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Functional Microgel Enables Effective Delivery and Colonization
of Probiotics for Treating Colitis
Cite This: ACS Cent. Sci. 2023, 9, 1260−1262
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Bingyu Chen, Wendan Pu, and Jianxiang Zhang*
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O
ver 2000 years ago, the Greek physician Hippocrates
of Kos, lauded as the father of western medicine,
Downloaded via 94.214.111.206 on August 2, 2023 at 16:30:23 (UTC).
proclaimed that “All disease begins in the gut”. The
gut microbiome exerts pivotal roles in health and diseases, by
regulating critical biological processes in metabolism,
inflammation, and immunity. Dysbiosis of the gut microbiota
is involved in the pathogenesis of numerous diseases, such as
obesity, diabetes, inflammatory bowel disease (IBD), liver
diseases, respiratory diseases, cardiovascular diseases, autism,
anxiety, schizophrenia, Parkinson’s disease, Alzheimer’s
disease, infectious diseases, and cancers.1−4 Accordingly,
regulation of the homeostasis of the gut microbiome represents
a promising strategy for the management of many human
diseases. Both preclinical and clinical studies have demon-
strated the effectiveness of microbiota manipulation in the
treatment of IBD and neurodegenerative diseases.4−6 In
particular, increasing attention has been paid to oral probiotic
therapies for treating or curing colitis. Tablets, capsules, and
powders of typical probiotic strains, such as Bifidobacteria and
Lactobacilli that have long been used in the clinic, are available
on the market; however, traditional formulations of such
probiotics show poor stability and low bioavailability, thus
limiting their therapeutic effects.
Regulation of the homeostasis of
the gut microbiome represents a
promising strategy for the
management of many human
diseases.
Most recently, different surface engineering approaches
and advanced delivery systems have been developed for
probiotics to improve their stability in the gastrointestinal
tract, increase oral delivery efficiency, and potentiate in vivo
efficacies. However, therapeutic benefits of probiotic
Published 2023 by American Chemical
Society
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therapies remain to be improved, with respect to clinical
translation. In this issue of ACS Central Science, Zhang, Liu,
Shi, and co-workers rationally designed and constructed a
multifunctional calcium tungstate microgel (CTM)-based
system for oral probiotic delivery.1 CTM was formulated by
the Ca2+-mediated cross-linking of sodium alginate and
sodium tungstate in aqueous solution, giving rise to calcium
tungstate (CaWO4) nanoparticle-loaded alginate microgels
(Figure 1A). Using this facile and eco-friendly approach,
probiotics can be conveniently packaged into CTM without
affecting their biological performances. CTM was stable in
simulated gastric fluid, while it gradually eroded upon
incubation in simulated intestinal fluid, leading to the
release of CaWO4 nanoparticles. More importantly, the
erosion of CTM and release of CaWO4 nanoparticles and
tungsten ions can be effectively triggered by calprotectin
(CP), a highly expressed protein at colitis sites, due to
strong interactions between CP and Ca2+. Released tungsten
can inhibit the growth of Enterobacteriaceae by attenuating
Enterobacteriaceae-dependent molybdenum enzyme activity.
Since the growth of probiotics is independent of moly-
bdenum enzymes, tungsten has no significant effects on
probiotics loaded in CTM. Consequently, CTM can
selectively suppress the growth of Enterobacteriaceae in
colitis, thus disrupting the ecological niche occupied by
pathogenic bacteria and promoting probiotic colonization.
Using Bacillus coagulans (BC) as a candidate probiotic, the
authors demonstrated that orally delivered BC-containing
CTM (i.e., BC@CTM) effectively inhibited the proliferation
Published: July 13, 2023
https://doi.org/10.1021/acscentsci.3c00773
ACS Cent. Sci. 2023, 9, 1260−1262
ACS Central Science
Figure 1. (A) Engineering of a calcium tungstate microgel (CTM) for the oral delivery of probiotics. (B) Oral delivery of Bacillus coagulans-
containing CTM (BC@CTM) shows desirable therapeutic effects on colitis in mice by selectively suppressing abnormally expanded
Enterobacteriaceae and promoting probiotic colonization.
of harmful bacteria, facilitated probiotic colonization, and
restored gut microbiota homeostasis in mice with dextran
sulfate sodium (DSS)-induced colitis (Figure 1B). Moreover,
treatment with BC@CTM significantly alleviated local
oxidative stress and inflammation and restored the intestinal
barrier function. These beneficial effects collectively contribute
to desirable therapeutic outcomes of BC@CTM on DSS-
induced colitis in mice.
Zhang, Liu, Shi, and co-workers
rationally designed and
constructed a multifunctional
calcium tungstate microgel
(CTM)-based system for oral
probiotic delivery.
Previously, various types of delivery systems and bacterial
functionalization approaches, such as biofilm-based encapsu-
lation, hydrogels, and chemical/physical coating via different
materials, have been established for the oral delivery of
probiotics.7−9 Despite their effectiveness in protecting pro-
biotics from damage in the gastrointestinal tract under
physiological conditions, these strategies cannot efficiently
and precisely normalize the pathological microenvironment, in
particular, the proliferation and abnormal colonization of
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pathogenic bacteria that may severely inhibit probiotic
colonization, thereby resulting in impaired pharmacological
effects. Whereas the use of antibiotics enables intestinal decol-
onization of harmful bacteria, it also eliminates beneficial
microbes and simultaneously causes antibiotic resistance. As a
proof of concept, this work provides an intriguing and facile
delivery strategy to improve oral delivery and colonization of
probiotics under inflammatory conditions simply by using a
rationally engineered microgel platform capable of selectively
breaking the ecological niche of pathogenic bacteria.
As a proof of concept, this work
provides an intriguing and facile
delivery strategy to improve oral
delivery and colonization of
probiotics under inflammatory
conditions simply by using a
rationally engineered microgel
platform capable of selectively
breaking the ecological niche of
pathogenic bacteria.
As for the limitations of this study, only one mouse model
of colitis and one probiotic were used. Future translation
studies should validate the proposed strategy in other
https://doi.org/10.1021/acscentsci.3c00773
ACS Cent. Sci. 2023, 9, 1260−1262
ACS Central Science FIRST REACTIONS

