By killing essential gut bacteria Antibiotics ravage athletes motivation and endurance

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New research demonstrates that by killing essential gut bacteria, antibiotics ravage athletes’ motivation and endurance. The UC Riverside-led mouse study suggests the microbiome is a big factor separating athletes from couch potatoes.

Other studies have examined the way that exercise affects the microbiome, but this study is one of few to examine the reverse—how gut bacteria also impact voluntary exercise behaviors. Voluntary exercise involves both motivation and athletic ability.

The researchers’ methods and results are now detailed in the journal Behavioural Processes.

“We believed an animal’s collection of gut bacteria, its microbiome, would affect digestive processes and muscle function, as well as motivation for various behaviors, including exercise,” said Theodore Garland, UCR evolutionary physiologist in whose lab the research was conducted. “Our study reinforces this belief.”

Researchers confirmed through fecal samples that after 10 days of antibiotics, gut bacteria were reduced in two groups of mice: some bred for high levels of running, and some that were not.

Neither group of mice exhibited any signs of sickness behavior from the antibiotic treatment. So, when wheel running in the athletic mice was reduced by 21 percent, researchers were certain the microbiome damage was responsible. In addition, the high runner mice did not recover their running behavior even 12 days after the antibiotic treatment stopped.

The behavior of the normal mice was not significantly affected either during the treatment, or afterward.

“A casual exerciser with a minor injury wouldn’t be affected much. But on a world-class athlete, a small setback can be much more magnified,” said Monica McNamara, UCR evolutionary biology doctoral student and the paper’s first author. “That’s why we wanted to compare the two types of mice.” Knocking out the normal gut microbiome might be compared with an injury.

One way the microbiome might affect exercise in mice or in humans is through its ability to transform carbohydrates into chemicals that travel through the body and affect muscle performance.

“Metabolic end products from bacteria in the gut can be reabsorbed and used as fuel,” Garland said. “Fewer good bacteria means less available fuel.”

Moving forward, the researchers would like to identify the specific bacteria responsible for increased athletic performance. “If we can pinpoint the right microbes, there exists the possibility of using them as a therapeutic to help average people exercise more,” Garland said.

A lack of exercise is known to be a major risk factor for aspects of mental health, including depression, as well as physical health, including metabolic syndrome, diabetes, obesity, cardiovascular disease, cancer, and osteoporosis. Many in the public health community would like to promote exercise, but few have found ways to do it successfully.

“Though we are studying mice, their physiology is very similar to humans. The more we learn from them, the better our chances of improving our own health,” Garland said.

Certain foods may also increase desirable gut bacteria. While research into “probiotics” is developing, Garland recommends that those interested in promoting overall health maintain a balanced diet in addition to regular exercise.

“We do know from previous studies that the western diet, high in fat and sugar, can have a negative effect on biodiversity in your gut and likely, by extension, on athletic ability and possibly even on motivation to exercise,” Garland said.


CONSEQUENCES OF ANTIBIOTIC‐INDUCED MICROBIOTA CHANGES FOR HEALTH AND DISEASE
In adults

Due to the role of the microbiota in host metabolism and physiology, many studies postulate that microbial imbalances can be related to obesity (Riley et al., 2013; Scott et al., 2016), diabetes (Boursi et al., 2015; Mikkelsen et al., 2015), and asthma (Arrieta et al., 2015; Kozyrskyj et al., 2007). Blaser and Falkow (2009) have suggested a link between the “missing microbes” and modern conditions such as obesity and juvenile diabetes. These multifactorial conditions can be controlled by identifying the controllable factors such as the microbiota component and dietary habits, thus preventing them from occurring if possible.

Studies have reported a link between antibiotic usage and obesity (Del Fiol et al., 2018). Some studies suggest that an increased ratio of Firmicutes to Bacteroidetes rather than specific levels is associated with obesity (Kasai et al., 2015), though results are conflicting (Duncan et al., 2008; Schwiertz et al., 2010).

While the microbial component of obesity is debated, studies have reported a common change at functional microbial levels. Indeed, obese individuals have higher short‐chain fatty acid (SCFA) content compared to lean individuals (Schwiertz et al., 2010; Turnbaugh et al., 2006). Furthermore, obesity is associated with metabolic alterations related to glucose homeostasis and insulin resistance and linked to the development of diabetes (Cani et al., 2012). In a study in 96 humans (48 each antibiotic group and controls), researchers reported significant and persistent weight gain after an episode of infectious endocarditis in patients who had been treated with vancomycin and gentamycin (Thuny et al., 2010).

