Biology subjects

Desai, M. S.

Publications and source records attributed to Desai, M. S..

6 recordsLinked to original sources

bioRxiv2023

Gut microbiome-based prediction of autoimmune neuroinflammation

Gut commensals are linked to neurodegenerative diseases, yet little is known about causal and functional roles of microbial risk factors in the gut-brain axis. Here, we employed a pre-clinical model of multiple sclerosis in mice harboring distinct complex microbiotas and six defined strain combinations of a functionally-characterized synthetic human microbiota. Discrete microbiota compositions resulted in different probabilities for development of severe autoimmune neuroinflammation. Nevertheless, assessing presence or the relative abundances of a suspected microbial risk factor failed to predict disease courses across different microbiota compositions. Importantly, we found considerable inter-individual disease course variations between mice harboring the same microbiota. Evaluation of multiple microbiome-associated functional characteristics and host immune responses demonstrated that the immunoglobulin A-coating index of Bacteroides ovatus before disease onset is a robust individual predictor for disease development. Our study highlights that the "microbial risk factor" concept needs to be seen in the context of a given microbial community network, and host-specific responses to that community must be considered when aiming for predicting disease risk based on microbiota characteristics.

microbiology↗

bioRxiv2023

Maternal diet and gut microbiome composition modulate early life immune responses

In early life, the intestinal mucosa and immune system undergo a critical developmental process to contain the expanding gut microbiome while promoting tolerance towards commensals, yet the influence of maternal diet and gut microbial composition on offspring immune maturation remains poorly understood. We colonized gnotobiotic mice with a defined consortium of 14 strains, fed them a standard fiber-rich chow or a fiber-free diet, and then longitudinally assessed offspring development during the weaning period. Unlike pups born to dams fed the fiber-rich diet, pups of fiber-deprived dams demonstrated delayed colonization with Akkermansia muciniphila, a mucin-foraging bacterium that can also utilize milk oligosaccharides. The pups of fiber-deprived dams exhibited an enrichment of colonic tissue transcripts corresponding to defense response pathways and a peak in Il22 expression at weaning. Removal of A. muciniphila from the community, but maintenance on the fiber-rich diet, was associated with reduced proportions of ROR{gamma}t-positive innate and adaptive immune cell subsets. Our results highlight the potent influence of maternal dietary fiber intake and discrete changes in microbial composition on the postnatal microbiome assemblage and early immune development.

microbiology↗

bioRxiv2022

Unravelling specific diet and gut microbial contributions to inflammatory bowel disease

Inflammatory bowel diseases (IBDs) are chronic conditions characterized by periods of spontaneous intestinal inflammation and are increasing in industrialized populations. Combined with host genetics, diet and gut bacteria are thought to contribute prominently to IBDs, but mechanisms are still emerging. In mice lacking the IBD-associated cytokine, Interleukin-10, we show that low dietary fiber promotes bacterial erosion of colonic mucus, leading to lethal colitis. A fiber-free exclusive enteral nutrition diet also induces mucus erosion but inhibits inflammation by simultaneously increasing an anti-inflammatory bacterial metabolite, isobutyrate. Diet-induced inflammation is driven by Th1 immune responses, which increase in the presence of mucin-degrading bacteria and are preceded by expansion of natural killer cells and altered immunoglobulin-A coating of some bacteria. Inflammation occurs first in intestinal regions with thinner mucus. Our work underscores the importance of focusing on microbial functions--not taxa--contributing to IBDs and some diet-mediated functions block those that promote disease.

microbiology↗

bioRxiv2022

Increased gut microbial mucin foraging promotes clearance of a parasitic worm

BACKGROUND & AIMSHost-secreted gastrointestinal mucus plays a key role in the expulsion of intestinal nematode parasites. A balance between mucin secretion by the host and the gut microbial mucin foraging is essential to maintain the intestinal homeostasis, yet little is known about how changes in the mucin-microbiome interactions affect worm infections. Here, we aimed to examine how mucin foraging activity by the microbiome changes the course of parasitic worm infections by modulating the host immune responses. METHODSWe utilized a gnotobiotic mouse model containing a synthetic human gut microbiota that allows for: 1) a complete removal of the mucin-degrading bacteria from the community; and 2) diet-driven manipulation of the microbiota toward mucin foraging. We infected mice with a murine nematode, Trichuris muris, which resembles human infection with Trichuris trichiura. We examined the temporal dynamics of worm infection including worm burden and the host immune responses, and coupled these readouts to the microbial changes and mucin foraging activity. RESULTSThe absence of mucin-degrading bacteria in the microbiota enhances susceptibility to parasitic infection--evidenced by higher worm number--by promoting stronger Th1 immune responses. Dietary fiber deprivation increases the microbial mucin-foraging activity, which coincides with a shift in host immune responses from susceptible (chronic, Th1 type) to resistant (acute, Th2 type), thereby promoting worm clearance. CONCLUSIONSOur results provide mechanistic insights into how the colonic mucin-degrading bacteria promote anti-parasitic immunity through modulation of the host immune responses. Our study documents a clinically-relevant, novel link in the microbiome-parasite-host immune axis that is useful prerequisite knowledge in managing parasitic infections.

