Prevention and treatment of antibiotics-associated adverse effects through the use of probiotics: A review

Graphical abstract

Highlights

• •Antibiotic-associated side effects: a widespread and multifaceted challenge.
• •Probiotics mitigate antibiotic-related side effects, supported by latest evidence.
• •Probiotic mechanisms against antibiotic-induced side effects are multifaceted.
• •Personalized probiotic approaches tailor to individual needs.
• •Ongoing research is vital for advancing probiotic solutions.

Abstract

Background

The human gut hosts a diverse microbial community, essential for maintaining overall health. However, antibiotics, commonly prescribed for infections, can disrupt this delicate balance, leading to antibiotic-associated diarrhea, inflammatory bowel disease, obesity, and even neurological disorders. Recognizing this, probiotics have emerged as a promising strategy to counteract these adverse effects.

Aim of review

This review aims to offer a comprehensive overview of the latest evidence concerning the utilization of probiotics in managing antibiotic-associated side effects.

Key scientific concepts of review

Probiotics play a crucial role in preserving gut homeostasis, regulating intestinal function and metabolism, and modulating the host immune system. These mechanisms serve to effectively alleviate antibiotic-associated adverse effects and enhance overall well-being.

Introduction

Since Alexander Fleming's groundbreaking discovery of penicillin [1], antibiotics have revolutionized medicine, saving countless lives [2]. These essential therapeutic agents are widely used to treat microbial infections and improve human survival rates [3]. However, recent research on the gut microbiome has highlighted the potential consequences of antibiotic misuse, particularly in exacerbating gut dysbiosis and related diseases [4]. The gut microbiota, comprising trillions of microorganisms crucial for overall health, is highly sensitive to disturbances in its delicate balance [5]. Environmental factors, such as diet and medication, significantly influence the composition of gut microbiota [6]. Antibiotic use, in particular, can lead to profound alterations in the host’s gut microbiota, disrupting the balance and compromising gut homeostasis [7], [8].

Furthermore, antibiotic resistance has emerged as a critical global concern in the 21st century [9]. The irrational use of antibiotics across various sectors, including clinical care, agriculture, animal health, and the food system, has exacerbated this crisis [10], [11], [12], [13], [14]. Global data indicate that deaths attributed to bacterial resistance exceeded 700,000 in 2019, with projections estimating a staggering 20 million deaths by 2050 if effective control measures are not implemented [14]. Sub-Saharan Africa and South Asia currently experience the highest mortality rates globally, primarily due to their large populations, inadequate regulations to combat antibiotic resistance, and insufficient awareness among prescribers and the public regarding the implications of antibiotic resistance [15], [16]. Addressing these challenges is imperative to mitigate the adverse effects of antibiotic use.

Probiotics, defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” [17], exert their positive effects through various mechanisms. They fortify the intestinal mucosa, enhancing gut barrier integrity [18]. Moreover, probiotics foster a balanced microbial environment by selectively nurturing beneficial microbes while inhibiting potentially harmful ones through competitive exclusion [19]. Additionally, they safeguard against infections by producing antimicrobial metabolites, altering toxins or pathogen receptors, and activating specific and non-specific immune responses against pathogens [20]. Well-documented are the beneficial effects of probiotics in restoring balanced gut microbiota during and after antibiotic therapy, thereby mitigating adverse effects like secondary infections and antibiotic-associated diarrhea (AAD) [18].

This review is based on a comprehensive literature search across PubMed and Web of Science databases. Specifically targeting probiotics and antibiotics research in clinical and animal intervention studies, our inclusion criteria encompassed research articles mainly published within the last decade, encompassing both positive and negative findings. To ensure study quality and reliability, incomplete experiments and quasi-randomized designs were excluded. This review summarizes the latest research findings on mechanisms through which probiotics ameliorate adverse effects induced by antibiotic use in humans and animals. In doing so, it advances our understanding of the beneficial impact of probiotics in mitigating the negative consequences of antibiotic therapy.

Classification and evolution of probiotics

Traditional probiotics

Traditional probiotics mainly comprise various strains of lactobacilli and bifidobacteria, commonly isolated from human samples and extensively used to promote human and animal health. Notably, certain probiotic strains have been demonstrated to have an anti-inflammatory activity. A meta-analysis of patients with inflammatory bowel disease revealed that probiotics, prebiotics, and synbiotics can induce and maintain disease remission and lessen symptoms of ulcerative colitis. These interventions were found to increase the population of beneficial bacteria within the gut microbiota [21]. Furthermore, specific strains, such as Lactiplantibacillus plantarum DSM 9843 and Bifidobacterium bifidum MIMBb75, have shown promising results in alleviating symptoms of irritable bowel syndrome [22]. However, the efficacy of probiotics in irritable bowel syndrome still requires further validation through randomized controlled trials, as systematic reviews and meta-analyses have not definitively demonstrated their effectiveness.

Clinical studies have provided compelling evidence that probiotic administration can have beneficial effects in various clinical scenarios. For instance, probiotics reduce the incidence of necrotizing enterocolitis and mortality, and are considered safe for use in combination with human milk [23]. In the specific context of necrotizing colitis, multistrain probiotics have demonstrated greater efficacy than single-strain products, as evidenced by a previous study conducted in a premature rat model [24]. Moreover, in patients with Clostridioides difficile (formerly Clostridium difficile, C. difficile) infection, the use of probiotic capsules containing two strains each of lactobacilli and bifidobacteria, in addition to antibiotic therapy, shorten the duration of diarrhea [25]. Furthermore, probiotics offer benefits to patients with Helicobacter (H.) pylori by alleviating the impact of antibiotics on the gut microbiome and inhibiting the growth of antibiotic-resistant bacteria, thus improving the success rate of H. pylori eradication [26]. The consumption of probiotic drinks containing strains such as Lacticaseibacillus paracasei DN-114001 can reduce the incidence and duration of AAD [27].

Furthermore, a probiotic mixture containing Lactiplantibacillus plantarum CCFM4, Lacticaseibacillus paracasei CCFM5, Lacticaseibacillus rhamnosus CCFM492, and Lactobacillus helveticus CCFM673 can restore the gut microbiome, reduce inflammation, and enhance immune and intestinal barrier function in mice [28]. While existing research suggests the potential of probiotics in regulating the gut microbiome, alleviating intestinal inflammation, and improving conditions associated with antibiotic use (Table 1, Table 2), further large-scale, multicenter, controlled, randomized clinical trials are needed to establish the efficacy of specific probiotics in these contexts.

Table 1.

Probiotic administration alleviates antibiotic-associated adverse effects in humans.

