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Lu et al. Microbiome Res Rep 2024;3:17 https://dx.doi.org/10.20517/mrr.2023.44 Page 7 of 14

Lipids and lipid derivatives
Lipids include fat, phospholipids, glycolipids, cholesterol, and cholesterol esters, and most of them are
[72]
transformed in the liver . Lipids and lipid derivatives are involved in the supply of energy and essential
fatty acids. They also play essential roles in the absorption of fat-soluble vitamins and the metabolism of
calcium and phosphorus. In addition, they form a hydrophobic barrier to maintain the normal structure
and function of cells. Animal studies suggest that the brain can perceive the levels of lipids in the blood. In
addition, lipids in the upper intestine increase the level of long-chain fatty acyl-coenzyme A (LCFA CoA) in
the small intestine, and both can inhibit the production of glucose in the liver through the gut-liver-brain
axis . In other words, lipids absorbed in the upper intestine can inhibit glucose production in the liver
[8]
through LCFA CoA as a mediator. LCFA CoA is also an important backbone for many bioactive molecules,
such as sphingosine, ceramides, phosphosphingolipids, and glycosphingolipids, which are the main
structural lipids of various membranes in nervous tissue. Lipids have other important biological functions
such as: messengers in signal transduction, for example, steroid hormones which can influence brain
[73]
function ; modulators for enzyme activity, for example, lecithin, which can activate β-hydroxybutyrate
dehydrogenase ; precursors of hormones, vitamins, growth factors, and antioxidants; and mediators of
[74]
signal recognition and immunity, for example, glycolipids . The intestinal microbiota is also pivotal for the
[75]
biosynthesis of hepatic membrane phospholipids and liver regeneration . Gut microbiome-derived lipids
[76]
can influence the function of brain and liver through the signaling pathway mediated by
macrophageinducible Ctype lectin, spleen tyrosine kinase, and nuclear factor kappa-B [77-79] . LPS, a
bacteria-derived lipid, can enter the bloodstream when the gut barrier function is impaired and the
permeability of the barrier is increased, to induce inflammation by activating the toll-like receptors
(TLRs) . Steroid hormones have been reported to have the ability to regulate the metabolism of
[80]
sphingolipids, which can inversely regulate the secretion of steroid hormones . Additionally, BAs can
[81]
[82]
regulate lipid metabolism via the FXR and TGR5 pathways which are linked to the gut-liver-brain axis .
Abnormal lipid accumulation may cause impairments of the brain and the liver . The liver is also
[83]
[84]
implicated in shaping the gut microbiome and lipid metabolism . Therefore, lipid metabolism is involved
[85]
in the physiological functions of organs such as the brain, gut, and liver, while dysregulation of lipid
metabolism can affect the structure and function of the gut microbiome.
Uric acid
Uric acid (UA), a scavenger of oxygen radical, is synthesized mainly in the liver, intestines, and the vascular
endothelium as the end metabolite of purine, and excreted via the kidney/intestine. UA is involved in
[86]
[88]
[89]
[87]
disorders of not only the kidney , but also the liver , the joint , the brain , and the cardiovascular
system via several mechanisms including oxidative stress, inflammation, and apoptosis. Well-known
[90]
causes of serum hyperuricemia include UA metabolism disturbance and reduction of its secretion by
kidney. Many intestinal bacteria, including species that belong to the genus Micrococcus, Streptomyces,
Pseudomonas, and Bacillus, carry genes coding for uricase/urate oxidase which can degrade dietary and
endogenous uric acid . Intestinal Akkermansia muciniphila exhibited beneficial effects of decreasing serum
[91]
urate and inhibiting xanthine oxidase in the liver . Additionally, recent studies have identified that a
[92]
dysbiosis of intestinal microbiota underlies the pathological association between serum UA and body mass
index (BMI) . UA has been implicated in the pathophysiology of liver damage and cognitive decline in
[93]
[94]
attention and executive function . Accumulating case studies and experiments in animal models have
[95]
provided mechanistic insights to explain the complicated pathophysiology of UA-associated disorders. UA
has been reported to have neuroprotective properties by activating the nuclear factor E2 related factor 2
(Nrf2) pathway including γ-glutamate-cysteine ligase catalytic subunit (γ-GCLC), heme oxygenase-1
(HO-1), and NQO1 . However, hyperuricemia can cause chronic inflammation by activating
[96]
inflammatory mediators such as TLR- 4 and the inflammatory vesicles of the Pyrin domain NOD-like
receptor family 3 (NLRP3) [97,98] . UA can also downregulate NO levels by enhancing arginase activity, thereby