such) into more beneficial metabolites. Including bacterial metabolites that are essential to health and cellular energy.

Consider processed fructose vs fructose from a fruit, eaten whole. The former starts entering the bloodstream directly upon consumption, where it then must be processed by our own liver at some metabolic expense. Some people refer to fructose as "toxic" for reasons such as this:

>fructose induces a number of proinflammatory, fibrogenic, and oncogenic signaling pathways that explain its deleterious effects in the body, especially in the liver. [1]

Furthermore, when there is excess free fructose in the upper intestines, more than the body can rapidly absorb, it is also metabolically expensive simply to clear it from the gut to get it into the liver. This process can lead to ATP depletion in the GI tract. [1] Thus it robs us of that magical substance that powers all of our cellular activity, from muscle firing to nerve impulse activation (both of which are critical to optimum digestive function) and beyond.

On the other hand, when fructose is bound up in in complex carbs (fruit), it gets farther down into the intestines where fructose loving bacteria such as F. prausnitzi can ferment it for us. [2] In addition to sparing our ATP reserves in the gut and sparing our liver the trouble of processing fructose, F. prausnitzi produces an incredibly beneficial nutrient, butyrate, in the process. Butyrate has protective effects on the gut and intestinal barrier, and it is also a key building block of that lovely neurotransmitter GABA, that helps keep all of our other neurotransmitters in check (which is why it is called the "calming neurotransmitter").

Finally, on a hunch, I went ahead and googled "butyrate and satiety" which immediately returned this:

> Fermentation of fiber in the gut generates short-chain fatty acids (SCFA), such as butyrate, which decrease food intake and promote weight loss in rodent models. SCFA have been shown to enhance secretion of the gut satiety hormone peptide YY (PYY). [3]

Further investigation shows that this peptide is also active in humans, reducing hunger signals in the brain. [4]

All of this is to say, while the popular phrase "a calorie is a calorie" can help people to understand diet and weight loss in terms of an energy budget, the reality is far, far more complex than that. And we have truly only scratched the surface of all the complexity going on in the microbiome as it relates to diet and cellular functions throughout the body. Especially our immune system, which appears to borrow many critical metabolites from bacterial activity on the foods we choose to eat. It will be exciting to see how far down this rabbit hole we get in the coming years. For now, whenever we hear "a calorie is a calorie," it is useful to remember that things are not nearly so simple, and this sometimes helpful simplification can lead us astray quickly if we are not judicious in how we apply it.

[0] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398149/

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267750/

[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697676/

[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818935/

[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516703