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Martin et al. Microbiome Res Rep 2023;2:17 https://dx.doi.org/10.20517/mrr.2023.10 Page 7 of 13

Several bacteriocins have been identified in the Bifidobacterium spp.. They usually have low molecular
weight (less than 10 kDa) and a wide range of acid and thermal stability, with Gram-positive bacteria as
[116]
their primary targets . Bifidocin A is produced by B. animalis and displays strong activity against Listeria
[117]
monocytogenes by acting on its cell membrane level . Bifidocin LHA, produced by B. adolescentis,
inhibited Pseudomonas aeruginosa in a corneal infection model . Bifidin I produced by B. infantis BCRC
[118]
14602 inhibits several Gram-positive bacteria, including lactic acid bacteria. A lantibiotic in B. longum
displays strong inhibitory activity against Clostridium perfringens and Bacillus subtilis .
[116]

In addition to their participation in cross-feeding interactions, SCFAs produced after fiber fermentation
inhibit some microbes, including pathogens . Being weak acids, SCFAs lower luminal pH and may enter
[78]
bacterial cells as protonated acids, disrupting the intracellular pH. Acetate is a preserving agent, and
[119]
Bifidobacterium longum inhibits pathogenic E. coli via acetate . Gut microbes are sensitive to pH and
adjust their habitats to achieve their optimum pH for growth. Bacteroides spp. are well known to prefer pH
values of approximately 6.5, with limited growth at acidic conditions . Butyrate reduces the expression of
[120]
Type III Secretion Systems (T3SS) in S. typhimurium mediated by the change in pH. Butyrate also inhibits
Bacteroides spp. in a strain- and glycan-dependent manner . Similarly, propionate inhibits Salmonella
[121]
growth by the same mechanism [122,123] .

Colonization resistance
Colonization resistance is a fundamental property of gut microbiota for preventing and controlling
infections [74,112] . This community poses a strong blockade against foreign microorganisms such as GI
pathogens, antibiotic-resistant bacteria (ARB), and even probiotics [Figure 1] . This property depends on
[112]
[72]
a stable and healthy balanced microbiota . It is based on direct mechanisms, including competition for
nutrients, niche exclusion, or the release of toxic substances, and indirect mechanisms, such as the
induction of host immune responses . Some pathogens have developed counterstrategies to overcome
[72]
colonization resistance, and the temporary loss of colonization resistance results in the expansion of certain
pathogens .
[72]
A diverse microbiota provides protection against Listeria monocytogenes (Lm) . This foodborne pathogen
[124]
causes severe diseases in immunocompromised individuals. Antibiotic-mediated depletion of gut
[124]
commensals reduces colonization resistance and increases Lm colonization . Animals require a high
infective dose of Lm to develop an infection, which is reduced to only a few cells when treated with
[124]
antibiotics . A consortium of four microbes displayed antilisterial activity in germ-free animals,
[124]
stimulating resistance to colonization against Lm . These consortia included Blautia producta and
Clostridium spp.. B. producta has also been implicated in other antimicrobial activities [125,126] . Vancomycin-
resistant enterococci (VRE) is a multidrug-resistant microorganism that can colonize the human gut and
cause bloodstream infections, especially after antibiotic therapy. The gut microbiota mounts resistance to
[125]
colonization by VRE and limits its colonization . Using a reductionist approach, a specific consortium of
four gut microbes was found to confer VRE resistance in animals. This consortium displayed cooperative
interactions; two Bacteroidales species possessed endogenous lactamase activity, allowing Clostridium
bolteae and Blautia producta to clear VRE from the intestine. It was shown that to support colonization of
the murine intestine by B. producta, the presence of the other species in the consortium and multilevel
[125]
cooperation between them was necessary . Later, it was found that B. producta produces a lantibiotic
similar to nisin against VRE . This study showed how interspecies cooperativity is important for
[126]
[125]
colonization resistance .