An association between antibiotic‐induced changes in microbial colonization and type 1 diabetes in male mice was reported (Candon et al., 2015). A combination of broad‐spectrum antibiotics or vancomycin alone was given to neonatal nonobese diabetic mice that spontaneously developed autoimmune type 1 diabetes. The microbiota was significantly altered with an increase in Escherichia and Lactobacillus species and a decrease of the Clostridiales order compared to controls.

A major reduction of IL‐17‐producing cells was also observed in the lamina propria of the ileum and the colon of vancomycin‐treated mice (Candon et al., 2015), which can affect host defense mechanisms. Some studies in human populations also suggest a link between repeated use of broad‐spectrum antibiotics and diabetes (Boursi et al., 2015; Mikkelsen et al., 2015), while some suggest a protective and preventative role of antibiotics and diet in diabetes development in diabetes‐prone animals partly due to lowering of specific antigenic load or development of tolerogenic APCs (Brugman et al., 2006; Hu et al., 2015).

Associations between altered microbial composition and type 2 diabetes are more established, with decreased levels of butyrate‐producing bacteria reported in type 2 diabetic patients (Gurung et al., 2020). X. Zhang et al. (2013) studied 121 subjects with normal glucose tolerance, prediabetes, and newly diagnosed diabetes and reported that there is modulation of the gut microbial composition at the prediabetes stage which can act as a marker for the development of diabetes state.

Antibiotics can lead to antibiotic‐associated diarrhea (AAD) and studies have demonstrated that clindamycin can result in alteration of the microbial community which can promote the colonization of potential pathogens such as C. difficile which can lead to diarrhea and colitis (Buffie et al., 2012; McDonald, 2017). Another study in a mouse model reported that antibiotic treatment resulted in decreased alpha and beta diversity, which potentially caused a decrease in levels of serotonin, tryptophan hydrolase, and secondary bile acids which can further affect gut motility and metabolism (Ge et al., 2017).

iNFLUENCE OF ANTIBIOTIC‐INDUCED CHANGES ON MICROBIOTA FUNCTIONALITY AND BACTERIAL BEHAVIOR AT THE SINGLE‐CELL LEVEL

Changes in metabolites
The gut microbiota is responsible for the production of many essential metabolites including SCFAs and amino acids (Mills et al., 2019). Studies have reported that commensal‐produced butyrate and propionate have anti‐inflammatory roles, promoting the generation and differentiation of regulatory T cells (Arpaia et al., 2013; Furusawa et al., 2013), with roles in energy metabolism (den Besten et al., 2013; De Vadder et al., 2014). By impacting the composition of the microbial community, antibiotics also alter microbiota functionality and thus the metabolites produced (Ferrer et al., 2017).

For example, metabolomics profiles were analyzed in antibiotic‐treated piglets fed a corn‐soy basal diet with or without in‐feed antibiotics from postnatal days 7–42. The antibiotic‐treated group had higher concentrations of metabolites associated with amino acid metabolism, decreasing the concentration of amino acids.

A reduction in SCFA production was also reported as levels of butyrate and propionate were decreased (Mu et al., 2017). Another study in piglets (Days 7–21) demonstrated that fecal microbiota transplant (FMT) and antibiotic (amoxicillin) treatment both resulted in lowering of fatty acid oxidative catabolism and amino acid biosynthesis, though antibiotics had a more significant effect (Wan et al., 2019).

Multiple studies performed in mouse models have elucidated the effects of antibiotic treatment on host metabolic functions. A study in antibiotic (streptomycin)‐treated mice reported that antibiotic administration can affect pathways of hormone synthesis such as steroids and eicosanoids, along with altering the pathways involved in sugar, bile acids, and amino acid metabolism, thus suggesting the role of the microbiota in these pathways (Antunes et al., 2011). Sun et al. (2019) reported that mice treated with antibiotics (enrofloxacin, vancomycin, and polymixin B sulfate) showed upregulated gene expression of various cytokines in the colon, with significant metabolic shifts in valine, leucine, and isoleucine biosynthesis pathways.

These alterations correlated to changes in microbial composition. One study reported that clindamycin treatment in mice resulted in significant changes in metabolite composition (30% of the compounds analyzed); the restoration of which was associated with recovery of the altered microbiota (Jump et al., 2014). Zhao et al. (2013) reported that antibiotic treatment altered the products of bacterial metabolism.