Probiotic strain(s) or product	Dose, intervention duration	Isolation source of probiotic(s)	Subjects	Antibiotic administration	Probiotic intervention outcome	Reference
Actimel® (Lacticaseibacillus paracasei DN-114001)	2 × 1010 CFU/day, 7.3 ± 4.2 days		Patients with antibiotic-associated diarrhea (AAD)	Antibiotic-associated diarrhea (AAD)	Reducing the prevalence of AAD during antibiotic treatment	[27]
Yakult® (Lacticaseibacillus paracasei Shirota)	2 × 1010 CFU/day, 6.0 ± 3.1 days		Patients with AAD	AAD	No observed beneficial effect on AAD	[27]
Bifidobacterium bifidum W23 and Lactobacillus acidophilus W37	109 CFU/day, maximum of 17 days		3 months to 18 years old patients	Broad-spectrum oral or intravenous antibiotic therapy	Reduced risk of diarrhea during and up to 7 days after antibiotic treatment	[58]
Bifidobacterium breve Bb99, Lacticaseibacillus rhamnosus Lc705, Lacticaseibacillus rhamnosus GG, Propionibacterium freundenreichi subsp. shermanii JS	2 × 108 CFU/day for Bifidobacterium breve Bb99, 2 × 109 CFU/day for Propionibacterium freundenreichii subsp. shermanii JS, 5 × 109 CFU/day for Lacticaseibacillus rhamnosus Lc705 and Lacticaseibacillus rhamnosus GG. Pregnant women: from 35 weeks of pregnancy until childbirth. Infants: first 6 months of birth		Infants	Early-life antibiotic treatment	Reverse undesired changes in infant gut microbiota composition and function associated with antibiotic therapy or cesarean section	[59]
Probiotic capsule (Florastor, containing Saccharomyces boulardii CNCMI-745)	500 mg, twice daily, 2 weeks	Peels of tropical fruits, including lychee and mangosteen	18–65 years old healthy volunteers	7 days of amoxicillin and clavulanate, twice daily	Co-administering Saccharomyces boulardii CNCM I-745 and antibiotic mix reduced microbiota changes, including Escherichia overgrowth, and prevented AAD. No observed effect after administering Saccharomyces boulardii CNCM I-745 alone.	[89]
Probiotic yogurt drink (containing Bifidobacterium animalis subsp. lactis BB-12, Lactobacillus acidophilus LA-5)	150 to 200 mL/day containing 1 × 108 CFU/mL of Bifidobacterium animalis subsp. lactis BB-12 and 5 × 106 CFU/mL of Lactobacillus acidophilus La-5, totaling 109 to 1010 CFU of probiotic strains per dose, 48 h after starting antibiotic therapy and up to 5 days after stopping the antibiotic	Breastfed infant feces	Adult patients admitted to the internal medicine and pneumology wards, monitored for 1 month for the occurrence of diarrhea	Amoxicillin-clavulanate or levofloxacin (oral or intravenous)	No significant difference in monitored effects between the probiotic and placebo groups	[152]
Probiotic capsule (Bio-K+, containing Lactobacillus acidophilus CL1285 and Lacticaseibacillus paracasei LBC80R)	One or two probiotic capsules (total 5 × 109 or 1010 CFU) per day for 5 or 21 days after the last antibiotic use	Human	50–70 years old adult hospitalized patients with various infections (n = 255)	Penicillin, cephalosporin, or clindamycin. Hospitalization for 5 days or more, antibiotic treatment for 3 to 14 days	Effectively reduced the risk of AAD and Clostridioides difficile-associated diarrhea	[53]
Probiotic capsule (Lacidofil, containing Lactobacillus helveticus R0052 and Lacticaseibacillus rhamnosus R0011	One probiotic capsule (2 × 108 CFU of Lactobacillus helveticus R0052, 3.8 × 109 CFU of Lacticaseibacillus rhamnosus R0011) per day for 2 weeks		18–50 years old healthy individuals (n = 160)	1-week amoxicillin-clavulanic acid	Probiotics adhered to epithelial cells, enhanced intestinal barrier, inhibited pathogen adhesion, and enhanced anti-inflammatory responses, thereby reducing diarrhea duration	[148]
Probiotic mix (Bio-K+, containing Lactobacillus acidophilus CL1285 and Lacticaseibacillus paracasei LBC80R)	49 g/day for the first two days, 98 g/day for the remaining treatment period	Human	Patients aged 18 years and older, treated in an emergency room or hospital ward	Patients receive at least 3 days and at most 14 days of antibiotic treatment	Efficacious in reducing the incidence and duration of AAD	[149]
Yogurt drink (containing Lacticaseibacillus paracasei DN-114 001, Streptococcus thermophilus, and Lactobacillus bulgaricus	97 mL (108 CFU/mL of Lacticaseibacillus paracasei DN-114 001, 108 CFU/mL of Streptococcus thermophilus, 107 CFU/mL of Lactobacillus bulgaricus), twice daily, 1 week		Hospitalized patients (mean age of 74 years, n = 135)	Patients took one or more antibiotics	Regulated gut microbiota and reduced incidences of AAD and Clostridioides difficile-associated diarrhea	[68]

Table 2.

Probiotic administration alleviates antibiotic-associated adverse effects in animal models.

Probiotic strain(s) or product	Dose, intervention duration	Isolation source of probiotic(s)	Animal model	Antibiotic administration	Probiotic intervention outcome	Reference
Lactiplantibacillus plantarum CCFM4, Lacticaseibacillus paracasei CCFM5, Lacticaseibacillus rhamnosus CCFM492, and Lactobacillus helveticus CCFM673	1 × 109 CFU/mL of lactobacilli cocktail, 0.2 ml per day, 4 weeks	Traditional fermented foods including Chinese pickled cabbage, dairy products, and camel yogurt	4 weeks old male C57BL/6J mice	2 antibiotic doses: 50 mg/kg or 150 mg/kg cefixime, twice daily for 2 weeks	Restoring gut microbiota and short-chain fatty acid levels, alleviation of intestinal inflammation	[28]
Faecalibacterium prausnitzii	Daily dose of 6 × log10 CFU/10 µL + potato starch (20 % w/v, 20 µL), 5 days	Healthy human feces	8–10 weeks old female CF-1 mice	3 daily subcutaneous injections of clindamycin	Co-administering Faecalibacterium prausnitzii and prebiotic minimized pathogen load and mitigated negative effects during antibiotic exposure	[83]
Lacticaseibacillus rhamnosus Probio-M9	5 × 109 CFU/day, 2 weeks	Human colostrum	6–8 weeks old BALB/c mice, tumor transplantation model	Antibiotic cocktail, comprising ampicillin metronidazole, neomycin, and vancomycin	Partial restoration of antibiotic-disrupted gut microbiota, improved responsiveness to immune checkpoint inhibitor treatment against tumor growth	[87]
Lacticaseibacillus rhamnosus GG	106 CFU/day, 1 week	Healthy human adult feces	6–8 weeks old C57BL/6 mice	7 days of metronidazole, neomycin sulfate, and vancomycin, administered in drinking water	Shortened duration and severity of antibiotic-associated diarrhea. Co-administration of Lacticaseibacillus rhamnosus GG and tributyrin prevented antibiotic-induced downregulation of genes and proteins involved in intestinal fluid and electrolyte homeostasis and intestinal barrier function	[115]
Bifidobacterium fragilis ZY-312	107, 108, and 109 CFU/day, 4 or 7 days	Healthy breastfed infant feces	230–250 g Sprague-Dawley rats	Daily gavage of antibiotic mixture, comprising clindamycin, ampicillin, and streptomycin at various doses	Ameliorated gastrointestinal symptoms of antibiotic-associated diarrhea and gut dysbiosis, restoring epithelial cell organization and barrier function. The beneficial effect was partly mediated through ERK signaling	[55]
Probiotic cocktail (JUP-Y4), comprising Lactiplantibacillus plantarum CCFM2602, Lacticaseibacillus paracasei CCFM2710, Lacticaseibacillus rhamnosus CCFM492, Lactobacillus helveticus CCFM671	2 × 109 CFU/day, 4 weeks	Lactiplantibacillus plantarum CCFM2602 and Lacticaseibacillus paracasei CCFM2710 isolated from a yogurt-like dairy product from Inner Mongolia, Lacticaseibacillus rhamnosus CCFM492 from pickled Chinese cabbage, Lactobacillus helveticus CCFM671 from fermented camel milk from Xinjiang	4 weeks old male C57BL/6J mice	14-day oral gavage of ampicillin, twice daily	Restored gut microbiota structure, enhanced microbial diversity, and reduced ampicillin-associated intestinal inflammation	[3]
Bacillus amyloliquefaciens TL106	5 × 109 CFU/kg, 2 weeks	Tibetan pig	28 days old piglets	14-day oxytetracycline calcium, added to the ration	Significantly reduced diarrhea of weaned piglets, effectively enhanced immunity, and improved gut microbiota stability	[126]
Lacticaseibacillus rhamnosus JB-1	1 × 109 CFU/day, given in drinking water until postnatal day 21		6–8 weeks old pregnant BALB/c mice	Penicillin V, administered until weaning of pups (postnatal day 21)	Reversed antibiotic-induced anxiety, impaired social behavior, and aggressive behavior, possibly due to reshaping gut microbiota through enhanced short-chain fatty acid secretion and gut lumen pH modulation	[82]
Limosilactobacillus reuteri ATCC PTA6475	3.3 × 108 CFU/mL in drinking water, 4 weeks		11 weeks old male BALB/c mice	2-week ampicillin and neomycin	Promoted bone formation, modulated gut microbiota composition and function	[84]

Next-generation probiotics

Advancements in cultivation techniques, genome and metagenome sequencing, and bacterial genome editing tools have ushered in a new era of probiotic research. These breakthroughs enable the development of customized probiotics tailored to individual consumer needs. Moreover, the expanding knowledge of the human gut microbiome, facilitated by parallel sequencing technologies, has widened the pool of organisms showing promise for health-promoting effects. While many of these organisms are still in the early stages of exploration, they hold significant potential to enhance our understanding of probiotics and their potential benefits. Referred to as next-generation probiotics, they fall within the category of living biological therapeutic products defined by the United States Food and Drug Administration as medicinal products: (1) containing live organisms, such as bacteria; (2) applicable to the prevention, treatment, or cure of diseases or human medical conditions; and (3) not vaccines [29], [30].

