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Page 10 of 25 Luo et al. Microbiome Res Rep 2025;4:10 https://dx.doi.org/10.20517/mrr.2024.57

[101]
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subunit (INHA) , heterotrimeric flagellin FlaB , and cytolysin A (ClyA) to the tumor tissues.
[99]
In a colon cancer mouse model, a combination therapy involving L-arginine and anti-PD-1 antibodies
[102]
significantly improved survival rates . To enhance the precise and efficient delivery of L-arginine to tumor
tissues, an engineered strain of EcN was developed, demonstrating high efficiency in L-arginine production
and synergistically enhancing the effects of anti-PD-1 antibody treatment .
[103]
Neurodegenerative disease
Neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are
characterized by progressive neuronal loss in the brain and spinal cord, leading to chronic neurological
dysfunction and cognitive or motor decline. Their pathogenesis encompasses intricate factors including
neuroinflammation, insulin resistance, mitochondrial dysfunction, and protein misfolding and
[104]
aggregation . GLP-1, originally recognized for its therapeutic role in metabolic disorders such as diabetes
and obesity, has now gained prominence in the realm of neurodegenerative diseases. Studies have
[106]
demonstrated its ability to mitigate neuroinflammation , improve insulin sensitivity , confer
[105]
neuroprotective effects , and preserve mitochondrial function . Engineered bacteria represent a
[108]
[107]
promising strategy to tackle the obstacles of GLP-1 therapy. By synthesizing GLP-1 in situ within the gut,
they can circumvent its limited half-life. Moreover, probiotics exert influence on the central nervous system
by modulating metabolism and immunity via the gut-brain axis . Therefore, the combination of
[109]
probiotics and GLP-1 is anticipated to play an increasingly significant role in the treatment of
neurodegenerative diseases.

In a previous study, we constructed the engineered bacterial plasmid pMG36e-GLP-1 containing the GLP-1
gene, which was subsequently transformed into Lactococcus lactis to generate the engineered strain
MG1363-pMG36e-GLP-1. Administering MG1363-pMG36e-GLP-1 orally to mice afflicted with LPS-
induced systemic inflammation led to decreased inflammation, substantial enhancements in spatial learning
[110]
and memory, and suppression of glial cell activation and Aβ accumulation . Subsequent investigations
utilized MG1363-pMG36e-GLP-1 in a murine model of MPTP-induced PD, revealing significant
enhancements in motor function, reduced dopaminergic neuron loss, diminished α-synuclein aggregation,
and suppression of ferroptosis through activation of the Keap1/Nrf2/GPX4 pathway [111,112] . Moreover,
MG1363-pMG36e-GLP-1 modulates the TLR4/NF-κB and AKT/GSK3β pathways to reduce the expression
of inflammatory factors and boost neuroprotective factor activity, thereby notably improving spatial
learning and memory in AD mice .
[8]

Potential applications of biosensors developed based on engineered bacteria for disease diagnosis
Engineered bacteria designed as biosensors represent an innovative approach in biotechnology, particularly
for detecting pathogenic bacteria via their quorum sensing (QS) systems. QS involves bacterial
communication via chemical signaling molecules, facilitating coordinated behavioral changes based on
population density and surrounding species . These biosensors utilize QS molecules as input modules,
[113]
computational gene networks for processing, and output modules, such as reporter genes (e.g., β-
galactosidase, fluorescent proteins, β-glucuronidase, β-lactamase), for detection [Figure 3].

For instance, researchers integrated the agrQS system from Staphylococcus aureus into Lactobacillus reuteri
DSM20016 to detect autoinducing peptide I (AIP-I), a QS molecule produced by Staphylococcus aureus .
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This engineered bacterium can sense AIP-I concentration-dependently by employing reporter genes such as
GusA, which is linked to the production of a yellow pigment. Upon AIP-I binding to AgrC, it initiates AgrA
phosphorylation, resulting in GusA expression repression and thereby indicating AIP-I presence indirectly