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A Review Article on Antibiotic Use and Type 1 Diabetes in Early Child Development 

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Patty Medina, MPH [1]

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[1] NYU School of Global Public Health

 

ABSTRACT

The gut microbiome is composed of a diverse flora of bacteria that are critical for health and disease development in humans. It consists of over one hundred trillion microbial cells that are responsible for metabolism and homeostasis, necessary functions that nourish and protect humans from infections. [1] The gut is resilient and attacks foreign pathogens that threaten homeostasis in the body, thereby making it a robust system. However, internal and external factors such as antibiotic use exacerbate the onset of metabolic disorders which disturbs homeostasis and contributes to inflammation that suppresses vital organ structure and function. [2] Recent studies show that early antibiotic use in childhood alters the microbiome, creating dysbiosis in the body which leaves it susceptible to Type 1 Diabetes (T1D), an autoimmune disease that destroys the insulin producing cells in the pancreas which are necessary to maintain blood sugar levels. [3,4] Antibiotic use is implicated with changes in gut microbiome diversity because good and bad bacteria are reduced, thus leaving the gut susceptible to future infections. [5] In the United States, chronic diseases are costly and reduce one’s quality of life. Therefore, if physicians limit antibiotic use in early childhood, the rate of autoimmune diseases may decline.

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INTRODUCTION

The gut microbiome is critical for health and disease development in humans. It is composed of various bacteria phyla but it is dominated by Bacteroidetes and Firmicute which make up 90% of the gut community.[6] Other subgroups of bacteria that coexist in the gut are Proteobacteria, Actinobacteria, and Verrucomicrobia.[7] The gut microbiome consists of over one hundred trillion microbial cells that are responsible for metabolism and homeostasis, necessary functions that nourish and protect humans from infections.[1] The gut is resilient and attacks foreign pathogens that threaten homeostasis in the body, thereby making it a robust system. However, internal and external factors such as antibiotic use exacerbate the onset of metabolic disorders which disturbs homeostasis and contributes to inflammation that suppresses vital organ structure and function.[2] Recent studies show that early antibiotic use in childhood alters the microbiome, creating dysbiosis in the body which leaves it susceptible to Type 1 Diabetes (T1D), an autoimmune disease that destroys the insulin producing cells in the pancreas which are necessary to maintain blood sugar levels.[3,4] Antibiotic use is implicated with changes in gut microbiome diversity because good and bad bacteria are reduced, thus leaving the gut susceptible to future infections.[5]

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SEARCH METHODS AND STUDY INCLUSION CRITERIA

A preliminary search strategy was conducted in 2018 after reading the article by Zhang XS et al (2018). Only peer reviewed articles published between 2013-2018 and with the following keywords “antibiotic use,” “autoimmune diseases,” “microbiome,” and “children” were included in the first draft of the review.

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A second review was conducted in July of 2020. Research articles were chosen from peer reviewed journals found through the EBSCO Discovery Service which included Elsevier, Nature, NCBI, PLOS, and PubMed databases. Articles published between 2010-2020 and international articles were chosen. The search criteria focused on antibiotic use and disease in early childhood. Key words included the MeSH terms “type 1 diabetes,” “antibiotics,” “microbiome,” “gut,” “gastrointestinal,” “metabolism,” “inflammation,” “immunity,” “childhood,” “children,” and “probiotics.” A search for the latest articles on immunity and regulatory T (Treg) cells was added in December 2020. References were updated in January 2021.

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CONSEQUENCES OF ANTIBIOTIC USE ON THE GUT MICROBIOME 

Antibiotics are a class of drugs that help the body fight bacterial infections by inhibiting reproduction and destroying bacteria.[8] They accomplish this by obstructing DNA, RNA and protein synthesis and disintegrating the bacteria’s cell wall.[8] When there is an infection, the immune system activates regulatory T (Treg) cells which are critical in maintaining self-tolerance, regulating immune responses, and protecting good bacteria in the body. [13] Treg cells are salient in the protection against autoimmune diseases, but homeostatic disruptions can have significant consequences on the gut microbiome. [13,14,15] The overprescription and misuse of antibiotics can render the body pregnable to infections by disrupting cell signaling in the gut, as a direct and indirect consequence of antibiotic resistance which alters metabolic and immune functions. [13,14,15,16] Antibiotics are implicated with decreasing production of short-chain fatty acids (SCFAs), Th17 and Treg cells, as well as increasing inflammation. [14,15] Acid production also becomes vulnerable to toxic metabolites and disturbs gut integrity which is intrinsic for the maintenance of a healthy gut microbiome. [14,15] Therefore, antibiotics have become a double-edged sword because although they treat common infections, they compromise the gut microbiome by destroying good bacteria and suppressing Treg cell activities which are imperative for healthy immune function.