Some gut-derived species, including Fecalibacterium prausnitzii, Akkermansia (A.) muciniphila, and Bacteroides fragilis, are typically regarded as emerging next-generation probiotics [31]. Current research in this field focuses on harnessing specific bacteria to restore or enhance microbiota-mediated colonization resistance after antibiotic treatment, aiming to reduce the incidence of pathogenic infections, particularly those caused by antibiotic-resistant bacteria [32]. One promising example is Fecalibacterium prausnitzii, which reduces chemically induced colitis in rats by modulating the differentiation of inflammatory and tolerogenic T cells, altering the cytokine profile, and increasing the number of regulatory T cells in peripheral blood cells and the spleen [33]. Another example is the Bacteroides fragilis HCK-B3 strain, which maintains gut microbial diversity, regulates cytokine production, and restores the balance between regulatory T cells and Th-17 cells in a colitis rat model [34]. A. muciniphila DSM 22959 is another notable bacterium resistant to certain clinically important antibiotics but lacking acquired resistance mechanisms. Its safety profile is enhanced due to the lower risk of drug resistance transfer, and it has demonstrated positive outcomes when administered in various metabolic conditions [35]. These examples show the promising potential of specific next-generation probiotics to restore or enhance colonization resistance, regulate immune responses, and combat pathogenic infections. Further research is necessary to fully elucidate their mechanisms of action and assess their efficacy in clinical settings.

Despite the potential therapeutic effects of these next-generation probiotics, it is important to consider their possible negative effects. For example, enterotoxigenic Bacteroides fragilis induces colitis in wild-type C57BL/6 mice and promotes oncogenic transformation in APC^Min/+ mice. This widely used animal model effectively duplicates human familial adenomatous polyposis and colorectal tumors [36]. Repeated oral administration of A. muciniphila results in colitis exacerbation in mice and promoted colitis in genetically susceptible hosts [37]. The presence of A. muciniphila is associated with exacerbation of intestinal inflammation caused by Salmonella Typhimurium infection [38]. Although these next-generation probiotics have good potential for medical applications, particularly in AAD, more comprehensive studies are required to confirm their beneficial effects, mechanisms, and environmental-ecological impacts.

Engineered bacteria

Bacterial engineering, a field involving the artificial alteration of bacteria biology, offers promising avenues for novel treatment approaches, known as therapeutic engineering. This field holds immense potential, as demonstrated by various studies. For instance, Escherichia coli genomes have been modified using synthetic biology techniques to enable quorum sensing and the production of pyocin, a metabolite capable of killing pathogenic Pseudomonas aeruginosa [39]. In another study, the genome of Escherichia coli strain Nissle1917 was modified to enhance its anti-biofilm properties, leading to efficacy in both preventing and treating infections in animal models [40]. Genetically modified bacteria are designed to directly or indirectly combat pathogens. In the case of C. difficile infection (CDI), most strains produce two major toxins, TcdA and TcdB. To address this, two probiotic strains, Lacticaseibacillus paracasei BL23 and Lactococcus lactis ATCC11454, were engineered to express TcdB-neutralizing antibodies and non-toxic fragments of Tcd-AC and Tcd-BC, respectively. These modifications enabled the genetically engineered bacteria to alleviate inflammation and reduce morbidity and mortality in mouse models of CDI [41], [42]. Furthermore, a vaccine was developed using a membrane fraction of C. difficile JND13-023, showing the ability to reduce pathogen load and mortality in C. difficile-infected mice [43]. These examples underscore the potential of bacterial engineering in therapeutic applications. Genetically modified bacteria can be designed to possess specific properties that enable them to combat pathogens, prevent biofilm formation, and deliver targeted therapies. Continued research in this field promises to provide further insights into the development of innovative treatments and prevention strategies against a wide range of infections and diseases.

While engineered bacteria offer substantial potential for research applications, their implementation raises notable uncertainties and challenges. The development of SYNB1020, an engineered probiotic strain by Synlogic Inc., exemplifies this complexity. Designed to convert ammonia into L-arginine for treating cirrhosis and hyperammonemia, SYNB1020 did not effectively reduce blood ammonia levels in a phase 1b/2a clinical trial, leading to the discontinuation of its development for hyperammonemia treatment [44], [45].

Genetically modified probiotics carry potential risks, including the production of modified proteins, peptides, nucleic acids, and other bioactive molecules that may adversely affect human health. These molecules can disrupt human cell metabolic pathways, trigger aberrant gene expression, or promote the synthesis of biologically active and harmful compounds [46]. Upon entering the human body, they can cause a range of health issues, including autoimmune disorders, inflammation, inflammatory bowel disease, obesity, and carcinogenesis [47]. Additionally, there is a risk of horizontal gene transfer of foreign genes and mobile genetic elements within the human microbiota, posing further health risks [48].

The use of engineered bacteria for bioremediation purposes also raises environmental concerns. Genetic exchange between engineered bacteria and naturally existing microorganisms can disturb ecological equilibrium [49]. Singh et al. (2011) highlighted challenges related to deploying engineered bacteria, emphasizing the significant risks associated with releasing genetically modified organisms into field conditions and recommending comprehensive molecular genetic studies to address these risks [50].

In brief, while engineered bacteria hold promise in healthcare and environmental cleanup through their unique genetic modifications, their potential adverse effects on living systems, the environment, and aquatic ecosystems must be acknowledged and addressed. Concerns about harmful molecules and undesired gene exchange underscore the need for rigorous safety assessment. Only with confirmed efficacy and safety can we fully leverage the potential of engineered bacteria for positive contributions to human health and environmental conservation. Alternatively, the human gut microbiota, with its over 100 trillion bacteria and microorganisms, represents a naturally available resource of genetic, metabolic, and functional potentials. The natural human gut microbiota represents a valuable and potentially safer alternative to the introduction of genetically modified strains, which may carry unforeseen risks in the future.

Probiotics in alleviating adverse effects associated with antibiotic use

Probiotics in AAD

Diarrhea is a prevalent side effect of antibiotic use, affecting 5 %–39 % of patients undergoing antibiotic therapy. Alarmingly, these symptoms can persist for up to two months after treatment completion [51]. While AAD can occur across all age groups, children typically experience faster onset and shorter duration of symptoms compared to adults. Hospitalized patients face a higher risk of developing AAD than those receiving outpatient treatment [52]. In a population-based trial involving hospitalized patients, administration of the probiotic product Bio-K + CL1285 resulted in a reduction in AAD duration compared to the placebo group [53]. This underscores the potential of probiotics as a protective measure against AAD when administered concurrently with or following antibiotic therapy. Moreover, Lactobacillus acidophilus, or its soluble factors present in the culture supernatant, were found to stimulate Cl-/HCO₃^– and Na⁺/H⁺ exchange activities. This stimulation primarily occurs through the modulation of the expression and functionality of DRA (downregulated in adenoma Cl⁻/HCO₃⁻ exchanger) and NHE3 (the Na⁺/H⁺ exchanger 3), facilitating water absorption in the intestinal epithelium and contributing to diarrhea cessation [54]. Additionally, the Bacteroides fragilis strain ZY-312 restored Aqp1 expression in rats with AAD and elevated the expression levels of Aqp3 and Aqp8, crucial for water movement and absorption in the colon [55].