animal models of colitis and using different probiotic strains.
In addition, gut microbiota-derived metabolites, such as
trimethylamine/trimethylamine-N-oxide, secondary bile
acids, and short-chain fatty acids, should be included in
future analyses, in view of their critical effects on host
immune responses and immune-related inflammatory diseases.
Both the formulations and treatment regimens remain to be
optimized to afford maximized efficacies and minimized side
effects. There are also safety concerns regarding the use of high
doses of tungsten and/or long-term exposure to tungsten.
In addition to its direct toxicities to specific organs/tissues,
emerging evidence suggests that tungsten can amplify the
effects of other toxicants and endogenous/exogenous
stressors.10 Finally, it would be interesting to explore the
effectiveness of the proposed strategy for the treatment of
other relevant diseases, such as periodontitis, liver diseases
(e.g., nonalcoholic fatty liver disease and nonalcoholic
steatohepatitis), common lung diseases (such as asthma and
chronic obstructive pulmonary disease), neurological disorders
(Alzheimer’s disease, Parkinson’s disease, stroke, etc.), and
vaginal diseases, considering the presence of the microbiota in
other tissues such as the oral cavity, respiratory tract, and
vagina as well as the well-recognized gut−liver, gut−lung, and
gut−brain axes.2,4,6,11
(3) Tang, W. H. W.; Bäckhed, F.; Landmesser, U.; Hazen, S. L.
Intestinal Microbiota in Cardiovascular Health and Disease: Jacc
State-of-the-Art Review. J. Am. Coll. Cardiol. 2019, 73, 2089−2105.
(4) Cryan, J. F.; O’Riordan, K. J.; Cowan, C. S. M.; Sandhu, K. V.;
Bastiaanssen, T. F. S.; Boehme, M.; Codagnone, M. G.; Cussotto, S.;
Fulling, C.; Golubeva, A. V.; Guzzetta, K. E.; Jaggar, M.; Long-Smith,
C. M.; Lyte, J. M.; Martin, J. A.; Molinero-Perez, A.; Moloney, G.;
Morelli, E.; Morillas, E.; O’Connor, R.; et al. The Microbiota-Gut-
Brain Axis. Physiol. Rev. 2019, 99, 1877−2013.
(5) Li, C.; Zhao, Y.; Cheng, J.; Guo, J.; Zhang, Q.; Zhang, X.; Ren,
J.; Wang, F.; Huang, J.; Hu, H.; Wang, R.; Zhang, J. A Proresolving
Peptide Nanotherapy for Site-Specific Treatment of Inflammatory
Bowel Disease by Regulating Proinflammatory Microenvironment and
Gut Microbiota. Adv. Sci. 2019, 6, No. 1900610.
(6) Sanders, M. E.; Merenstein, D. J.; Reid, G.; Gibson, G. R.;
Rastall, R. A. Probiotics and Prebiotics in Intestinal Health and
Disease: From Biology to the Clinic. Nat. Rev. Gastroenterol. Hepatol.
2019, 16, 605−616.
(7) Li, Z.; Behrens, A. M.; Ginat, N.; Tzeng, S. Y.; Lu, X.; Sivan, S.;
Langer, R.; Jaklenec, A. Biofilm-Inspired Encapsulation of Probiotics
for the Treatment of Complex Infections. Adv. Mater. 2018, 30,
No. 1803925.
(8) Luo, H.; Chen, Y.; Kuang, X.; Wang, X.; Yang, F.; Cao, Z.;
Wang, L.; Lin, S.; Wu, F.; Liu, J. Chemical Reaction-Mediated
Covalent Localization of Bacteria. Nat. Commun. 2022, 13, 7808.
(9) Yu, S.; Sun, H.; Li, Y.; Wei, S.; Xu, J.; Liu, J. Hydrogels as
Promising Platforms for Engineered Living Bacteria-Mediated
Therapeutic Systems. Mater. Today Bio 2022, 16, No. 100435.
(10) Bolt, A. M.; Mann, K. K. Tungsten: An Emerging Toxicant,
Alone or in Combination. Curr. Environ. Health Rep. 2016, 3, 405−
415.
(11) Albillos, A.; de Gottardi, A.; Rescigno, M. The Gut-Liver Axis
in Liver Disease: Pathophysiological Basis for Therapy. J. Hepatol.
2020, 72, 558−577.