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The gut of an infant is sterile until it becomes colonized by microbes at birth when the infant is delivered through the mother’s vaginal canal.[1,6] Significant findings reveal that infants delivered vaginally share a similar gut microbiome with their mother which is essential for a robust gut microbiome in adulthood.[6] For example, multiple studies indicate that infants delivered via cesarean section have fewer microbes in the gut due to not having the mother’s vaginal microbiome.[9,1,10] These infants only have the microbes that live on the skin, not those found in the gut microbiome which are critical for metabolic and immune function.[10] Antibiotic use in children is linked with a higher burden of autoimmune diseases such as T1D, asthma and food allergies.[11,12] A plausible hypothesis for this phenomenon is the high prevalence of antibiotic use in early childhood to treat ear infections and respiratory tract infections.[3] This is implicated with changes in gut microbiome diversity because with antibiotic use, the healthy bacteria that colonize the gut also become reduced.[5]

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ANTIBIOTIC USE AND TYPE 1 DIABETES 

T1D commonly develops in childhood resulting in the destruction of pancreatic beta cells and the inability to produce sufficient insulin.[5] In addition, children with T1D have decreased levels of intestinal regulatory T (Treg) cells which are essential for immune response and in preventing autoimmune disease.[5,13] Treg cells work alongside T helper cells to suppress pathogenic activity and trigger the activation of chemokines which are released when there is inflammation in the body.[13,16] When Treg cell activities become deregulated as a result of homeostatic disturbances, communication between the immune system and the gut microbiome become impaired, leaving the body susceptible to infections. [13,14,15] This imbalance in the body triggers a series of cascading effects that suppress vital metabolic and immune interactions that are necessary to maintain healthy gut function. [13,14,15] Consequently, disease progression becomes prevalent as pathological cells infiltrate the immune system and decrease the immune system’s ability to carry out proper immune responses to combat proinflammatory effects. [13,14,15,16]

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Antibiotic use is a suspected culprit because it disrupts biochemical pathways, depletes beneficial bacteria and results in accelerated T1D. [5] For instance, antibiotic use in early childhood has been found to diminish five types of Bifidobacerum species which are important for digestion. [3,17] A different study assessed the relationship of antibiotic use and asthma which revealed that children had a significant reduction of Faecalibacterium, Lachnospira, Veillonella and Rothia (FLVR) bacteria that also increased their risk with the amount of antibiotic courses they were prescribed.[12] Other studies indicate that where there is an imbalance of inflammatory responses, the body’s natural ability to combat infections is overwhelmed.[18] When the body's immune system is compromised, it becomes hypersensitive to acute changes and more susceptible to debilitating and chronic diseases. [13,14,15] The use of animal model systems has contributed significantly to humanity’s understanding of disease and drug therapies have provided practical alternatives for disease management. By further exploring the role of the microbiome and antibiotic use at different stages of childhood development, we can introduce microbiome therapies to regain homeostasis and protect against T1D and other autoimmune diseases.[19]

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An experimental study conducted in 2018 by a team of researchers from New York University Langone Medical Center and collaborating partners found a strong relationship between antibiotic use in early life and the development of T1D in mice who were given therapeutic-dose pulsed antibiotic treatment (PAT) with antibiotics as a single dose (1PAT), three doses (3PAT) or no dose for ten days.[5] The research team wanted to understand changes in the microbiome after antibiotic treatment and found various differences in male and female mice up until the pup day of life P147.[5] At P12, the researchers noticed differences that persisted until P49 which demonstrates that antibiotic use drastically altered the microbiome even after discontinuation of antibiotics at P10.[5] As a result of antibiotic use, intestinal microbiome diversity demonstrated a reduction in beneficial species such as Lactobacillus, Bifidobacterium, Blautia coccoides/Eubacterium rectale group and Prevotella and resulted in an increase in opportunistic species that exacerbated the development of T1D.[5,17] Similarly, butyrate-producing and mucin-degrading bacteria were found in lower quantities which are critical for maintaining gut function while Clostridium, Bacteroides and Veillonella bacteria increased.[17] Due to these changes in the gut, mucin levels decrease and genes are reduced in the intestines which impairs innate immunity.[5]