Probiotics exert their beneficial effects by promoting and restoring the delicate balance of gut microecology through various mechanisms, including competition for nutrients and receptors with pathogens and the production of antimicrobial substances inhibiting harmful bacteria growth while enhancing the host's immune response (Fig. 1) [56].

Fig. 1.

Diverse mechanisms of probiotics in promoting host health. a. Probiotics possess the capability to suppress the proliferation of pathogenic bacteria within the gut, thereby preserving and fostering a balanced and resilient intestinal microecological environment. b. Probiotics augment NaCl transport via ion exchanges, namely DRA (the down-regulated in adenoma Cl−/HCO3− exchanger) and NHE3 (the Na+/H+ exchanger 3), promoting water absorption through aquaporins, particularly by upregulating Aqp1, Aqp3, and Aqp8. They also secrete organic acids, fostering an environment conducive to short-chain fatty acid (SCFA) production, which further facilitates NaCl and water absorption in the gut. SCFAs additionally reinforce intestinal barrier integrity by modulating MUC2 intestinal mucin expression. Concurrently, the probiotic cell wall component, lipoteichoic acid, activates TLR2/p38-MAPK pathways, enhancing MUC2 levels, and suppressing NF-κB, thus mitigating intestinal inflammation. c. Probiotics initiate the phosphorylation of the epidermal growth factor (EGF) receptor (EGFR), subsequently activating the MAPK pathway, thereby promoting the growth, proliferation, and survival of intestinal epithelial cells. d. Through metabolic activities and the secretion of organic acids, probiotics reduce the pH and oxygen levels within the gastrointestinal environment, thereby establishing conditions conducive to their proliferation. Additionally, probiotics release extracellular serine proteases that more efficiently degrade C. difficile toxins (TcdA and TcdB) under acidic conditions, simultaneously preventing these toxins from attaching to and harming intestinal cell receptors. e. The proliferation of probiotics in the gastrointestinal tract facilitates the breakdown of undigested carbohydrates, thereby mitigating diarrhea risk associated with osmotic pressure imbalances. f. Probiotics effectively catalyze the transformation of primary bile acids into secondary bile acids and the deconjugation of bile acids and uncoupling of bile acids, mediated by bile salt hydrolases. This process elevates the levels of unconjugated bile acids and potentially diminishes inflammation in individuals with hypercholesterolemia.

A study in rats demonstrated that Bacteroides fragilis ZY-312 administration effectively mitigated AAD induced by clindamycin, streptomycin, and ampicillin, associated with a decrease in Escherichia (a potentially harmful bacterial genus) and an increase in beneficial bacteria [55]. Probiotics, alone or in combination, have shown efficacy in preventing AAD and enhancing overall treatment efficacy [57]. For example, administering a multistrain probiotic product containing eight strains, including Bifidobacterium bifidum W23 and Lactobacillus acidophilus W37, during antibiotic therapy reduced AAD risk in children and adolescents aged 3 months to 18 years [58]. Supplementation with a probiotic mixture consisting of Bifidobacterium breve Bb99, Lacticaseibacillus rhamnosus Lc705, Lacticaseibacillus rhamnosus GG, and Propionibacterium freundenreichi subsp. shermanii JS modulates the gut microbiota of breastfed infants, reducing AAD risk by increasing beneficial bifidobacteria and reversing antibiotic-induced increases in Bacteroidaceae, Enterococcaceae, and Enterobacteriaceae, thus affecting the gut microbiota of breastfed infants and reducing the risk of AAD [59]. While these studies generally demonstrate the beneficial effect of probiotics in preventing AAD, clinical efficacy appears to depend on various factors, including age, nutritional status, diet, stability and composition of the gut microbiota, pre-existing chronic diseases, frailty, place of residence, and elderly care facilities [60]. Further research is needed to understand the exact mechanisms by which antibiotics cause diarrhea and how probiotics counteract AAD. In addition, the use of probiotics as an adjunct to antibiotic therapy has limitations, such as varying individual responses due to different host factors and the need for long-term administration.

Probiotics in CDI

The anaerobic toxin-producing bacterium, C. difficile, is the causative agent of C. difficile-associated diarrhea (CDAD) [61]. One-third of the incidence of AAD is CDAD, and it is more common in older adults [62]. Currently, macrolides are utilized as antibiotic therapy for mild CDAD cases [63], with relapses being common after antibiotic treatment [64]. Numerous trials have demonstrated that probiotic supplementation significantly reduces CDAD risk with minimal short-term side effects [65], [66]. For instance, two probiotic strains, Bifidobacterium longum IPLA20022 and Bifidobacterium breve IPLA20006, have shown efficacy in suppressing C. difficile growth and reducing toxin levels [67]. Another study investigated the effectiveness of a probiotic drink containing three probiotic strains in preventing CDAD resulting from antibiotic use, with no reported adverse effects [68]. Additionally, probiotic capsule consumption, containing Lactobacillus acidophilus, Lacticaseibacillus paracasei, and Bifidobacterium animalis ssp. lactis, significantly reduced CDAD duration [25].

In patients with CDI, antibiotic treatment such as vancomycin or metronidazole often leads to a reduction in the Bacteroides genus in the gut microbiota. Intake of a multistrain probiotic formulation, comprising Lactobacillus acidophilus NCFM, Lacticaseibacillus paracasei Lpc-37, and Bifidobacterium animalis ssp. lactis B1-04, Bi-07, may help mitigate antibiotic-induced gut microbiota changes, including Bacteroides reduction [69]. Certain probiotic strains secrete extracellular serine proteases that effectively neutralize C. difficile toxins by degrading them, thus blocking their ability to bind to receptors and inhibit protein synthesis via TcdA and TcdB. This action significantly diminishes the cellular damage caused by these toxins, highlighting the therapeutic potential of these probiotics in combating infections [70], [71].

Although probiotics may help alleviate symptoms, they cannot eliminate the harmful effects of CDI [72]. Large-scale randomized controlled trials are needed to establish clinical treatment guidelines and protocols for probiotic use as adjunctive therapy for CDI. These studies will provide further insights into the potential of probiotics in managing this challenging condition.

Probiotics in the spread of antibiotic resistance

The clinical importance of antibiotics in treating bacterial infections is undeniable; however, overuse or misuse of antibiotics can lead to the development and spread of drug tolerance or even antibiotic resistance genes (ARGs) and bacteria [73]. In some instances, initially susceptible bacteria can evolve into antibiotic-resistant strains through the selection or activation of ARGs [74]. To mitigate the risk of antibiotic resistance emergence and dissemination, new therapeutic approaches are necessary. Probiotics have demonstrated the potential in reducing antibiotic resistance, but a deeper understanding of the transmission and mechanisms of ARGs in probiotics is essential [75]. The escalating use of probiotics in sustainable aquaculture practices [76] raises concerns about the environmental dissemination of ARGs, necessitating close monitoring and risk assessment.

Many lactobacilli do not tend to transfer resistance genes [77]. For instance, prolonged exposure of Lactiplantibacillus plantarum P-8 to antibiotics does not result in the acquisition of typical ARGs associated with ampicillin tolerance. Instead, the increased resistance is linked to the overexpression of stress-related proteins, such as the small heat shock protein, ATP-dependent Clp protease/ATP-binding subunit ClpL, and a hypothetical protein (Fig. 2) [78], indicating that the use of probiotics as an adjunct to antibiotic therapy is less likely to cause the development of “evolved” probiotics harboring novel antibiotic-resistance traits. In fact, probiotics offer various health-promoting effects, including enhancing host immunity, restoring colonic microbiota and homeostasis, promoting beneficial gut microbiota, and suppressing potential pathogens, which can contribute to reducing antibiotic dependence or dosage. Thus, the combined use of probiotics and antibiotics can decrease selection pressure and minimize the risk of antibiotic resistance development and spread. A randomized controlled trial conducted on patients positive for vancomycin-resistant Enterococcus faecium showed that the administration of Lacticaseibacillus rhamnosus GG resulted in a reduced prevalence of vancomycin-resistant enterococci in the gut [79]. This finding underscores the potential of clinical probiotic therapy in curbing the spread of antibiotic resistance.

