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Microbial Metabolites and Neuroactive Compounds Dysbiosis induced by NCSs may have functional consequences for host physiology through an altered microbial ecosystem.Since B. fragilis has been identified as a GABA-producing bacterium [46,47], its proliferation under NCSs exposure may help explain the observed increases in appetite, body weight, and altered glucose metabolism.Specifically, NCS-induced changes have been associated with (1) a reduction in the production of SCFAs such as butyrate and propi onate [38]; (2) increased intestinal permeability, potentially due to loss of mucin-degrading andtight-junction-stabilizing microbial species [13,39,40]; (3) elevated circulating endotoxin Int.Mechanistically, GM-derived GABA is hypothesized to inhibit satiety hormone secretion, which, through the vagus nerve, disinhibits orexigenic hypotha lamic neuropeptide Y (NPY) and the Agouti-related protein (AgRP) neurons (NPY/AgRP), thereby enhancing appetite [44].Similarly, germ-free mice colonized with microbiota from saccharin-exposed donors exhibited a marked increase in B. fragilis, mir roring the donor profile [13].J. Mol.Sci.

Microbial Metabolites and Neuroactive Compounds
Dysbiosis induced by NCSs may have functional consequences for host physiology
through an altered microbial ecosystem. Specifically, NCS-induced changes have been
associated with (1) a reduction in the production of SCFAs such as butyrate and propi
onate [38]; (2) increased intestinal permeability, potentially due to loss of mucin-degrading
andtight-junction-stabilizing microbial species [13,39,40]; (3) elevated circulating endotoxin
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(e.g., lipopolysaccharide, LPS) levels in systemic circulation, often exacerbated by high-fat
diet, contributing to low-grade inflammation and insulin resistance [41–43].
NCSs may selectively alter specific gut microbial populations that modulate both
satiety-promoting metabolites such as SCFAs, serotonin and GLP-1, and appetite-enhancing
signals such as GABA [44]. These shifts can disrupt the regulation of homeostatic feeding,
potentially leading to overeating and metabolic dysregulation. A recent study in rabbits
found that particularly Bacteroides species are enriched in GABA-producing pathways [44].
Intragastric GABA administration suppressed satiety hormones (i.e., GLP-1, PYY, CCK) and
stimulate feeding behavior. Mechanistically, GM-derived GABA is hypothesized to inhibit
satiety hormone secretion, which, through the vagus nerve, disinhibits orexigenic hypotha
lamic neuropeptide Y (NPY) and the Agouti-related protein (AgRP) neurons (NPY/AgRP),
thereby enhancing appetite [44]. Interestingly, one study reported that sucralose intake may
promote energy imbalance and increase appetite via an NPY-dependent mechanism [45]. If
both saccharin and Ace-k are capable of shifting gut microbiota composition and increasing
Bacteroides abundance [13,42], it is conceivable that chronic intake of specific NCSs may
increase appetite by engaging GABA-mediated inhibition of satiety signals and disinhibi
tion of orexigenic neuropeptides such as NPY. Although direct evidence for NCS-induced
GABAalterations remains limited, increased or disrupted Bacteroides diversity may enhance
GABAproduction, potentially affecting enteric neurons and appetite control via the GBA.
Furthermore, sucralose ingestion in rats has been shown to increase the abundance of
Bacteroides fragilis (B. fragilis) and circulating pro-inflammatory cytokines while reducing
occludin expression, a key tight-junction protein [41]. These effects were exacerbated when
sucralose was combined with a high-fat diet, leading to metabolic endotoxemia, weight
gain, adiposity, and glucose intolerance [41]. Similarly, germ-free mice colonized with
microbiota from saccharin-exposed donors exhibited a marked increase in B. fragilis, mir
roring the donor profile [13]. Since B. fragilis has been identified as a GABA-producing
bacterium [46,47], its proliferation under NCSs exposure may help explain the observed
increases in appetite, body weight, and altered glucose metabolism.