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IMMUNOLOGY, REGULATORY T (TREG) CELLS, AND INFLAMMATION 

Every interaction in the gut microbiome carries consequences and if there is a slight imbalance, the immune system, and its network of Treg cells are unable to detect foreign pathogens. Communication and coordination between all players in the immune system (B cells, antibodies, T cells, and Tregs) have a role that is necessary to maintain cell integrity.[13] T cells interrogate any threat and activate a series of signals that release cytokines to destroy pathogens.[20,8] However, with the overuse of antibiotics, harmful pathogens trick T cells into destroying their own cells and take over the immune system.[20] This in turn affects adaptive immunity, which destroys pancreatic cells and contributes to the development of T1D, among other types of autoimmune diseases and cancers.[5,17]

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The complex nature of the immune system and the intersecting biochemical pathways involved in the gut are not fully understood which makes it difficult for scientists and physicians to prevent the onset of autoimmune disease. However, by identifying specific biomarkers in the gut microbiome as well as leveraging precision medicine, we can strengthen disease surveillance mechanisms to intervene earlier for chronic disease management. By employing existing literature on T2D, scientists and physicians can be more successful in targeting inflammation, which is responsible for metabolic disorders. The NLR Family Pyrin Domain Containing 12 protein coding (NLRP12) gene has anti-inflammatory properties which can be used to improve nutrition and diet.[21] Increasing this gene can be a potential avenue to combat dysbiosis and inflammation in the gut. Various studies confirm that diets high in fat are responsible for inflammation because they modify the phenotype of macrophages in adipose tissue, altering them from anti-inflammatory macrophages (M2) to pro-inflammatory macrophages (M1).[18] Scientists have discovered that inflammation is caused by lipopolysaccharides (LPS) endotoxins which decrease NLRP12 in the gut.[21] Inflammation in the gastrointestinal tract inversely follows a reduction in Bacteroidales, Clostridiales and Lachnospiraceae bacteria.[21] Therefore, targeting NLRP12 in drug therapies can greatly reduce inflammation to inhibit irritation in the gut.

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Expanding our understanding of the inflammatory pathways as well as strategically incorporating precision medicine will strengthen disease management and improve health outcomes by identifying who is more susceptible to certain pathologies. For example, the same study conducted by New York University Langone Medical Center and collaborating partners revealed that a higher incidence of T1D was found in female mice, despite the fact that males in the PAT group had overall significant rates in accelerated T1D.[5] Beginning, at P23 a startling 1,511 differential ileal gene expressions were found in the male PAT group, whereas in females only 124 changes were present.[5] These genes are necessary for immunity function but once they get disrupted, homeostasis in the microbiome is compromised as inflammation weakens the intestinal lining of the gut. Supplementary metagenomic analyses revealed that the microbiome becomes colonized by opportunistic bacteria which modifies metabolic pathways until disease develops.[5] Opportunistic bacteria that were found in abundance included groups of Enterococcus, Blautia, Enterbacteriaceae and Akkermansia species which were exceedingly high in the PAT groups while species of S24-7, Clostridiales, Oscillospira and Ruminococcus were greatly reduced.[5] This relationship illustrates the devastating effects that antibiotics have on the microbiome and indicates a high vulnerability for disease. Consequently, by P70 the pancreatic islets revealed major inflammation in males which is suggestive that antibiotic use can lead to T1D. [5]

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Another significant finding in the study noted a reduction in Th 17 and Treg cells of the lamina propria among mice.[5] These T cells are integral in the small intestine as they work together to regulate inflammatory responses. Therefore, exposure to antibiotics early in life can result in inhibition of T-cells which fail to mature especially when one mechanism is disrupted. [5] As a result, immune intolerance threatens the integrity of the microbiome. These biochemical changes result in an unresponsive switch that turns genes on and off and triggers cascading effects that lead to inflammation to other tissue in the body. [5] Since the body believes it is being attacked, the immune system goes into overdrive and attacks anything in its pathway. Thus, early antibiotic use disrupts normal immune regulation and homeostasis which increases the risk for T1D development. [18] For this reason, robust studies on mice models are groundbreaking because they give scientists and researchers a better understanding of how antibiotics can have harmful impacts on the body especially if restrictions are not set-in place. Ultimately, understanding the specific biochemical pathways in the microbiome that are affected by antibiotics can help develop new intervention strategies to address autoimmune diseases in children.