Fig. 2.

The molecular mechanism of Lactiplantibacillus plantarum P-8 in ampicillin adaptation. Ampicillin is an irreversible inhibitor of transpeptidase, a key enzyme required for cell wall assembly. This inhibition suppresses bacterial growth. Ampicillin resistance is achieved via regulating bacterial transpeptidases, such as penicillin-binding protein (PBP). Under ampicillin stress, the growth of Lactiplantibacillus plantarum is altered, accompanied by changes in the expression of specific proteins, including the increase in key proteins encoded by fatty acid biosynthesis operon, such as an acyl-coenzyme A (CoA) thioester hydrolase (LBP_cg1294). In the process of fatty acid biosynthesis, acyl-CoA thioester hydrolase catalyzes the hydrolysis of acyl-CoAs to free fatty acid and CoA. Moreover, inactivating the ATP binding subunit ClpL (LBP_cg2905) of the ATP-dependent Clp protease results in an apparent reversal of the ampicillin-resistant phenotype, suggesting that this protein plays a role in protecting bacterial cells from external ampicillin.

Future research is imperative for understanding the optimal use of probiotic therapy in clinical settings to prevent antibiotic resistance, thus aiding in the development of evidence-based guidelines.

Probiotic mechanisms to attenuate antibiotic-associated adverse effects

• 1.Prevention of antibiotic-induced dysbiosis

A healthy individual's gut harbors a diverse array of microorganisms, including bacteria, viruses, fungi, protozoa, and archaea, totaling over 100 trillion in number [80]. However, antibiotic therapy can significantly disrupt the gut microbiota (Fig. 3). For instance, Arslanova et al. (2019) demonstrated that administering antibiotics to mice led to a substantial reduction in the ratio between thick-walled Bacillota and Bacteroidota (formerly Firmicutes: Bacteroidetes) in the gastrointestinal tract, indicating gut dysbiosis [81]. Nevertheless, co-administering probiotics and antibiotics to mice reduced the abundance of several bacterial families in the colon, including phyla Proteobacteria and Deferribacteres, suggesting that this approach may help maintain a relatively balanced gut bacterial community. Lacticaseibacillus rhamnosus JB-1 mitigates dysbiosis associated with penicillin administration in early-life stage mice [82]. De Wolfe et al. (2018) demonstrated that co-administering probiotics with antibiotics improved symptoms of CDI [69]. Similarly, a study suggests that combining Fecalibacterium prausnitzii with prebiotics can reduce the impact of negative bacteria during exposure to C. difficile [83], although further research is required to elucidate the underlying mechanisms. Along with a direct effect on intestinal permeability, gut dysbiosis can also affect bone health. Antibiotic use disrupts the microbiota, but intervention with Limosilactobacillus reuteri 6475 reduces the increase in the ratio of Bacillota to Bacteroidota, which is associated with the protection against femoral and vertebral trabecular bone reduction [84].

Fig. 3.

Effects of different antibiotics on gut microbiota and immune function. This figure illustrates the diverse effects of various antibiotics on the gut microbiota equilibrium, attributed to their distinct modes of action. Some antibiotic classes have shown profound effects on the host immune response. For example, glycopeptide antibiotics have been shown to diminish IFN-γ, TNF-α, and IL-22 levels, whereas beta-lactam antibiotics regulate the expression of IFN-γ, NF-κB, MCP-1, RegIIIγ, and sIgA. Lincomycin has been found to modulate IFN-γ, TNF-α, IL-6, and IL-17 levels. Furthermore, antibiotic administration reduces the intestinal concentrations of colonic short-chain fatty acids (SCFAs) and compromises intestinal barrier integrity, resulting in reduced expression of tight junction proteins like claudin, occludin, and ZO-1. IFN-γ = interferon-gamma, TNF-α = tumor necrosis factor-alpha, IL = interleukin, NF-κB = nuclear factor-kappa B, MCP-1 = monocyte chemoattractant protein-1, RegIIIγ = regenerating islet-derived protein 3 gamma, and sIgA = secretory immunoglobulin A.

When using antibiotics, it is important to consider their potential impact on intestinal health. The gut microbiota, with its diverse and balanced community of microorganisms, plays a crucial role in maintaining the overall health of the host. Probiotics can help restore and preserve gut homeostasis through their intervention. Therefore, implementing strategies like the co-administration of probiotics and antibiotics is necessary for preventing gut dysbiosis and maintaining optimal intestinal health.

• 2.Restoring a healthy gut microbiota

Chronic diseases pose a significant global health challenge, often influenced by diet and medication. The gut microbiota plays a critical role in health and disease [85], and unfavorable changes in its composition can exacerbate symptoms. Maintaining a healthy gut microbiota is crucial for overall well-being, as it provides numerous beneficial functions such as efficient energy acquisition, protection against pathogen invasion, and enhanced immune responses [86]. The links between chronic diseases, diet, medication, and gut microbiota are well-established. Therefore, prioritizing the restoration and maintenance of a healthy gut microbiota is essential to harness its positive contributions and support overall health while mitigating the risk and progression of chronic diseases. In a study involving mice, treatment with ampicillin reduced microbial diversity in the gut, leading to a dominance of Proteus. Antibiotic use resulted in intestinal inflammation and increased intestinal permeability. However, administration of a mixture of probiotic lactobacilli (JUP-Y4) restored the structure and diversity of the fecal and cecal microbiota, with a more pronounced effect observed in the cecal samples [3]. Another study administering cefixime to mice showed a decrease in beneficial bacteria such as bifidobacteria and lactobacilli, while opportunistic pathogens like Enterococcus and Pseudomonas increased. However, treatment with potential probiotic lactobacilli cocktails, especially those composed of strains capable of utilizing fructooligosaccharides, reversed these changes, restoring the gut microbiota almost to its original state. Interestingly, the use of fructooligosaccharides alone had minimal effect on the gut microbiota [28]. Additionally, a previous study in mice reported a growth-stimulatory effect after the intake of Lacticaseibacillus rhamnosus Probio-M9, beneficial bacteria, such as Bifidobacterium pseudolongum and some Bacillus spp. increased in comparative abundance in antibiotic-treated mice with tumors [87].

In a human intervention study, patients with H. pylori were divided into two groups: one received standard triple therapy, and the other received the same therapy along with probiotics for 6 weeks. The results revealed that the probiotic recipients had a gut microbiota profile similar to that of healthy individuals, while the group receiving only antibiotics showed a decrease in gut microbiota diversity. However, the administration of Bacillus subtilis was found to reduce the abundance of undesired bacteria and fungi without significant alleviation of the diarrhea caused by H. pylori or the infection itself [88]. Another study explored the effects of Saccharomyces boulardii CNCMI-745 administration during augmentin treatment. The findings suggested that this probiotic could attenuate gut dysbiosis and Escherichia coli overgrowth, while also reducing the intestinal levels of Parabacteroides [89]. Additionally, antibiotic use may delay the restoration of a healthy gut microbiota, but autologous fecal microbiome transplantation has shown promise in effectively alleviating this situation [90]. Further research is necessary to fully understand the effects of probiotics on gut microbiota recovery following antibiotic treatment.

Regulation of nutrient metabolism

Probiotics play a crucial role in mitigating the negative effects of antibiotics by regulating the metabolism of vital nutrients, such as short-chain fatty acids (SCFAs), bile acids, and glucose. These nutrients are essential for the proper functioning of the gut microbiota and the overall health of the body.