Author Information
Corresponding Author
Jianxiang Zhang − Women and Children’s Hospital,
Chongqing Medical University, Chongqing 401147, China;
Department of Pharmaceutics, College of Pharmacy, Third
Military Medical University (Army Medical University),
Chongqing 400038, China; orcid.org/0000-0002-0984-
2947; Email: jxzhang1980@gmail.com, jxzhang@
tmmu.edu.cn
Authors
Bingyu Chen − Women and Children’s Hospital, Chongqing
Medical University, Chongqing 401147, China
Wendan Pu − Department of Pharmaceutics, College of
Pharmacy, Third Military Medical University (Army Medical
University), Chongqing 400038, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscentsci.3c00773

Notes
The authors declare no competing financial interest.

■
REFERENCES
REFERENCES
(1) Yang, J. L.; Peng, M. Y.; Tan, S. C.; Ge, S. C.; Xie, L.; Zhou, T.
H.; Liu, W.; Zhang, K. X.; Zhang, Z. Z.; Liu, J. J.; Shi, J. J. Calcium
Tungstate Microgel Enhancs the Delivery and Colonization of
Probiotics During Colitis Via Intestinal Ecological Niche Occupancy.
ACS Cent. Sci. 2023, DOI: 10.1021/acscentsci.3c00227.
(2) Lee, J.-Y.; Tsolis, R. M.; Bäumler, A. J. The Microbiome and Gut
Homeostasis. Science 2022, 377, No. eabp9960.

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