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PREVENTATIVE MEASURES TO LIMIT ANTIBIOTIC USE 

Antibiotics are a blessing to humankind because not only do they save lives, but they have greatly improved health outcomes for many infectious diseases. Despite these advancements in medicine, the over-prescription and dependency on antibiotics to treat disease has reduced the immune system’s beneficial bacteria and has compromised the body’s susceptibility to disease. Thus, reducing antibiotic use in early childhood will be a public health challenge because although childhood infections should not be taken lightly, single use of antibiotics has been strongly linked to have severe long-term health consequences.

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One way to overcome the over-prescription of antibiotics to treat minor infections is to strictly regulate the type of antibiotic, dose, and duration of treatment since various animal studies have identified a relationship between antibiotics use and disease. [19] Because the microbiota in early childhood is still developing, health care professionals must be cautious in prescribing antibiotics which can greatly reduce beneficial bacteria in the child’s microbiome and place them at risk for autoimmune diseases. Instead of prescribing broad-spectrum antibiotics such as Amoxicillin, Azithromycin, Tetracycline, and the Quinolones which inhibit beneficial and opportunistic bacteria; the use of narrow spectrum antibiotics such as Penicillin, Cephalosporin, Lincomycins should be used to prevent complete depletion of healthy gut bacteria. [19,22]

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Granted that there is no cure for T1D yet, a potential intervention to re-establish homeostasis in the gut microbiome is the introduction of probiotics and other foods that include S24-7, as well as Clostridiales, Oscillospira, Ruminococcus and Anaeroplasma which are critical to reduce opportunistic bacteria in the gut and reduce inflammation. [11,23] Foods rich in probiotics include yogurt, fermented foods, kombucha, sauerkraut, and kefir. [23] These species of bacteria have been identified to protect against the development of T1D and other autoimmune diseases if they are implemented in the diet before and after the use of antibiotics. In addition, targeting Blautia and Akkermansia species as well as intestinal degrading bacteria can significantly improve robust treatments to reduce opportunistic bacteria that triggers inflammation. [5] With more robust research in the field of antibiotic use, rates of T1D in children may decline.

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LIMITATIONS 

Some limitations to the literature and studies discussed in this review include the use of mice models which have different health profiles than humans. For example, humans have complex comorbidities that require multiple interventions to keep diseases under control. Likewise, the anatomy of mice does not consider other factors such as hereditary diseases, the environment, or stress which can increase one’s risk for disease development and severity. Biomedical research funding is time-consuming, costly, and competitive especially since there are many medical institutions trying to find cures for various diseases. The process of drug development and clinical trials is also rigorous and extensive. It can take several years for new medications to be released to the public. Lastly, scientists and physicians have a limited understanding of complex disease mechanisms, in particular the biochemical pathways and the long-term drug interactions which can contraindicate with other health conditions and medications.

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CONCLUSION

In the United States, chronic diseases are costly and greatly reduce one’s quality of life. Given the essential role that the gut microbiome plays in maintaining metabolism and homeostasis in the body, strengthening research in this domain will greatly benefit other areas in medicine. It is critical that scientists and physicians from different disciplines and countries collaborate in their research endeavors to broaden their understanding between the relationship of antibiotic use on specific health outcomes. This interdisciplinary approach between medicine, public health and research will greatly benefit humankind especially since the rates of T1D and autoimmune diseases are a growing threat worldwide. In addition, by incorporating literature and studies that focus on T2D and cancer, the future of antibiotic research and the health implications it has on metabolic disorders can help explain the gaps that exist in disease pathways to develop more targeted microbiome therapies. Likewise, physicians must promote antibiotic stewardship so that the overuse of antibiotics does not result in future emerging disease outbreaks and compromise the health and well-being of vulnerable populations. Therefore, balancing research, antibiotic use and incorporating microbiome therapies, together can combat autoimmune diseases and address antibiotic resistance.

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Conflicts of Interest: The author of this review has no conflicts of interest to disclose. 

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