• 1.Metabolism of SCFAs

The production of SCFAs in the gut is influenced by various factors, including host, environmental, nutritional, and microbial factors. On average, the gut microbiota produces 500 to 600 mmol of SCFAs daily [91], with acetate, propionate, and butyrate being the most abundant [92]. SCFAs play a vital role in maintaining the functions of the gut and other tissues and organs [93].

Antibiotic-associated dysbiosis can significantly impact the production and metabolism of SCFAs, thus affecting overall health. For instance, the administration of vancomycin and ciprofloxacin-metronidazole in mice resulted in reduced intestinal levels of acetic, butyric, and propionic acids [94]. The intake of probiotics, such as Lacticaseibacillus paracasei Zhang, can promote the growth of SCFA-producing bacteria in the human gut [95]. In an in-vitro intestinal model, a probiotic mixture containing Lactobacillus acidophilus NCIMB 30175, Lactiplantibacillus plantarum NCIMB 30173, Lacticaseibacillus rhamnosus NCIMB 30174, and Enterococcus faecalis NCIMB 30176 increases lactate concentration, which is then converted to SCFAs [96]. Similarly, probiotic cocktails can help avoid the decrease in gut microbiota diversity and SCFAs caused by antibiotics like cefixime in mice [28]. The underlying mechanism may include the promotion of butyrate-producing bacteria and subsequent butyrate production. Furthermore, Lactobacillus acidophilus and Lactobacillus gasseri increase glucose transport in Caco-2 intestinal cells by producing SCFAs and polyamines [97]. Low biosynthesis of SCFAs causes AAD, and SCFA synthesis promotes intestinal absorption of NaCl and water (Fig. 1) [98]. Furthermore, probiotics increase the content of SCFAs in the colon by producing organic acids, such as lactic and acetic acids, or by creating a favorable environment for SCFA-producing bacteria. In short, probiotics can alleviate the negative effects of antibiotics by regulating SCFA metabolism (Fig. 4).

• 2.Metabolism of bile acids

Fig. 4.

Mechanisms by which probiotics restore antibiotic-disrupted intestinal barrier. Antibiotic treatment can disrupt the balance of the intestinal microbiota, leading to pathogen overgrowth and damage to the intestinal barrier. Firstly, probiotics can restore gut homeostasis and inhibit the growth of potential pathogens by regulating the intestinal microbial community. Secondly, probiotics promote the conversion of primary bile acids into secondary bile acids by regulating the gut microbiota composition. This, in turn, enhances immune homeostasis and intestinal barrier function. Antibiotic treatment can heighten inflammation by altering cytokine and chemokine levels, such as interleukin (IL)-4, IL-13, IL-12, IL-6, monocyte chemoattractant protein-1 (MCP-1), interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and immunoglobulins, but probiotic administration can reverse these changes. The anti-inflammatory effect is also attributed to the presence of short-chain fatty acids (SCFAs), especially butyrate, which can be enhanced by probiotic intake through microbial metabolism. Meanwhile, SCFAs can stimulate the production of glucagon-like peptide-1 (GLP-1), promoting insulin secretion and maintaining stable blood glucose levels. Probiotics may upregulate tight junction proteins, such as occludin, claudin, and ZO-1, as well as other adhesion proteins, subsequently enhancing epithelial cell proliferation and intestinal barrier function.

Bile acids, synthesized in the liver from cholesterol, serve as vital signaling metabolites for the gut microbiota [99]. The gut microbiota significantly influences the composition, metabolism, and function of bile acids [100]. Microorganisms in the gut can convert primary bile acids into secondary bile acids, crucial for lipid digestion and absorption in the small intestine [101], [102]. However, administration of antibiotics can diminish the production of secondary bile acids by inhibiting the growth of microorganisms responsible for their formation [103].

Certain probiotic lactobacilli, bifidobacteria, and clostridia possess bile acid hydrolases capable of directly breaking down bile acids into secondary and tertiary forms [104]. These genes encoding bile acid hydrolases are often found in lactobacilli species associated with vertebrates. By promoting this metabolic pathway, probiotics enhance the secretion of secondary bile acids, thus improving nutrient absorption in the body. Furthermore, the gut microbiota plays a role in regulating the signaling of the farnesoid X receptor, a transcription factor governing bile acid synthesis, presenting a potential treatment avenue for metabolic diseases [105].

Some probiotics also demonstrate antibacterial properties against various foodborne pathogens through bile acid deconjugation. While promising, the physiological role of this action remains controversial within the scientific community, warranting further research to elucidate underlying processes and validate the efficacy of these probiotic actions (Fig. 1) [106], [107]. Probiotics can thus modulate bile acid composition and enhance lipid metabolism, particularly during antibiotic treatment (Fig. 4).

• 3.Glucose and energy metabolism

Antibiotics can adversely affect both gut microbiota and glucose and lipid metabolism, increasing the risk of obesity and dysbiosis, especially in children [108]. Conversely, probiotics and prebiotics offer promise in mitigating these effects and improving metabolic health [109]. The JAK/STAT pathway, regulating metabolism, can be influenced by SCFAs produced by the gut microbiota. This interference may result in increased colonic energy absorption and adipogenesis, contributing to various metabolic disorders, including obesity [110]. A previous study showcased that Lacticaseibacillus paracasei could alleviate chronic enteritis in mice by modulating the STAT-3 signaling pathway [111]. Thus, targeted treatments focusing on the JAK/STAT pathway hold the potential for managing metabolic disorders [112].

Regulation of the intestinal barrier

Antibiotic therapy has multifaceted effects on the intestinal barrier [113]. The intestinal epithelium serves as a critical interface between the gut and host tissues, acting as a physical barrier against pathogen invasion into the vascular system [114]. Typically, antibiotic treatment suppresses the growth of butyrate-producing bacteria, resulting in reduced butyrate concentration in the colon. An immunofluorescence labeling study demonstrated that antibiotic-treated mice exhibited significantly decreased levels of tight junction proteins, such as ZO-1 and occludin. However, this effect was reversed with the administration of Lactobacillus GG and tributyrin [115].

Epithelial cell adhesion molecules play pivotal roles in reinforcing intestinal tight junctions. In a mouse study, the administration of Limosilactobacillus reuteri SLZX19-12 for 14 days notably increased the gene expression of epithelial cell adhesion molecules compared to the control group [116]. Moreover, in a rat study, AAD was linked to evident physical damage to the intestinal mucosal barrier and epithelial structure, characterized by a decrease in mucus-filled goblet cells and abnormal tight junctions. Yet, high doses of Bacteroides fragilis ZY-312 administration restored the integrity of the intestinal mucosal barrier. This restoration was marked by increased expression and protein levels of tight junction proteins (ZO-1 and occludin), enhanced mucin synthesis, and augmented proliferation of epithelial cells, thereby alleviating physical damage in the colon and associated clinical symptoms [55].

Administration of other probiotics, such as Ligilactobacillus salivarius ZLP-4b, Lactiplantibacillus plantarum FBL-3a, and Bacillus velezensis JT3-1, also enhances the mucosal barrier in the ileum and colon tissues. These probiotics increased villus heights and ratios of villi heights to crypt depths [117]. Furthermore, outer membrane proteins synthesized by A. muciniphila have been found to improve intestinal barrier function [118]. The mechanisms through which probiotics restore the gut barrier are depicted in Fig. 1 and Fig. 4.

• 1.Innate immunity

Our intestinal immune system primarily comprises intestinal Our intestinal immune system primarily comprises intestinal epithelial cells and innate immune cells. The intestinal epithelium is composed of epithelial cells, Paneth cells, and goblet cells. Innate immune cells include macrophages, dendritic cells, natural killer cells, and innate lymphoid cells [119].

