Beyond who's there: what your gut microbes actually make

Clear glass sample vials and a pipette on a pale cool-grey surface

By Paniz Jasbi, PhD, Chief Executive Officer, Works Probiotics.
Reviewed by Alex Mohr, PhD, Chief Product Officer.
Reading time about 7 minutes.

What to take away

  • A microbiome is usually described as a list of species. That list is only half the picture.
  • What those microbes make, the molecules they produce and transform, is what acts on the body.
  • The best studied of these molecules are short-chain fatty acids and secondary bile acids.
  • Two people can carry similar bacteria and still produce different molecules, so "who is present" and "what is being made" are different questions.
  • Parts of this are early science. We mark what is well established and what is not.

The question most microbiome science skips

Open almost any article about the gut microbiome and you will read a list of names. Bacteroides. Bifidobacterium. Akkermansia. The at-home tests answer the same question: who lives in your gut. It is a reasonable question. It is also only half of one.

The gut holds a microbial community roughly on the scale of the body's own cells[1], collectively carrying millions of microbial genes[2]. What makes that community matter is not the roster. It is the chemistry. These microbes ferment what we cannot digest, transform compounds our own cells release, and in doing so produce a stream of small molecules that reach the gut lining and the bloodstream. Composition is the parts list. The molecules are the activity. This post is about the activity.

Presence is not the same as function

There is a technical reason the parts list dominates the conversation. It is what the common tools measure. Sequencing the 16S ribosomal RNA gene, the cheaper and more common method, sorts bacteria into groups that are often only as precise as the genus[3]. Shotgun metagenomics goes further. It reads the community's genes, which resolves organisms closer to the species and strain level and catalogs what those genes are capable of doing[3][4]. Even shotgun sequencing, though, reports capability, not activity. A gene for producing a molecule is not the same as the molecule being produced.

That gap matters because of a well-documented feature of the gut: functional redundancy. Across healthy people, the species present vary widely, while the community-level metabolic pathways are comparatively stable, because different organisms can do the same job[5]. The taxonomy varies more than the function. So a parts list can look different between two people whose guts are, in the ways that matter, doing similar work. The opposite is the harder problem, and it is the interesting one: similar-looking communities can still produce different amounts of the molecules that act on the body.

What the microbes actually make

Two families of molecules are the best characterized, and they are a good place to start.

Short-chain fatty acids. When gut bacteria ferment dietary fiber, the main products are three short-chain fatty acids: acetate, propionate, and butyrate[6][7]. These have been measured directly in the human gut and in blood, so this is not a modeling exercise[8]. And they are not waste. Butyrate is the preferred fuel of the cells lining the colon, which take up most of it before it ever reaches general circulation[9][10]. Beyond fuel, short-chain fatty acids act as signals. They bind specific receptors on gut and immune cells, and they influence how genes are switched on and off inside cells[11][12]. The through-line is simple. A molecule made by bacteria, from food the human body could not break down on its own, then goes on to feed and to signal to human cells.

Bile acids. The body makes bile acids to help absorb fat. Gut bacteria then chemically alter them, first removing an attached amino acid, then converting the primary bile acids the liver made into a set of secondary bile acids the body cannot make on its own[13]. Those transformed molecules are themselves signals, recognized by dedicated receptors that participate in metabolism[14]. Here the microbes are not fermenting food. They are editing the body's own chemistry, and the edited version does different things than the original.

These are two examples, not the whole set. The broader point is that the gut community substantially shapes the pool of small molecules circulating in the body. In mice, removing the gut community changes a large fraction of the metabolites found in the blood[15]. In people, microbiome features are among the strongest explanations for the levels of many blood metabolites[16]. The organisms on the parts list are, in effect, a distributed chemical plant.

Why two similar microbiomes can behave differently

Put the pieces together and a practical conclusion follows. Because capability is not activity, and because different organisms can fill the same role, knowing which species are present tells you less than you would hope about what is being produced. Diet, the rest of the community, and the individual all shape the output. This is the honest basis for the idea that gut health is individual. It is not that everyone harbors a unique zoo. It is that the same inputs can yield different chemistry in different people.