This included decreased levels of SCFAs, amino acids (correlated with the abundance of Prevotella, Alistipes, and Barnesiella), and increased precursors like bile acids and oligosaccharides (associated with high levels of facultative anaerobic bacteria, Enterococcus faecalis, Enterococcus faecium, and Mycoplasma; Zhao et al., 2013).

Microbial depletion in mice due to antibiotic uptake decreased baseline serum glucose levels, improved insulin sensitivity (Zarrinpar et al., 2018), altered systemic glucose metabolism along with changes in expressions of the genes in the liver and ileum involved in glucose and bile acid metabolism (Rodrigues et al., 2017). This was reported to be accompanied by reduced levels of SCFAs and secondary bile acid pools (Zarrinpar et al., 2018). Similar results were reported following vancomycin treatment (Vrieze et al., 2014). This can lead to impairment of barrier function (Kelly et al., 2015); act as a causative factor in the development of ulcerative colitis (Machiels et al., 2013), and Salmonella infection (Gillis et al., 2018).

Studies have also reported that antibiotic uptake can result in changes in protein expression, energy metabolism in the microbiota, with a slight increase following antibiotic therapy, which may be as a coping mechanism to antibiotic stress but decreased at later stages and post‐antibiotic usage (Pérez‐Cobas & Artacho et al., 2013). Another study demonstrated that antibiotics have a sex‐dependent effect on host metabolism.

They reported that vancomycin and ciprofloxacin–metronidazole treatment resulted in significant reductions of Firmicutes and SCFAs in female mice, which was only observed after vancomycin treatment in males. They also reported that both antibiotic exposures significantly decreased the levels of alanine, branched‐chain amino acids (leucine, isoleucine, and valine), and aromatic amino acids in colonic contents of female mice but not in male mice (Gao et al., 2019).

Changes in bacterial signaling pattern

Antibiotics can alter the transcription of several major functional genes such as those encoding transport proteins, genes involved in the metabolism of carbohydrates, and protein synthesis (Goh et al., 2002; J. T. Lin et al., 2005). A study demonstrated induced expression of virulence‐associated genes in Pseudomonas aeruginosa leading to higher secretion of rhamnolipids and phenazines on exposure to subinhibitory concentrations of antibiotics (Shen et al., 2008).

Many studies have reported that aminoglycosides (Hoffman et al., 2005), β‐lactams (Kaplan et al., 2012; K. M. Ng et al., 2014), vancomycin, and oxacillin (Mirani & Jamil, 2010) can induce biofilm formation even at sublethal concentrations. These biofilms then act as reservoirs of antibiotic resistance.

This confers additional resistance to bacteria against several antibiotics and host defense, which can make treatment difficult in humans and can cause several issues such as blockage of pipes/equipment in healthcare settings and food industries (Muhammad et al., 2020).

Bacteria interact with their host using pattern recognition receptors (PRR) via signaling through the production of bile acids, SCFAs, fatty acids, amino acids, LPS, lipoteichoic acid, flagellin, CpG DNA, and peptidoglycan. These signaling molecules either serve as a source of energy for other cells, regulate or modulate the function of immune cells such as monocytes, macrophages, T cells via G‐protein coupled receptor and nuclear receptor family, free fatty acid receptors (Brestoff & Artis, 2013).

Antibiotic use results in a reduction of these bacteria and hence the PRRs such as TLR signaling and downstream regulation of innate defenses (Willing et al., 2011). A study reported that an antibiotic‐mediated decrease in butyrate‐producing bacteria resulted in reduced epithelial signaling through the intracellular butyrate sensor peroxisome proliferator‐activated receptor γ (Byndloss et al., 2017).

Similarly, antibiotic disruption of the commensal microbiota in newborn mice increases their susceptibility to pneumonia, due to interrupted migration of IL‐22 producing lymphoid cells (IL‐22 + ILC3; Gray et al., 2017). This effect could be reversed by the transfer of commensal microbiota to mice at birth (Gray et al., 2017). Another study reported the importance of commensals in protecting against colon injury and maintaining intestinal homeostasis (Rakoff‐Nahoum et al., 2004). In this case, commensals induced release of protective factors via TLRs; these factors were not released in mice treated with antibiotics lacking the commensal bacteria (Rakoff‐Nahoum et al., 2004). Antibiotics can thus impact complex host‐microbial interactions due to changes in microbial community composition.

REFERENCE LINK :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8756738/


More information: Monica P. McNamara et al, Oral antibiotics reduce voluntary exercise behavior in athletic mice, Behavioural Processes (2022). DOI: 10.1016/j.beproc.2022.104650

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