Antibiotic ingestion may impair the respiratory activity and phagocytosis of immune cells, indirectly affecting the composition of the gut microbiota, which, in turn, regulates intestinal immunity [113]. Certain probiotics can modulate the body's immune function. For instance, the administration of a complex lactobacilli product (Jup-Y4) to ampicillin-treated mice resulted in lower levels of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, monocyte chemoattractant protein-1, and interferon-γ (IFN-γ), compared to the natural recovery group without probiotic intervention (Fig. 4) [3]. Additionally, microorganisms influence the development of the innate immune system of the intestinal in early life [119]. For example, administering the Lacticaseibacillus rhamnosus GG-derived protein p40 to mice promoted proliferation, differentiation, and formation of tight junctions in mouse intestinal epithelial cells. Moreover, p40 increased immunoglobulin (Ig)A production through the epidermal growth factor receptor signaling pathway, thereby regulating the mechanisms of functional maturation of intestinal innate immunity [120]. Furthermore, the pilus adhesin SpaC of Lacticaseibacillus rhamnosus GG can bind to the immature intestinal epithelium and directly regulate the expression of innate immune system genes in intestinal epithelial cells [121].

• 2.Adaptive immunity

Certain antibiotics, like vancomycin, can impact specific bacteria involved in T-cell maturation, leading to a notable reduction in regulatory T cells [122]. Furthermore, the previous intestinal bacterial cluster known as Cytophaga-Flexibacter-Bacteroides, which is now recognized as the Bacteroidota phylum, has been found to be associated with Th17 cells in mice [123]. Numerous studies have underscored the detrimental effects of antibiotic ingestion on immune responses. In human subjects with low pre-existing antibody titers, antibiotics have been shown to impair vaccine responses, alter the structure of the colonic bacterial community, inhibit CD8⁺ T cells during viral infections, and diminish CD4⁺ T lymphocyte and IFN-γ production [124], [125]. Weaning stress can elevate serum inflammatory factors while decreasing immunoglobulins (IgA, IgG, and IgM), particularly IgG. Nevertheless, the administration of Bacillus amyloliquefaciens TL106 can reverse these effects (Fig. 4) [126].

In a study involving influenza patients, individuals with low infection titers displayed a diminished immune response and reduced levels of IgG, IgA, and secondary bile acids following antibiotic therapy [124]. Certain probiotics can modulate host immunity by influencing the composition of the intestinal microbiota, which in turn regulates various T-cell subsets [127]. Moreover, administering probiotics to antibiotic-treated mice enhances the tumor-inhibitory effect of immune checkpoint blockers in carcinoma in situ and ectopic carcinoma [87].

Regulation of the nervous system by the gut-brain axis

The bidirectional communication between the brain and the gut microbiome is an evolving area of research, necessitating further studies to comprehensively understand the impact of probiotics on brain functions [128]. This association between the gut microbiota and the brain can influence brain functions because certain members of the gut microbiota, such as bifidobacteria and lactobacilli, can impact the synthesis and metabolism of neurotransmitters and neuroactive metabolites, such as gamma-aminobutyric acid (GABA) [129]. Although the blood–brain barrier restricts the direct effect of gut-derived neurotransmitters on the brain [130], GABA transporters present in the blood–brain barrier can facilitate GABA access to the central nervous system [131]. Administering probiotics can improve the GABA synthesis pathway in the gut. For instance, ingestion of Lacticaseibacillus rhamnosus alleviates anxiety and depression in mice through a vagus-dependent mechanism by augmenting GABA-ergic activity [132].

While antibiotics are commonly used to treat infections during early childhood, they may have long-term detrimental effects on brain development [133]. A clinical study investigating the link between antibiotic exposure and cognitive deficits in 342 children, assessed 11 years after birth, revealed an elevated risk of general cognitive impairment, attention deficit hyperactivity disorder, anxiety, and mood disorders in children who had received antibiotics at approximately 6 months of age [134]. In another study, mice given ceftriaxone exhibited lower levels of brain-derived neurotrophic factors in the hippocampus than the control group. This alteration was linked to abnormal behaviors, including anxiety, depression, and aggression [135]. Gut bacteria can also affect behavioral development in mice. Specific pathogen-free mice, compared with germ-free mice, displayed significantly reduced expression of the N-methyl-D-aspartic acid receptor subunit NR2B in the amygdala, increased expression of brain neurotrophic factor in the hippocampus, and decreased expression of serotonin receptor 1A in the dentate gyrus [136]. Overexpression of NR2B in neurons enhances synaptic plasticity and memory [137]. The serotonin receptor 1A plays a crucial role in preserving cognitive functions and has a significant impact on the increase of DCX-positive cells in the dentate gyrus of the hippocampus. This, in turn, leads to the restoration of hippocampal function [138]. The antibiotic administration in mice has been shown to disrupt the intestinal microbiota, which can potentially impact behavioral development. Additionally, there is a positive association between corticosterone levels and anxious behaviour [139].

In another study conducted in rats, the administration of Limosilactobacillus fermentum NS9 effectively reversed antibiotic-induced physiological and psychological abnormalities [140]. Alzheimer's disease (AD) is a neurological disorder influenced by factors such as age-related inflammation, poor nutrition, and dysbiosis. Dysbiosis can affect behavior, stress response, and cognitive function. However, administration of beneficial microbes, such as certain strains of lactobacilli and bifidobacteria, alleviates various pathological markers of AD, including muscle atrophy, amyloid proteasome degradation, and autophagy [141]. Animal models of AD have been created using antibiotics like streptozotocin. Following the application of this drug in mice, an increase in amyloid-β and neurofilament in the hippocampus was observed, which affected learning and memory performance [142].

In a clinical study, patients with AD were given probiotic yogurt containing Lactobacillus acidophilus, Lacticaseibacillus paracasei, Bifidobacterium bifidum, and Limosilactobacillus fermentum for 12 weeks. The group that received probiotic treatment exhibited significant improvements in AD-associated clinical scores and metabolic parameters, including the Mini-Mental State Examination, insulin metabolic markers, triglycerides, and C-reactive protein, compared with the control group. These findings suggest a substantial improvement following the probiotic intervention [143]. Similar positive outcomes were noted when a combination of selenium and probiotics was administered to patients with AD [144]. Some studies have shown that intestinal inflammation triggers AD-associated symptoms [145], [146], suggesting probiotics as a potential preventive measure and management approach to protect against cognitive decline in AD and alleviate stress-related conditions associated with antibiotic use (Fig. 5).

Fig. 5.

Mechanisms by which probiotics improve antibiotic-induced neurological diseases and symptoms through the gut-brain axis. a. Antibiotics increase the amyloid-β level in the hippocampus. b. Antibiotics significantly reduce mRNA expression of the N-methyl-d-aspartate (NMDA) receptor subunit (NR2B) in the amygdala and serotonin receptor 1A (5HT1A) receptor in the dentate gyrus. In addition, antibiotics decrease the level of hippocampal neurotrophic factor (BDNF). c. Antibiotics lower the level of mineralocorticoid receptor (MR). Probiotics can ameliorate antibiotic-associated neurological damage via modulating the composition of the intestinal microbial community. d. Probiotic intake stimulates the production of neuroactive metabolites, such as gamma-aminobutyric acid (GABA).

Considerations on the use of probiotics in antibiotic interventions

While many studies have consistently demonstrated the potential benefits of probiotic ingestion, including the promotion of beneficial microorganisms like bifidobacteria, inhibition of harmful gut microorganisms, and potential alleviation of symptoms associated with adverse reactions and inflammation, conflicting results have also been reported.

Multiple studies have indicated that the consumption of probiotic drinks or food supplements aimed at mitigating antibiotic-associated adverse effects may not consistently demonstrate positive effects, and in certain instances, may even lead to unfavorable outcomes. For example, administration of Lacticaseibacillus paracasei DN114001 (in the form of a yogurt drink containing common yogurt culture) did not exert beneficial effects in reducing AAD and CDAD in patients aged more than 55 years [147]. In a separate clinical study, supplementation with Lactobacillus helveticus R0052 and Lacticaseibacillus rhamnosus R0011 significantly reduced the duration of diarrheal bowel movements in healthy adults treated with antibiotics; however, a small number of patients experienced adverse effects, inducing infection and gastrointestinal discomfort [148]. Similarly, while Bio-K+ was effective in reducing AAD severity, a significant percentage of patients (33.3 %) experienced side effects during the intervention, including constipation, flatulence, and nausea [149]. Moreover, probiotic consumption does not have a clear clinical efficacy in reducing the AAD risk in older adults [150].