It also gives a precise meaning to a word the supplement aisle uses loosely. "Postbiotics" has a formal consensus definition: a preparation of inactivated microbes or their components that confers a benefit[17]. Whether microbial molecules on their own belong under that exact label is still debated[17]. The debate itself is telling. The field is moving its attention from the organisms to what they produce and leave behind.

What this means for choosing a probiotic

If the molecules are what act on the body, then the useful question about any probiotic is not how many organisms it contains. It is what those organisms are selected to do. A defined strain chosen for a specific functional reason is a different proposition than a large, unexamined blend. We think formulation should follow function. That is the whole idea behind precision, and it is why Works is a small, defined formulation rather than a bigger count. Works supports a healthy gut microbiome.*

We are not going to tell you this settles anything. It does not.

What is still open

Most of what is above is well established. Short-chain fatty acids and secondary bile acids exist, microbes make and transform them, and they act as fuel and as signals. What is far less settled is the step everyone actually wants: predicting, for a given person, which strains will change which molecules by how much, and whether that produces a difference the person can feel. Much of the mechanistic work is in cells and in animals, which is a starting point, not a conclusion in humans. Measuring the molecules directly, rather than inferring them from a species list, is still an emerging practice.

That frontier is where we work. It is why our own published research to date is preclinical, and why our human study is IRB approved and will commence Fall 2026. We will report what it shows when we have it. In the meantime, the honest version of the science is the more interesting one. Your microbiome is not just who is there. It is what they make.

* These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

References

  1. Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 2016;14(8):e1002533. PMID 27541692.
  2. Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59-65. PMID 20203603.
  3. Quince C, Walker AW, Simpson JT, Loman NJ, Segata N. Shotgun metagenomics, from sampling to analysis. Nat Biotechnol. 2017;35(9):833-844. PMID 28898207.
  4. Ranjan R, Rani A, Metwally A, McGee HS, Perkins DL. Analysis of the microbiome: advantages of whole genome shotgun versus 16S amplicon sequencing. Biochem Biophys Res Commun. 2016;469(4):967-977. PMID 26718401.
  5. Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature. 2012;486(7402):207-214. PMID 22699609.
  6. Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell. 2016;165(6):1332-1345. PMID 27259147.
  7. den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud DJ, Bakker BM. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res. 2013;54(9):2325-2340. PMID 23821742.
  8. Cummings JH, Pomare EW, Branch WJ, Naylor CP, Macfarlane GT. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut. 1987;28(10):1221-1227. PMID 3678950.
  9. Donohoe DR, Garge N, Zhang X, et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 2011;13(5):517-526. PMID 21531334.
  10. Roediger WE. Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man. Gut. 1980;21(9):793-798. PMID 7429343.
  11. Tan J, McKenzie C, Potamitis M, Thorburn AN, Mackay CR, Macia L. The role of short-chain fatty acids in health and disease. Adv Immunol. 2014;121:91-119. PMID 24388214.
  12. Brown AJ, Goldsworthy SM, Barnes AA, et al. The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem. 2003;278(13):11312-11319. PMID 12496283.
  13. Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res. 2006;47(2):241-259. PMID 16299351.
  14. Wahlström A, Sayin SI, Marschall HU, Bäckhed F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 2016;24(1):41-50. PMID 27320064.
  15. Wikoff WR, Anfora AT, Liu J, et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci U S A. 2009;106(10):3698-3703. PMID 19234110.
  16. Bar N, Korem T, Weissbrod O, et al. A reference map of potential determinants for the human serum metabolome. Nature. 2020;588(7836):135-140. PMID 33177712.
  17. Salminen S, Collado MC, Endo A, et al. The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics. Nat Rev Gastroenterol Hepatol. 2021;18(9):649-667. PMID 33948025.

Read about how we write and review these posts in our editorial and review standards.