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Martin et al. Microbiome Res Rep 2023;2:17 https://dx.doi.org/10.20517/mrr.2023.10 Page 3 of 13

arabinogalactans [31,32] . Bifidobacterium and Bacteroides species are the primary degraders of these
[25]
polysaccharides , and molecular mechanisms have been resolved in part. Although utilization of plant-
derived oligosaccharides is common among gut microbes, recent studies have increased our understanding
of the molecular adaptations of these genera to use more complex polysaccharides, especially host-derived
glycans . These findings highlight the ability of Bifidobacterium and Bacteroides to adapt to the intestinal
[33]
environment. One of these complex substrates is human milk oligosaccharides (HMOs), an important
carbon source for Bifidobacterium provided to infants via breast milk. HMOs are composed of lactose with
repetitions of N-acetylglucosamine, fucose, and sialic acid. HMOs have a strong bifidogenic effect, which
can be explained by multiple molecular adaptations in their genomes, including ABC transporters and
specialized glycosyl hydrolases. The gut microbiota can also target other host-derived dietary substrates
[33]
such as mucins and milk glycoproteins . N- and O-Glycans found in IgA and mucins can be accessed and
used as carbon and energy sources for bacteria such as Bifidobacterium bifidum, Bacteroides
thetaiotaomicron, and Akkermansia muciniphila .
[34]

Microbiome-derived metabolites influence several physiological processes within the host. The gut
[35]
microbiome produces millimolar concentrations of short-chain fatty acids (SCFAs) , such as acetate,
propionate, and butyrate. Their concentrations vary in different segments of the intestine and are released
in a ratio of 3:1:1 for acetate, propionate, and butyrate [35,36] . Other acids, such as lactate and succinate, are
considered intermediates in gut microbiota metabolism and participate in cross-feeding reactions, generally
absent in fecal samples [37-39] . Bifidobacterium central metabolism, the bifid shunt, theoretically produces
[40]
acetate and lactate in a 3:2 ratio, together with 2.5 moles of ATP per mole of glucose . This ratio could
indeed show variations according to the dietary source. In addition, Bifidobacterium has been found to
contribute significantly to butyrate and propionate production through different mechanisms of cross-
feeding with other gut bacteria [41-45] . Other end-products, such as ethanol, succinate, and formate, are
commonly produced by these species. For instance, the fermentation of fucose by Bifidobacterium results in
formate production in the infant gut . Recently, aromatic lactic acids derived from infant-associated
[39]
Bifidobacterium, such as indole lactic acid, were found to have a strong immunomodulatory effect on CD4+
T cells by activating the aryl hydrocarbon receptor, AhR .
[46]
SCFAs maintain host intestinal homeostasis because of their anti-inflammatory and protective effects on the
intestinal epithelium, and participate in the regulation of multiple cellular processes [4,47,48] . Acetate is
absorbed by the epithelium and reaches systemic micromolar concentrations. Propionate is primarily used
in the liver . Butyrate is the primary energy source for the colonic epithelium [49,50] and its utilization by host
[35]
cells requires oxygen, thereby contributing to luminal anaerobiosis . Additionally, butyrate is an epigenetic
[49]
regulator that inhibits histone deacetylases in colonocytes and suppresses inflammatory pathways via G-
[51]
protein-coupled receptors . Butyrate can be synthesized by four distinct metabolic pathways. Most
[52]
butyrate-producing bacteria (BPB) contain butyrate kinase or butyryl-CoA: acetate-CoA transferase .
[53]
Moreover, BPB are considered critical species in the gut microbiota and essential for its stability and
function [54-56] . BPB includes microorganisms from unrelated genera, representing a more functional than
taxonomic category . Representative BPB include Anaerostipes caccae, Roseburia intestinalis,
[57]
Lachnoclostridium symbiosum, Faecalibacterium prausnitzii, Clostridium saccharolyticum among
[41]
others [58,59] . BPB are highly oxygen-sensitive Gram-positive bacteria that, while capable of using simple
oligosaccharides, appear to prefer molecules such as lactate, succinate, or acetate to produce butyrate [54,60] .
Although BPB have beneficial effects, and a decrease in their abundance can be an indicator of declining
intestinal health and response to microbial diseases [12,61] , the role of butyrate in host physiology has been
controversial due to conflicting evidence in the literature. Variations in diet, gut microbiota composition,
and individual genetic differences may also play a role in determining the effects of butyrate in a dose-