Moreover, the efficacy of probiotics in mitigating antibiotic-related side effects varies among different strains. While some strains, like Lacticaseibacillus rhamnosus GG and Saccharomyces boulardii, have demonstrated protective effects against AAD [151], others such as Lactobacillus acidophilus La-5 and Bifidobacterium animalis subsp. lactis BB-12 have shown limited efficacy in preventing AAD [152]. Similarly, Limosilactobacillus reuteri DSM17938 failed to prevent diarrhea or AAD in children [151]. Notably, a study by Suez et al. (2018) revealed that although probiotics aided in the reestablishment of gut microbiota post-antibiotic treatment, there was a substantial delay in the recovery of intestinal mucosal structure, function, and bacterial populations. This dysbiosis persisted for at least five months after probiotic cessation [90].

Critically ill patients present unique challenges regarding probiotic use. In a study involving severe acute pancreatitis patients receiving a probiotic mixture, although infectious complication rates were comparable to those of the placebo group, the probiotic group exhibited higher mortality and increased incidence of bowel ischemia [153]. This underscores the importance of cautious evaluation and monitoring in probiotic administration to critically ill individuals.

Additionally, adverse effects associated with probiotic use have been documented. For instance, an older adult female patient with diabetes and end-stage renal disease developed a liver abscess and lactobacilli bacteremia after receiving metronidazole and a lactobacilli-containing probiotic for C. difficile enteritis treatment [154]. While causality between the liver abscess and the probiotics was inconclusive, it underscores the need for awareness of potential risks, especially in specific populations with underlying conditions.

Similarly, a case involving a boy with ulcerative colitis was initially treated with systemic corticosteroids and infliximab, followed by the administration of Lacticaseibacillus rhamnosus GG. However, one week later he developed Lacticaseibacillus rhamnosus GG bacteremia [155]. This underscores the importance of a cautious approach to probiotic use, particularly in individuals with specific risk factors or underlying conditions. Close monitoring and thorough risk assessment are crucial to ensure the safe and appropriate use of probiotics in these populations.

Another critical aspect to consider is the impact of antibiotic use on the integrity of the intestinal barrier, which probiotics can help restore. Antibiotic misuse can disrupt the gut microbiota, creating an environment conducive to the survival and proliferation of pathogenic bacteria. Hence, one key function of probiotics is to create an unfavorable environment for pathogen colonization [156]. Probiotics with limited colonization ability may not effectively inhibit pathogen growth. Moreover, antibiotic-induced dysfunction of macrophages can be mitigated by bioactive low molecular weight peptides derived from the gut microbiota, particularly those from Bacteroides and lactobacilli [157]. Despite their numerous benefits, misuse of probiotics can lead to adverse outcomes. One concerning issue is the potential translocation of probiotics from the gut to other tissues and the bloodstream, resulting in bacteremia, especially in immunocompromised patients, critically ill individuals, and children [154], [158]. Additionally, probiotics can acquire or transfer ARGs through horizontal gene transfer in the human digestive tract, leading to harmful metabolic activities and excessive immune stimulation in susceptible individuals. Therefore, a comprehensive understanding of host factors and the microbiota is crucial to ensure the success and safety of probiotic use. Factors such as age, diet, intake of supplements, antibiotics and medications, underlying conditions, and circadian rhythms all contribute to individual variations in the gut microbiome [159]. Furthermore, the colonization of probiotics relies heavily on interactions with the intestinal mucosa and existing gut microbiota, which are influenced by individual gut physiological characteristics and ecological niches [160]. Hence, personalized probiotic regimens should be tailored to individual needs based on host differences [161].

Conclusions and future directions

The advent of antibiotics has undoubtedly been a major advancement in medical science. However, their widespread use has raised concerns about associated side effects. Probiotics, as natural biological agents, show promise in mitigating adverse effects caused by antibiotics. Nevertheless, their use comes with challenges and limitations. Individual responses to probiotics can vary due to genetic background, age, and overall health status. Moreover, the dosage and duration of probiotic treatment play crucial roles in determining their effectiveness [162].

As our understanding of the human gut microbiota and omics technologies continues to advance, we are gaining deeper insights into the taxonomy and functions of these microorganisms [163]. They not only play a crucial role in maintaining gut homeostasis but also contribute to various physiological and pathological processes. This knowledge opens up new possibilities for personalized probiotics to address medical issues associated with antibiotic use. In this setting, it is critically important to thoroughly understand the systemic pathways involved in diseases caused by bacterial resistance. The field of epigenetics in probiotics is burgeoning and holds potential to illuminate the reasons behind the varying effectiveness of probiotics among individuals [164], [165]. To this end, integrating pharmacokinetic approaches with in vitro techniques and computational simulations is essential for investigating novel antibiotics thoroughly. This strategy is vital to preempt the rise of new microbial pathogens potentially spurred by advanced antibacterial agents [166], [167]. Probiotics can be combined with other potential bioactive functional products, such as prebiotics, and other natural and synthetic compounds, to enhance the therapeutic effects and increase clinical efficacy [168], [169], [170], [171]. Studying the mechanisms of interaction between these agents can lead to more comprehensive and effective treatment programs. Innovations in probiotic dosage forms, such as microencapsulation and nano-encapsulation, offer the potential for targeted delivery of probiotics in the intestine [172], [173]. These advancements improve the stability, bioavailability, and colonization of probiotics in the gut, enhancing their therapeutic effects. Ensuring the biosafety of probiotics is essential, although relatively few side effects and risks have been described in the literature. Ensuring their safety and efficacy remains a major concern in any clinical treatment program. Adequate evaluation and research are needed before promoting the widespread use of probiotics. Additionally, probiotic use may require more caution and individualization for specific populations, such as older adults, children, and immunocompromised individuals.

Through thorough research and exploration of the mechanisms and potential applications of probiotics in preventing and treating antibiotic-associated adverse effects, the development of more precise and effective therapeutic strategies for clinical practice is conceivable. Nonetheless, attaining this objective demands continued efforts and research from the medical and scientific community.

Funding

This work was supported by the Fundamental Research Funds of Inner Mongolia Agricultural University (BR220301), the National Natural Science Foundation of China (Grant No.32372304), and the Program for Young Talents of Science and Technology in Universities of Inner Mongolia Autonomous Region (NMGIRT2411).

Compliance with Ethics Requirement

This article does not address ethical requirements.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Biographies

Shuwei Yang, the major research focus on antibiotics and gut flora, probiotics and host health.

Jiaqi Qiao, the major research focus on antibiotics and gut flora, probiotics and host health.

Meng Zhang, the main research interests are probiotics, intestinal flora and host health.

Lai Yu Kwok is a PhD and an associate professor of Inner Mongolia Agricultural University. Lai Yu Kwok's main research interests are probiotics and intestinal flora.

Bojana Bogovič Matijašić, Senior research fellow, and Biotechnology, Department of Animal Science, Institute of Dairy Science and Probiotics, Chair of Dairy Science. The main research focus on lactic acid bacteria, application of molecular biological methods in dairy science and probiotic research, and gut microbiota/microbiome and interactions probiotics - gut microbiota.

Heping Zhang is a professor at Inner Mongolia Agricultural University. His research spans probiotics, the human microbiome, human nutrition, and lactic acid bacteria.

Wenyi Zhang is a professor of Inner Mongolia Agricultural University. Wenyi Zhang’s research mainly focuses on the areas of lactic acid bacteria biodiversity, genomics, and intestinal microbiology.