immunology↗

bioRxiv2021

Deprivation of dietary fiber in specific-pathogen-free mice promotes susceptibility to the intestinal mucosal pathogen Citrobacter rodentium

The change of dietary habits in Western societies, including reduced consumption of fiber, is linked to alterations in gut microbial ecology. Nevertheless, mechanistic connections between diet-induced microbiota changes that affect colonization resistance and enteric pathogen susceptibility are still emerging. We sought to investigate how a diet devoid of soluble plant fibers impacts the structure and function of a conventional gut microbiota in specific-pathogen-free (SPF) mice and how such changes alter susceptibility to a rodent enteric pathogen. We show that absence of dietary fiber intake leads to shifts in the abundances of specific taxa, microbiome-mediated erosion of the colonic mucus barrier, a reduction of intestinal barrier-promoting short-chain fatty acids, and increases in markers of mucosal barrier integrity disruption. Importantly, our results highlight that these low fiber diet-induced changes in the gut microbial ecology collectively contribute to a lethal colitis by the mucosal pathogen Citrobacter rodentium, which is used as a mouse model for enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC, respectively). Our study indicates that modern, low-fiber Western diets might make individuals more prone to infection by enteric pathogens via the disruption of mucosal barrier integrity by diet-driven changes in the gut microbiota, illustrating possible implications for EPEC and EHEC infections.

microbiology↗

bioRxiv2021

Dietary modulation alters susceptibility to Listeria monocytogenes and Salmonella typhimurium in a gut microbiota-independent manner

Food safety has considerably improved worldwide, yet infections with food-borne human enteric pathogens, such as Listeria spp. and Salmonella spp., still cause numerous hospitalizations and fatalities. Thus, the need to shed more light on the mechanisms of enteropathogenesis is apparent. Since dietary alterations, including fiber deficiency, might impact the colonization resistance by the gut microbiota, studying diet-microbiota-pathogen axis holds promise in further understanding the pathogenesis mechanisms. Using a gnotobiotic mouse model containing a 14-member synthetic human gut microbiota (14SM), we have previously shown that dietary fiber deprivation promotes proliferation of mucin-degrading bacteria leading to a microbiota-mediated erosion of the colonic mucus barrier, which results in an increased susceptibility towards the rodent enteric pathogen Citrobacter rodentium. Here, we sought to understand how low-fiber diet affects susceptibility to Listeria monocytogenes and Salmonella typhimurium infections in our 14SM gnotobiotic mouse model, in BALB/c and C57BL/6N backgrounds, respectively. Intriguingly and in contrast to our results with C. rodentium, we observe that depriving mice of dietary fiber protected them from infections with the pathogens compared to mice fed a standard chow. The microbiota delayed the overall pathogenicity as compared to the onset of disease observed in germ-free control mice; nevertheless, we observe the same effect of diet in germ-free mice, suggesting that the susceptibility is microbiota independent. Our study points out an important observation that dietary fiber plays a crucial role on either the host susceptibility, the virulence of these pathogens, or both, which would be judicious to design and interpret future studies. ImportanceHuman enteric pathogens Listeria monocytogenes and Salmonella typhimurium are employed as classical models in rodent hosts to understand the pathogenesis mechanisms of food-borne pathogens. Research in the past decade has stressed importance of the composition of the gut microbiota in modulating susceptibility to these pathogens. Our results--using gnotobiotic mice and germ-free control animals--additionally suggest that the dietary fiber components dominate the impact of enteropathogenic virulence over the pathogenicity-modulating properties of the gut microbiota. The significance of our research is in the need to carefully choose a certain chow when performing the enteropathogen-associated mouse experiments and to cautiously match the rodent diets when trying to replicate experiments across different laboratories. Finally, our data underscore the importance of germ-free control animals to study these pathogens, as our findings would have been prone to misinterpretation in the absence of these controls.

microbiology↗